Demonstration of a second rapidly conducting cortico-diaphragmatic pathway in humans

Functional imaging studies in normal humans have shown that the supplementary motor area (SMA) and the primary motor cortex (PMC) are coactivated during various breathing tasks. It is not known whether a direct pathway from the SMA to the diaphragm exists, and if so what properties it has. Using transcranial magnetic stimulation (TMS) a site at the vertex, representing the diaphragm primary motor cortex, has been identified. TMS mapping revealed a second area 3 cm anterior to the vertex overlying the SMA, which had a rapidly conducting pathway to the diaphragm (mean latency 16.7 ± 2.4 ms). In comparison to the vertex, the anterior position was characterized by a higher diaphragm motor threshold, a greater proportional increase in motor-evoked potential (MEP) amplitude with voluntary facilitation and a shorter silent period. Stimulus–response curves did not differ significantly between the vertex and anterior positions. Using paired TMS, we also compared intracortical inhibition/facilitation (ICI/ICF) curves. In comparison to the vertex, the MEP elicited from the anterior position was not inhibited at short interstimulus intervals (1–5 ms) and was more facilitated at long interstimulus intervals (9–20 ms). The patterns of response were identical for the costal and crural diaphragms. We conclude that the two coil positions represent discrete areas that are likely to be the PMC and SMA, with the latter wielding a more excitatory effect on the diaphragm.     

Conservative Surgery in T3–T4 Pharyngolaryngeal Squamous Cell Carcinoma: An Alternative to Radiation Therapy and to Total Laryngectomy for Good Responders to Induction Chemotherapy

Objective To evaluate the possibility of preservation of the larynx after neoadjuvant chemotherapy by performing a conservative surgery instead of total laryngectomy initially planned, in patients with previously untreated laryngeal and piriform sinus squamous cell carcinoma (SCC). Study Design Retrospective study. Methods A total of 115 patients treated at Tenon Hospital with induction chemotherapy from 1985 to 1995, all with initial indication of radical surgery, were available for the study. The clinical tumor response was evaluated after three cycles of chemotherapy. According to this response, to preserve laryngeal functions, some patients had a modification of the treatment initially planned: radiation therapy essentially for complete responders, and conservative surgery for some partial responders. Results Of 69 patients with laryngeal cancer, 14 were treated by partial laryngectomy and 19 by radiation therapy; of 46 patients with piriform sinus cancer, 8 were treated by partial surgery and 12 by radiation therapy; the other patients were treated as was initially planned (total laryngectomy with partial pharyngectomy). Overall survival rates, estimated by the Kaplan‐Meier method, were not statistically different between the three treatment groups. The laryngeal functions were preserved in 54% of the patients who were alive at 3 years. Conclusion This report is a retrospective study, but these results suggest the possibility of using conservative surgery, instead of initially planned total laryngectomy, for good responders to induction chemotherapy with a small residual tumor.     

Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct-acting antivirals

Chronic hepatitis C virus (HCV) infections compromise natural killer (NK)-cell immunity. Direct-acting antivirals (DAA) effectively eliminate HCV, but the long-term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56⁺ NK cells of chronic HCV-infected patients before and 1 year after DAA therapy. Donor-variation was observed in NK-cell proteomes of HCV-infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56⁺ NK-cell proteome remained altered 1 year post-therapy, indicating a phenotypic shift with low donor-variation. NK cells from virus-negative cured patients exhibited global regulation of RNA-processing and pathways related to “stimuli response”, “chemokine signaling”, and “cytotoxicity regulation”. Proteomics identified downregulation of vesicle transport components (CD107a, COPI/II complexes) and altered receptor expression profiles, indicating an inhibited NK-cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN-γ and recruited CD107a. Conversely, reduced surface expression levels of Tim-3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long-term effects on the CD56⁺ NK-cell compartment in convalescent HCV patients 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK-cell phenotype.     

On the road to collaborative treatment planning: Consumer and provider perspectives

Although consumers have made significant gains in having their voices heard in several areas within mental health, they have made less progress in being able to collaborate with their own treaters in setting treatment goals. On the basis of several years of groundwork by staff at the Connecticut Mental Health Center (CMHC), the Patient Care Committee conducted a needs assessment of providers and consumers to assess both groups' current involvement, interest in, and attitudes toward collaborative treatment planning. The results indicate that providers tend to place much of the responsibility for the difficulties in implementing collaborative treatment planning on consumers. Also, providers tend to underestimate consumers' interest in participating in this process. Implications of these findings for the development of an agency-wide training to enhance the collaborative nature of treatment planning are discussed.     

