Synaptic plasticity in the dentate gyrus of aged rats is altered after chronic nimodipine application.

We examined ultrastructural correlates of synaptic plasticity in the hippocampus of young (3 months) vs aged (30 months) Wistar rats and established the effects of the calcium antagonist nimodipine in animals chronically treated from 24 to 30 months. The effects of nimodipine was studied since this compound improves hippocampal neuronal physiology and enhances cognitive function during aging. In the supragranular layer of the dentate gyrus we found a 24% decrease in synaptic density (Nv) in aged animals, while synaptic size (S) was not significantly altered. After nimodipine treatment Nv in aged rats was not significantly different from young adults, thus being significantly increased compared to age-matched controls. The size of synapses was not significantly altered after nimodipine administration. Total synaptic surface area (Sv) in nimodipine-treated animals was significantly increased compared to aged controls, however, Sv remained significantly lower than in young adults. These data indicate that chronic administration of nimodipine enables granular cells in the dentate gyrus to maintain its number of synaptic contacts during the aging process. Furthermore, the presented influence of nimodipine on synaptic plasticity processes may underlie previously reported improved cognitive functioning of aged animals treated similarly with nimodipine.     

Coronary vasomotion in patients with syndrome X: evaluation with positron emission tomography and parametric myocardial perfusion imaging

The aim of this study was to elucidate further the causative mechanism of abnormal coronary vasomotion in patients with syndrome X. In patients with syndrome X, defined as angina pectoris and documented myocardial ischaemia during stress testing with normal findings at coronary angiography, abnormal coronary vasomotion of either the micro- or the macrocirculation has been suggested as the causative mechanism. Accordingly, we evaluated endothelial function, vasodilator reserve, and perfusion heterogeneity in these patients. Twenty-five patients with syndrome X (definitely normal coronary arteriogram, group A), 15 patients with minimal coronary artery disease (group B) and 21 healthy volunteers underwent [¹³N]ammonia positron emission tomography at rest, during cold pressor stimulation (endothelial function) and during dipyridamole stress testing (vasodilator reserve). Heterogeneity of myocardial perfusion was analysed by parametric polar mapping using a 480-segment model. In both patient groups, resting perfusion was increased compared to the normal subjects: group A, 127±31 ml·min^–1·100 g^–1; group B, 124±30 ml·min^–1·100 g^–1 normal subjects, 105±21 ml·min^–1·100 g^–1 (groups A and B vs normals,P<0.05). These differences were abolished after correction for rate-pressure product. During cold pressor stimulation, the perfusion responses (ratio of cold pressor perfusion to resting perfusion) were similar among the patients and the control subjects (group A, 1.20±0.23; group B, 1.24±0.22; normal subjects, 1.23±0.14). Likewise, during dipyridamole stress testing, perfusion responses were similar among the three groups (group A, 2.71±0.67; group B, 2.77±1.29; normal subjects, 2.91±1.04). In group A the heterogeneity of resting perfusion, expressed as coefficient of variation, was significantly different from the volunteers (20.1±4.5 vs 17.0±3.0,P<0.05). In group B (coefficient of variation 19.4±3.9) the difference from normal volunteers was not significant. In this study, patients with syndrome X and patients with minimal coronary artery disease showed normal perfusion responses during cold pressor stimulation and dipyridamole stress testing. Our findings therefore suggest that endothelial dysfunction and impaired vasodilator reserve are of no major pathophysiological relevance in patients with syndrome X. Rather, other mechanisms such as increased sympathetic tone and focal release of vasoactive substances may play a role in the pathogenesis of syndrome X.     

Altered corticomotor representation in patients with Parkinson's disease.

In 6 patients with Parkinson's disease (PD) and 6 age-matched controls, transcranial magnetic stimulation was applied at 56 regions over the motor cortex and premotor cortex of each hemisphere, with the first dorsal interosseous (FDI) muscle of both hands activated at 15% maximum voluntary contraction during stimulation. For each site, motor evoked potential (MEP) landmarks were recovered, including MEP amplitude, MEP onset latency, and silent period duration. Scaled MEP amplitudes were used to construct individual cortical maps of the FDI muscles. The maps revealed an anterior displacement of the muscle representation in PD patients. This anterior shift over motor cortical areas may reflect increased contributions of corticocortical connections between motor cortex and premotor cortical areas, possibly enhanced by the visual feedback aspect of the task. These alterations may reflect adaptations to the impairments in striatocortical circuits in PD.     

Nationwide survey on the use of image-guided functional endoscopic sinus surgery.

