Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection.

Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.

Cerebral network deficits in post-acute catatonic schizophrenic patients measured by fMRI.

Twelve patients with catatonic schizophrenia and 12 matched healthy controls were examined with functional MRI while performing a motor task. The aim of our study was to identify the intracerebral pathophysiological correlates of motor symptoms in catatonic patients. The motor task included three conditions: a self-initiated (SI), an externally triggered (ET) and a rest condition. Statistical analysis was performed with SPM5. During the self-initiated movements patients showed significantly less activation than healthy controls in the supplementary motor area (SMA), the prefrontal and parietal cortex. Our results suggest a dysfunction of the "medial motor system" in catatonic patients. Self-initiated and externally triggered movements are mediated by different motor loops. The "medial loop" includes the SMA, thalamus and basal ganglia, and is necessary for self-initiated movements. The "lateral loop" includes parts of the cerebellum, lateral premotor cortex, thalamus and parietal association areas. It is involved in the execution of externally triggered movements. Our findings are in agreement with earlier behavioral data, which show deficits in self-initiated movements in catatonic patients but no impairment of externally triggered movements.

Cerebral changes and cognitive dysfunctions in medication-free schizophrenia - an fMRI study.

Proposing cognitive impairment in working memory (wm) functions as a cognitive core deficit in schizophrenia, 23 first episode, medication-free schizophrenic patients in a comparison of healthy adults have been investigated by fMRI. Additionally, the effects of different attentional demands in wm tasks were analysed. A wm paradigm was applied, in which stimuli were presented in a 2-back and a 0-back condition in a non-degraded and degraded version. As hypothesized in healthy controls increased activity during both 2-back tasks was found in the ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), parietal regions, the thalamus and the cerebellum. Different activation patterns were found for the cingulate cortex in the 2-back degraded conditions. The comparison between healthy controls and schizophrenic patients revealed decreased activity in the right VLPFC in patients as well as increased activity in temporal regions. Furthermore patients' task performance quality was significantly lower for 2-back conditions. Schizophrenic patients use different cognitive strategies to solve working memory tasks, reflected in significantly altered cerebral activity. However, the different fMRI working memory correlates found in schizophrenic patients seem to be insufficient in terms of overall task performance.

[Treatment of vitally endangered anorexia nervosa patients based on guardianship laws]. / Behandlung vital gefährdeter Anorexia-nervosa-Patienten unter Berücksichtigung der Möglichkeiten des Betreuungsrechts.

Anorexia nervosa is a psychiatric disorder occurring primarily in young women. Especially when chronic or the body mass index is less than 12 kg/m(2), it has a mortality of up to 20%. Often these patients are admitted to emergency units and treated internistically. If they accept psychiatric treatment, they are normally transferred to specialized psychosomatic units for further therapy. If patients are not able to accept necessary further therapy to overcome the danger to health and life, the question arises in terms of guardianship law of whether they are able to handle their personal concerns alone. After several vitally endangered anorexia nervosa patients had been admitted to our closed psychiatric ward, we developed a therapeutic concept for this subgroup of patients, taking the possibilities of guardianship law into account. This concept aims at restoring the body weight continuously and finally enable the patients to be transferred to less restrictive psychosomatic units. The chosen treatment is shown with the therapy courses of 25 patients treated according to this concept.

Effects of treatment with the atypical neuroleptic quetiapine on working memory function: a functional MRI follow-up investigation.

BACKGROUND: Working memory as a part of higher-order executive functions is defined by the parallel storage and processing of information. Recent functional fMRI studies have revealed a functional, interregional disintegration of a neuronal network connecting cortical, subcortical and cerebellar regions in schizophrenic patients (SZ). Cognitive impairment in working memory is a core psychopathological correlate of schizophrenic symptoms. Atypical neuroleptics such as quetiapine have shown good efficacy in treating positive and negative symptoms. The presented study evaluated the impact of a neuroleptic steady state treatment with quetiapine on the altered working memory activation patterns in schizophrenia. METHODS: Patients were examined by fMRI at baseline and after 12 weeks of steady state treatment with quetiapine. Matched healthy controls (HC) underwent baseline examination. In the scanner, stimuli were presented in a 2-back and 0-back condition of a working memory (wm) paradigm, whereby a degraded and a non-degraded version were used each time. Additionally, behavioural responses (reaction time to target stimuli and error ratio) were measured. RESULTS: At baseline, healthy controls revealed increased activity in the frontal lobe, especially in regions of the prefrontal cortex. Compared to HC, SZ showed hypoactivation in the right dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal cortex (VLPFC) bilaterally for the 2-back condition. In the 2-back degraded condition there was a hypoactivation in both, the right DLPFC and the VLPFC. Additionally, patients showed bilaterally decreased activation in the basalganglia in the 2-back and in the right caudatus in the 2-back degraded condition compared to healthy controls. After treatment with quetiapine, patients activations patterns were increased. The pre-post comparison of the 2-back condition revealed a significant increase of activation in the left VLPFC at a significance level of 0.001 (uncorrected). The 2-back degraded condition led to a significant activation pattern in the lingual gyrus and the right precuneus. In both wm conditions, at baseline there were no differences in reaction time but only a worse performance in SZ. After treatment, behavioural measurement of responses, including reaction time and performance, showed slight improvements in SZ, although these did not reach statistical significance. CONCLUSIONS: The neuronal networks underlying working memory are clearly altered in schizophrenia. After 12 weeks of treatment with quetiapine monotherapy, patients showed significant clinical improvement and revealed increased BOLD activity in the VLPFC during a working memory task, although there was no improvement of cognitive performance.