Falsely elevated intraocular pressure due to increased central corneal thickness

· Purpose: To evaluate whether ocular hypertensive subjects have a higher central corneal thickness than other individuals. · Methods: In this prospective study, 48 subjects with ocular hypertension, 63 patients with open-angle glaucoma, 56 nonglaucomatous patients with diabetes mellitus, and 106 control subjects were evaluated. Corneal thickness was measured by ultrasound pachymetry, and intraocular pressure was determined by Goldmann applanation tonometry. · Results: Central corneal thickness was significantly higher in the ocular hypertensive subjects, mean ±S.D., 592±39 μm, than in the patients with glaucoma (536±34 μm), the nonglaucomatous patients with diabetes mellitus (550±31 μm), and the normal subjects (545±33 μm), P<0.001. The three latter groups did not vary significantly in central corneal thickness, P>0.05. · Conclusion: In some individuals with increased transcorneal measurements of intraocular pressure, the cornea is thicker than in subjects with normal intraocular pressure readings or patients with glaucoma. It suggests that in ocular hypertensive subjects, corneal pachymetry should be performed to rule out an abnormally thick cornea as a reason for falsely high measurements of intraocular pressure. Received: 14 April 1998 Revised version received: 10 July 1998 Accepted: 23 July 1998     

Patients' and doctors' perception of long-term morbidity in patients with testicular cancer clinical stage I

Patient-based questionnaires were designed with the aim to identify and rank long-term somatic and psychosocial morbidity in patients with low-stage testicular cancer. A further intention was to compare patients' assessments with experienced doctors' general opinion on quality of life items in cured testicular cancer patients. In pilot study I, 103 tumour-free patients ranked items of physical and psychosocial morbidity after having had various kinds of treatment. Though the ranking procedure appeared to cause some difficulties amongst the patients and subsequently was abandoned, the results indicated considerable differences between the patients' and doctors' evaluations. In pilot study II patients were asked to score the different items. The questionnaire of pilot study II was completed by 107 patients from the Norwegian Radium Hospital (NRH) and 99 relapse-free patients from the Royal Marsden Hospital (RMH) with testicular cancer stage I at least 1 year after infradiaphragmatic radiotherapy (n = 94) or adjuvant chemotherapy (2 cycles,n=26), or patients who had been followed on the surveillance program (n = 86). A total of 93 doctors completed a similar questionnaire, thereby expressing their general opinion on long-term morbidity in comparable testicular cancer patients as seen during routine clinical follow-up. Both the irradiated patients and those on the surveillance program reported slight degrees of Raynaud-like phenomena, neurotoxicity and ototoxicity, most probably representing background morbidity in an age-matched general male population. Doctors tended to underestimate their patients' somatic morbidity, but often overestimated the degree of psychological distress, in particular in patients on the surveillance program. Significant differences between RMH and NRH patients with regard to sexual problems and to leisure time activity may be explained by cultural differences in the two countries. The items presented in the questionnaire used identify important issues for patients cured of testicular cancer which may be used in future multicentre trans-cultural studies assessing these patients' quality of life. This will provide sufficient data for psychometric testing and, together with the findings from patients' free comments, support the final design of a testicular cancer quality of life module.     

Inhibitory action of clozapine on rat ventral tegmental area dopamine neurons following increased levels of endogenous kynurenic acid.

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and alpha7(*) nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.     

Sensitised locomotion does not predict conditioned locomotion in cocaine-treated mice: further evidence against the excitatory conditioning model of context-dependent sensitisation.

The excitatory conditioning model of contextual sensitisation proposes that the progressive emergence of the locomotion-activating effect of cocaine (or any other stimulant drug) characterising that phenomenon is due to a growing conditioned response (the test context cues) that mimics the unchanging unconditioned response (the drug effect). The present study aimed at verifying whether the relationship between the amplitude of sensitisation and the size of the conditioned response was positive, a direct implication of that view. Sensitisation to the locomotion-activating effect of cocaine (10 mg/kg, s.c.) was firstly generated over 10 daily sessions in 25 mice (strain C57Bl/6J), another lot of 25 mice receiving the same dose of cocaine outside of the testing context. Conditioned locomotion was assessed 24 h later. No significant linear correlations were found between the magnitude of the conditioned response and the magnitude of the sensitised response (delta scores), the rate of sensitisation (individual regression coefficients) or the magnitude of the initial unconditioned response to cocaine (scores in the first session of sensitisation treatment). Accordingly, there was no significant correlation between the magnitude of the initial unconditioned response and the magnitude of the sensitised response or that of the initial unconditioned response. Therefore, the conditioned response is neither necessary nor sufficient for the development of context-dependent sensitisation of the locomotion-activating effect of cocaine, a conclusion that refutes the excitatory conditioning model of that chronic effect.     

Biodegradable microparticles for sustained release of a new GnRH antagonist--part I: Screening commercial PLGA and formulation technologies.

The formulation of a new GnRH antagonist (degarelix) in biodegradable poly(DL-lactide-co-glycolide) (PLGA) microparticles was investigated for the development of a 3-month sustained release formulation to treat prostate cancer. The aim was to screen formulation technologies and distinct copolymers to produce microparticles (MP) of different types with good entrapment efficiency (>85%) and peptide purity (>95%) after gamma sterilization. Basically, three types of degarelix-loaded MP (4, 8 and 16% w/w nominal content) were produced with solvent and non-solvent technologies, namely double-emulsion solvent evaporation, spray-drying and two extrusion methods. Besides composition, commercial copolymers differing in residual monomer content and functional group at the carboxylic terminus (acid or ester) were characterized and employed. Peptide loading capacity and purity, as well as shape, size characteristics, and porosity of the produced microparticles were discussed in relation to technology and copolymer choice. Spray-drying and micro-extrusion were the two preferred formulation technologies because of higher entrapment efficiency and better preservation of peptide purity during production and gamma-sterilization. The impact of formulation technologies on the MP characteristics overwhelmed the impact of copolymer selection. Nevertheless, one particular polymer was discarded since it was more susceptible towards radiolytic degradation. The resulting degarelix-MP will be tested in a biological assay for selection of the formulation based on performance.