Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice.

Huntington's disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.

[Asthma phenotypes and phenotyp-specific treatment]. / Asthma-Phänotypen und die Phänotyp-spezifische Therapie.

Asthma is not a homogenous disease but a bundle of different phenotypes producing common symptoms due to swelling of bronchial mucosa and constriction of the airway smooth muscle. Beyond the treatment with a combination of topical steroids and long-acting beta agonists, new therapeutic options arise with the knowledge of different phenotypes. One option, specifically in allergic asthma, is the long known allergen immunotherapy. To identify the individual phenotype a diagnostic work up is warranted when the asthma is diagnosed and whenever asthma control cannot be maintained.

[Lung function testing in private practice]. / Spirometrie für die klinische Praxis.

According to the international guidelines of COPD (GOLD) and asthma (GINA) diagnosis and treatment of both diseases necessitate spirometry in the private practice as well as in hospital setting. However today, spirometry is not sufficiently used in Switzerland. This paper intends to give an easy overview how spirometry is performed and spirometric values can be interpreted.

[COPD and Asthma: same same but different]. / COPD und Asthma: same same but different.

In clinical practice, differentiation of COPD and asthma is difficult. A case report of an asthma patient with a drifter type of asthma imitating COPD is presented. In this context differences and similarities of both diseases are high-lighted. The definitions of asthma and COPD in international guidelines leave some space to misdiagnosing.

[COPD--Update 2009]. / COPD - Update 2009.

In the last years understanding of mechanisms in COPD has grown. At the same time therapeutic options have increased. Therapeutic nihilism is not anymore indicated when facing a patient with newly diagnosed COPD. Different strategies are important: Nicotine cessation, long-acting bronchodilators acting against bronchial obstruction and exertional dynamic hyperinflation, and an intensive physical training in the setting of a pulmonary rehabilitation program. They allow altogether a significant improvement of life quality and daily life activities.

[Trial end-point in chronic obstructive pulmonary disease (COPD): minimal clinically important difference]. / Studienendpunkte bei der chronisch-obstruktiven Lungenerkrankung (COPD): "Minimal Clinically Important Difference".

The concept of the minimal clinically important difference (MCID) is intended to provide a measure of relevance for a statistically applied in patients with COPD. Clinically important differences are those differences relevant to the individual patient and important to the patient's life. However, people's difference in a diagnostic parameter perception of what is important vary. Furthermore, physicians may rate the significance of a particular marker and its difference which can be achieved by a pharmacological intervention differently from the patient. Thus, the major problem with defining an MCID for any measure is that the most important differences, which require the most subtle measures for an individual patient, are likely to have the least general application. Conversely, measures that can be generalised are unlikely to have much individual importance and will be very crude tools for an individual assessment. In medical trials both, statistical rigor and clinical relevance are generally required, and MCID is without doubt a key application tool defining treatment success or treatment failure. This paper gives an update on the concept of a minimal important difference of most relevant parameters in COPD treatment.

Dynamics of cortical theta activity correlates with stages of auditory avoidance strategy formation in a shuttle-box.

By comparing behavioral performance and cortical theta activity (4-8 Hz) on a trial by trial basis we examined how the different behavioral stages of tone-induced avoidance learning in the shuttle-box may be distinguishable by theta power as a potential correlate of changing strategies of information processing. Electrocorticograms with pronounced theta content were recorded across the cortical surface of gerbils during avoidance learning and analyzed in each trial in conjunction with reaction times and unconditioned and conditioned responses. The focus of theta analysis in this paradigm with a 5-s delay between tone and foot-shock onsets was on the 14-s periods after hurdle crossing where feedback information from a trial is available. The strongest theta activity occurred in stage 1 of initial tone conditioning which was sharply reduced to a minimum during stage 2 of optimization of unconditioned escape responses from the foot shock. A few initial successful avoidance responses gave rise to a reversal of the decline of theta activity that later reached a second maximum. A systematic increase of theta activity during this stage 3 of avoidance conditioning was found for the occasional trials with unconditioned responses and not for the increasing number of conditioned responses suggesting that error processing is a major correlate of this new increase of theta power. After the second maximum the theta power slowly declined together with a further improvement of behavioral performance indicating that stage 4 of retrieval of the consolidated avoidance response was reached. The results suggest that behind a previously reported general trend of decreasing theta power with increasing performance in this paradigm there is a hidden microstructure of theta activity across trials which separates stages of avoidance conditioning and is partially mirrored by known changes of prefrontal dopamine release.

Using RRT-PCR analysis and virus isolation to determine the prevalence of avian influenza virus infections in ducks at Minto Flats State Game Refuge, Alaska, during August 2005.