[Aggressiveness in schizophrenia: prevalence, psychopathological and sociodemographic correlates]. / Aggression bei Schizophrenien: Prävalenz, psychopathologische und soziodemographische Korrelate.

In a retrospective study we evaluated the patient files of all schizophrenic patients (ICD-criteria) admitted to the psychiatric hospital of the university of Munich between 1990 - 1995 (N = 2093). Relevant sociodemographic, clinical and psychopathological data as assessed by means of the AMDP protocol were studied. 292 (14 %) of patients fullfilled the criterion aggression on admission. While there were few differences concerning many sociodemographic variables including, male schizophrenics were rated significantly more often to be aggressive than female schizophrenics. With respect to schizophrenic subtype disorganized patients were most likely to be aggressive. Psychopathological symptoms significantly associated with aggression were e.p. delusional ideas and disorganized thinking. Possible risk factors for aggression in schizophrenia and clinical implications are discussed.

[Counseling on contraception following interruption of pregnancy. Responsibility of the hospital gynecologist. Model of contraceptive counseling at the Gynecological Clinic Berlin-Neukölln]. / Kontrazeptionsberatung nach Schwangerschaftsabbruch. Eine AUfgabe des klinisch tätigen Frauenarztes. Das Modell der Kontrazeptionsberatung an der Frauenklinik Berlin-Neukölln.

PIP: Providing counseling concerning methods of contraception is the responsibility of the hospital gynecologist during the immediate postabortion period. It is during this period that patients prove unexpectedly receptive to contraception instruction. Form and contents of this instruction as practiced at the School of Contraception of the Frauenklinik Berlin-Neukolln are described. (author's modified)^ieng

Electrodeposited iridium oxide pH electrode for measurement of extracellular myocardial acidosis during acute ischemia.

In the present paper, fabrication, characterization, and physiological applications of a solid-state pH electrode are described. The pH sensing layer was based on an anodic electrodeposited iridium oxide film (AEIROF). Sputtered platinum electrodes (1 mm diameter) fabricated on flexible Kapton films or platinum wires were used as planar or cylindrical supports. Each electrode site was coated with Nafion to attenuate the interference of anionic redox species and to protect the electrode surface during in vivo measurements. Performance of the AEIROF was evaluated, for the first time, as a pH electrode and proved to have a slightly super-Nernstian response with slope of -63.5 +/- 2.2 mV/pH unit for both wire and planar sputtered platinum electrodes. Linear pH responses were obtained in the pH range 2-10. The electrodes have a working lifetime of at least 1 month with accuracy of about 0.02 pH unit and fast response time. The electrodes showed very low sensitivities for different species, such as Na+, K+, Li+, NH4+, Ca2+, Mg2+, dissolved oxygen, lactate, ascorbate, and urate, which are important for physiological applications. The electrodes were applied in extracellular pH measurements during brief regional ischemia in a swine heart and no-flow ischemia in an isolated rabbit papillary muscle. A first report on extracellular pH, K+, and lactate simultaneous measurements during no-flow ischemia using the AEIROF pH electrode and the previously described K+ and lactate electrodes is presented as well.

Ion-selective membranes with low plasticizer content: electroanalytical characterization and biocompatibility studies.

High molecular weight poly(vinyl chloride) and aliphatic polyurethane (Tecoflex)-based ion selective membranes, with normal and reduced amounts of plasticizer, as well as without plasticizer, were tested with respect to their analytical properties, their biocompatibility, and cellular responses. The analytical properties of the membranes did not change significantly within a wide range of polymer to plasticizer ratios. However, the membranes with reduced plasticizer content had better adhesive properties, less anion interference, extended life time, and better biocompatibility. Using the cage implant system, the results showed that an increase of plasticizer weight percent in Tecoflex membranes correlated positively with the increase in host inflammatory response up to 14 days of implantation. The results also demonstrated that both PVC and Tecoflex-based ion-selective membranes with the most common membrane composition (1:2 polymer to plasticizer ratio) exhibited a similar acute inflammatory response, but the PVC-based membrane elicited a reduced chronic inflammatory response when compared with the Tecoflex-based membrane.

Analytical performance characteristics of thin and thick film amperometric microcells.

The analytical performance of amperometric microcells with different electrode geometries is compared for enzyme activity measurements. The microcells were fabricated with thin film photolithography or thick film screen-printing in four different designs. The cells made with the thin film process used flexible substrate with microelectrode array or a circular, disk-shaped working electrode. The screen-printed working electrodes had semicircle or disk shape on ceramic chips. Putrescine oxidase (PUO) activity measurement was used as a model. The determination of PUO activity is important in the clinical diagnosis of premature rupture of the amniotic membrane. An electropolymerized m-phenylenediamine size-exclusion layer was used to eliminate common interferences. The size exclusion layer revealed also to be advantageous in protecting the electrodes from fouling by putrescine (enzyme substrate). The electrode fouling of bare electrodes was insignificant for screen-printed electrodes, but very severe for electroplated platinum working electrodes. The microelectrode array electrodes demonstrated smaller RSD and higher normalized sensitivities for hydrogen peroxide and PUO activity. All the other electrodes were demonstrating comparable analytical performances.