This study describes surveillance for avian influenza viruses (AIV) in the Minto Flats State Game Refuge, high-density waterfowl breeding grounds in Alaska. Five hundred paired cloacal samples from dabbling ducks (Northern Pintail, Mallard, Green Wing Teal, and Widgeon) were placed into ethanol and viral transport medium (VTM). Additional ethanol-preserved samples were taken. Of the ethanol-preserved samples, 25.6% were AIV RNA-positive by real-time RT-PCR. The hemagglutinin (HA) and neuraminidase (NA) subtypes were determined for 38 of the first-passage isolates, and four first-passage isolates could not be definitively subtyped. Five influenza A virus HA-NA combinations were identified: H3N6, H3N8, H4N6, H8N4, and H12N5. Differences in the prevalence of AIV infections by sex and by age classes of Northern Pintail and Mallard ducks were detected, but the significance of these differences is undefined. In the 500 paired samples, molecular screening detected positive birds at a higher rate than viral isolation (chi(2) = 8.35, p = 0.0035, df = 1); however, 20 AIV isolates were recovered from PCR-negative ducks. Further research is warranted to compare the two screening protocols' potential for estimating true prevalence in wild birds. Our success during 2005 indicates Minto Flats will be a valuable study site for a longitudinal research project designed to gain further insight into the natural history, evolution, and ecology of AIV in wild birds.

[How is your asthma today?--A case report considering different parameters of asthma control]. / Wie geht es denn heute mit dem Asthma? Eine Fallstudie unter Berücksichtigung verschiedener Parameter der Asthma-kontrolle.

Any anti-asthmatic therapy aims to control the disease activity. The amount of medication necessary to maintain asthma control over a longer period may vary. In the course of a long-term treatment, achievement of asthma control has regularly to be assessed. This case reports of a patient suffering from steroid dependent intrinsic asthma illustrates the different parameters being used to evaluate asthma control.

[Clinical significance of gastrooesophageal reflux in asthma]. / Klinische Bedeutung des gastroösophagealen Refluxes beim Asthma bronchiale.

In clinical practice, gastrooesophageal reflux (GER) and bronchial asthma often coincide. In the case of sufficient asthma control, the asthma does not need to be taken into account when treatment of GER is being evaluated. In patients with symptomatic asthma despite adequate antiasthmatic treatment, a possible causal relationship between GER and the poor responsiveness to asthma therapy has to be considered. An algorithm to guide the diagnostic and therapeutic steps in such cases is presented.

Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development.

Serotonergic neurones are among the first to develop in the central nervous system. Their survival and maturation is promoted by a variety of factors, including serotonin itself, brain-derived neurotrophic factor (BDNF) and S100beta, an astrocyte-specific Ca(2+) binding protein. Here, we used BDNF-deficient mice and cell cultures of embryonic raphe neurones to determine whether or not BDNF effects on developing serotonergic raphe neurones are influenced by its action on glial cells. In BDNF-/- mice, the number of serotonin-immunoreactive neuronal somata, the amount of the serotonin transporter, the serotonin content in the striatum and the hippocampus, and the content of 5-hydroxyindoleacetic acid in all brain regions analysed were increased. By contrast, reduced immunoreactivity was found for myelin basic protein (MBP) in all brain areas including the raphe and its target region, the hippocampus. Exogenously applied BDNF increased the number of MBP-immunopositive cells in the respective culture systems. The raphe area displayed selectively reduced immunoreactivity for S100beta. Accordingly, S100beta was increased in primary cultures of pure astrocytes by exogenous BDNF. In glia-free neuronal cultures prepared from the embryonic mouse raphe, addition of BDNF supported the survival of serotonergic neurones and increased the number of axon collaterals and primary dendrites. The latter effect was inhibited by the simultaneous addition of S100beta. These results suggest that the presence of BDNF is not a requirement for the survival and maturation of serotonergic neurones in vivo. BDNF is, however, required for the local expression of S100beta and production of MBP. Therefore BDNF might indirectly influence the development of the serotonergic system by stimulating the expression of S100beta in astrocytes and the production MBP in oligodendrocytes.

Learning a new behavioral strategy in the shuttle-box increases prefrontal dopamine.

Using microdialysis from medial prefrontal cortex of gerbils during aversive auditory conditioning in the shuttle-box we have previously shown a transient increase of dopamine efflux correlated with the establishment of avoidance behavior. We hypothesized that the acquisition of a new behavioral strategy is generally accompanied by this extra prefrontal dopamine release. The present experiment aimed at further testing this hypothesis. In a pre-training period in the shuttle-box the gerbils acquired an active avoidance response by generalizing two different tone signals to a GO-meaning (change of shuttle-box compartment). Thereafter, they were subjected in relearning sessions to differentially associate the known tone stimuli with GO- and NOGO- (no change of shuttle-box compartment) conditions, respectively. The following formation of discrimination behavior led to a similar extra dopamine increase as found during establishment of the avoidance strategy. This significant enhancement was limited to rapidly relearning individuals. Furthermore, the dopamine increase attenuated in these animals with increasing performance during the course of the discrimination training, similar to the retrieval stage of the avoidance strategy. Therefore, the dopamine system seems to be critically involved in the initial formation of associations for new behavioral strategies, i.e. learning. We assume that the prefrontal dopamine increase during initial learning of the complex discrimination behavior indicates an involvement of working memory principles and a goal-directed formation of a behavioral strategy.

Early onset of glutamatergic and GABAergic synaptic activity in the visual layers of the rodent superior colliculus.

During postnatal development, the retinocollicular pathway undergoes activity-dependent refinement, resulting in the precise retinotopic map seen in adults. Previous studies established that retinal efferents reach the mouse superior colliculus (SC) by embryonic day 16. Morphologically, synapses were found in the rat SC before birth. As part of an extended project aimed at understanding the development of synaptic transmission in the visual layers of the SC, we report here the presence of functionally active synapses immediately after birth. Circuit activity in mouse SC neurons was detected in horizontal slices of the visual layers using cell-attached voltage clamp. The spontaneous discharge of action potentials was abolished by glutamatergic blockers and facilitated by bicuculline, showing that circuit activity is based on synaptic transmission and that the action of gamma-aminobutyric acid is inhibitory. Using whole-cell voltage clamp, spontaneous glutamatergic postsynaptic currents as well as miniature GABAergic postsynaptic currents were recorded on postnatal day 1. Excitatory and inhibitory postsynaptic currents could also be evoked by electrical stimulation. Glutamatergic postsynaptic currents comprised both (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor-mediated components. The early function of glutamatergic and GABAergic synaptic transmission in the visual layers of SC suggests that SC neurons are able to process information originating from retinal axons immediately after birth.

[Double aortic arch: clinical aspects, diagnosis and therapy in children and adults]. / Doppelter Aortenbogen. Klinik, Diagnose und Therapie bei Kindern und Erwachsenen.

Double aortic arch is a rare vascular anomaly which usually causes tracheal and esophageal compression in the first few months of life. During the last 30 years, 7 children, 2 to 24 months old, and one 29-year-old woman with double aortic arches have been treatedatour institution. Symptoms, diagnosis and treatment of these patients were evaluated. Dyspnoe, stridor, recurrent pulmonary infections, feeding problems and failure to thrive were the leading symptoms. Despite typical symptoms from early childhood, the diagnosis was missed in our adult patient. Typical compression of the esophageus and the trachea was visualized by esophagography by 7 and bronchoscopy/-graphy by 6 patients. Angiography was performed in all children, whereas magnetic resonance angiography and computed tomography were done in the adult patient. Resection of the smaller aortic arch, left in 3 and right in 5, through a right or a left posterolateral thoracotomy was uncomplicated and fully resolved the symptoms in all patients. Typical symptoms in early childhood should lead to prompt diagnosis and surgical treatment of double aortic arch. Surgical resection of the smaller aortic arch should also be performed in oligosymptomatic patients to prevent complications later. Preoperative angiography can be replaced by the less invasive magnetic resonance imaging and computed tomography.

Case-control study of risk factors for clinical mastitis in postpartum dairy heifers.

A case-control study was carried out to evaluate risk factors for clinical mastitis occurring in dairy heifers between 1 and 14 d postpartum. Case and control heifers were matched on herd; the control was the heifer that calved closest in time, before or after, the particular case. Data were analyzed by conditional logistic regression. The final multivariate model included 339 case-control pairs. Blood in the milk, udder edema, teat edema, and milk leakage, all recorded at the time of parturition, were significant risk factors. Purchased heifers and heifers with skin lesions between udder and thigh were not at increased risk of clinical mastitis. Separate analysis of a subgroup of case-control pairs identified teat edema, blood in the milk, and milk leakage at calving as risk factors for clinical mastitis caused by Staphylococcus aureus.

[Nasal CPAP therapy in obstructive sleep apnea syndrome: patient compliance]. / Nasale CPAP-Therapie beim obstruktiven Schlafapnoesyndrom: Patienten-Compliance.

We aimed in 186 patients with obstructive sleep apnoea, consecutively treated with nasal CPAP between January 1990 and December 1997, to evaluate compliance with nCPAP therapy and to explore factors influencing compliance. At 3 to 6 months (K1), 1 to 2 years (K2) and more than 3 years (K3) patients were reexamined regarding clinical conditions, the mean time of nCPAP usage per night, nCPAP pressure, and body mass index (BMI). The regularly conducted controls consisted of checking mask fitting, polygraphy with automatic pressure titration and once, mostly at K1, polysomnography. Compliance with nCPAP was considered to be sufficient more than 4 hours of usage per night. At K1, 9 patients had stopped therapy, 5 had moved away, 6 had changed therapy, 6 had died, and 41 had not been treated long enough to have a follow-up at K1. Thus we were able to reexamine 119 patients with ongoing nCPAP therapy. We found no correlation between indices of severeness of sleep apnoea (apnoea/hypopnea index, mean low of night time oxygen saturation, nCPAP pressure, and BMI) and compliance. At K1 87 patients (73%) had sufficient nCPAP compliance. All of them showed sufficient compliance at K2 and K3 too. We conclude that a sufficient compliance at an initial control implies sufficient compliance later on. 32 patients (27%) showed insufficient compliance at K1. Of this group 41% (13 patients) improved compliance at K2. This result underlines the value of a second instruction in nCPAP therapy when patient compliance was lacking initially.

Rapid genotyping of newborn gene mutant mice.

One important aspect of utilizing transgenic mice is the need to genotype them in order to distinguish mice that carry a disrupted gene or a transgene from mice that do not. Current methods for genotyping include isolation of genomic DNA from tail biopsies followed by PCR amplification. Particularly, both digestion of tail tissue using proteinase K as well as resuspension of purified DNA are time-consuming and were usually carried out overnight. Here, we describe a rapid and robust method for the genotyping of bdnf targeted mice which allows us to determine the genotype of newborn mice at the day of birth within 6 h. After a freezing-thawing step tail tissue is digested in less than 2 h, and the DNA is precipitated, resuspended and ready for PCR in about 60 min. The method could be easily adapted to a variety of different mutant mice and especially should benefit neuroscientists interested in using animals with known genotype very early in postnatal development.

Accuracy of glaucoma detection with frequency-doubling perimetry.

PURPOSE: To determine the accuracy of glaucoma detection by frequency-doubling perimetry. METHODS: Stereoview optic nerve photographs, visual field examination, intraocular pressure measurements, medical and ocular history, and a screening and full threshold frequency-doubling perimetry examination were performed in a prospective study of consecutive subjects. Inclusion criteria included age of 45 years or older, absence of ocular disease other than glaucoma, cataract, or mild drusen, and Snellen visual acuity of 20/60 or better. A total of 125 eyes in 102 glaucoma subjects and 95 eyes of 95 normal subjects were included. Each eye was classified as "normal," "glaucoma," or "uncertain" by each of three ophthalmologists on the basis of all available clinical information with the exception of frequency-doubling perimetry results. Those in the glaucoma group were subclassified as having early (n = 51), moderate (n = 42), or severe (n = 32) glaucoma on the basis of automated Humphrey visual field criteria. In the glaucoma group, two eyes from a subject were allowed to be included (23 of 102 subjects) if they differed in level of damage because they were never analyzed within the same statistical analysis. RESULTS: Several diagnostic algorithms were evaluated. Algorithms based on the most depressed single point, pair of adjacent points, and cluster of three points performed nearly identically. For the screening test, if any abnormality was identified, specificity was 95%, whereas sensitivity was 39%, 86%, and 100% for early, moderate, and severe glaucoma, respectively. For the full threshold test, with at least one point depressed to the P < 0.5% level, specificity measured 91%, whereas sensitivity was 35%, 88%, and 100% for early, moderate, and severe glaucoma, respectively. The two global indices, mean deviation and pattern standard deviation, were also evaluated and were generally less accurate. CONCLUSION: Frequency-doubling perimetry, which is rapid and easily administered, is effective at detecting moderate and severe disease and appears well suited for glaucoma screening.

Accuracy of scanning laser polarimetry in the diagnosis of glaucoma.

OBJECTIVE: To determine the diagnostic accuracy of scanning laser polarimetry. SUBJECTS AND METHODS: A total of 95 healthy subjects and 102 patients with glaucoma met all inclusion criteria. Data collected on each participant included an automated visual field examination, stereoview optic nerve head photographs, intraocular pressure measurement, and a screening and full scanning laser polarimetry study. Each participant was classified as "normal," "glaucoma," or "uncertain" by each of 3 ophthalmologists based on all available clinical information, with the exception of the scanning laser polarimetry results. Before data analysis, 4 diagnostic algorithms for the full-test mode and 2 for the screening mode were chosen to be evaluated for their sensitivity and specificity in detecting glaucoma. RESULTS: Of the 4 algorithms tested for the full-test mode, "the number" (abnormal test score, >35) had sensitivities of 57%, 71%, and 81% for early, moderate, and severe glaucoma, respectively. Specificity was 89%. For the screening test, sensitivities were much lower, particularly for those with severe glaucoma damage. CONCLUSIONS AND CLINICAL RELEVANCE: Scanning laser polarimetry can help to differentiate subjects with normal findings from patients with glaucomatous damage. Even the best algorithm tested, however, failed to detect a substantial number of subjects with severe damage. Further study is needed before scanning laser polarimetry can be recommended as a screening method for glaucoma.