OBJECTIVE: To evaluate impressions and usage of sinus surgery image-guided surgical (IGS) systems by ENT surgeons in the United States. STUDY DESIGN AND SETTING: A survey was mailed to selected practicing ENT physicians, investigating regional information, practice type, IGS usage patterns, perceived benefits and limitations, and usage of the 61795 surgery code. RESULTS: Seventy-three percent of respondents use IGS. Nonusers respond that it provides no benefit or is too expensive. Eighty percent of respondents replied that IGS may allow for increased safety in certain procedures. Most users attempt reimbursement with the 61795 code. CONCLUSION: IGS usage is increasing but appears to be perceived as expensive and nonbeneficial in certain situations. Most respondents, however, felt that IGS may lead to safer surgery in certain situations, including revision and frontal procedures. Several factors appear to limit routine use including ease of use, technical setup, code reimbursement, and initial purchase costs. SIGNIFICANCE: IGS use appears to be increasing. The most frequent users appear to agree with the previously issued AAO-HNS guidelines regarding appropriate indications. Expanded use may depend on ease of use, reimbursement, and affordability. EBM rating: D-5.     

Functional outcome of a U-shaped ileocystoplasty (the Camey I procedure) in cancer of the bladder. Apropos of 14 cases

The authors studied postoperatively fourteen men who underwent urinary diversion with a Camey ileal bladder for bladder cancer in association with radical cystoprostatectomy, from March 1986 to June 1988. Mean follow-up was 19.5 +/- 9 months. Three patients died (21.4%), two other patients are alive with metastases. Ureteral reflux and upper tract dilatation occurred in 14.3 and 28.6% of the renal units, respectively. Daytime continence was achieved in 92.9% of the patients (13 patients), frequently 6 months after the operation. Nocturnal incontinence was almost universal (1 patient circumvented this problem by getting up to void every three hours during the night). Thirteen patients had urodynamic testing after the operation. Mean capacity of the ileal bladder was 344 ml with mean intraluminal pressure of 24 cm water. Mean urethral closing pressure was 49 cm water. Voiding was accomplished by abdominal straining concomitant with external sphincter relaxation. Post-void residual was less than 50 ml, except in one patient. The authors discuss these results and compare them to those of other studies.     

Recall of medication during pregnancy: Validity and accuracy of an adjusted questionnaire

Objective — To study the validity and accuracy of an adjusted questionnaire on medical drug use during pregnancy eight years after the pregnancy. Methods — The ability of a questionnaire on medication during pregnancy to detect actual use (= sensitivity) was tested against information collected 8 years previously (in 1983–1984) from 473 women with high-risk pregnancies who delivered at the University Hospital Nijmegen, the Netherlands. Results — For separate drug groups, the sensitivity varied between 5% and 91%. The timing of use was recalled moderately well. Although specific questions on drug groups did improve the sensitivity as compared to an earlier questionnaire, the improvement was not enough to make the questionnaire valid. High maternal education, low birth weight, low gestational age and a low 5-min Apgar score were related to better recall. The sensitivity of the questionnaire depended on the behavioural score of the child, implying recall bias. Conclusion — Questionnaire data on drug use during pregnancy obtained eight years after delivery are not a valid source of information.     

Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig.

At present, isoniazid (INH) is being used prophylactically to reduce the side effects of intravesical BCG therapy for superficial bladder cancer, although it is not clear whether or not this reduces the antitumor efficacy of BCG. In this study the impact of INH treatment on the immune response after repeated intravesical BCG administration was investigated in guinea pigs. INH was given on the 3 days around each BCG instillation. We found that the administration of INH severely impaired the immunological effects of BCG. The induction of mononuclear cell infiltration in the bladder wall was reduced. Enlargement of the regional lymph nodes (weight and number of cells), and increase of MHC Class II expression on the lymph node cells, normally observed after intravesical BCG administration, were inhibited by INH. Systemic immunity, measured by the DTH reaction in the skin to PPD, was also diminished due to the combined treatment of BCG with INH. When INH was administered during the last 4 of 6 BCG instillations, the immune response to BCG was still impaired. A five-fold increase of the dose of BCG did not overcome the effect of INH. INH probably did not exert a direct suppression of the immune system of the guinea pig as the DNCB skin reactivity was not influenced. Although INH concentrations in the urine were high at the onset of the instillation, in vitro experiments indicated that the effect of INH may not be caused by killing of the BCG organisms shortly after application in the bladder. In conclusion, our data in guinea pigs suggest that the use of INH may impair the immune response to intravesical BCG. As this response may be important for the antitumor effect of BCG, urologists should be cautious with the prophylactic use of INH. The influence on the antitumor efficacy is now investigated in man.     

Astigmatism and visual recovery after phacoemulsification and conventional extracapsular cataract extraction

In this study we wanted to investigate the post-operative astigmatism and visual acuity after phacoemulsification and conventional extracapsular cataract surgery. Patients operated between April and June 1993 (n=150) were retrospectively analyzed. The patients were examined prior to surgery and at day 1, at day 10, and in week 6 post-operatively. The difference between the post-operative log mean visual acuity in the Phaco group and in the CECCE group was significant after 1 and 10 days, however it was not significant (p=0.191) after 6 weeks. The mean astigmatism was significantly less in the Phaco group than in the CECCE group during the whole post-operative check-up period. This study suggests that Phaco results in a lower post-operative astigmatism and an earlier visual rehabilitation compared to the CECCE technique.Abbreviations Phaco Phacoemulsification - CECCE Conventional extracapsular cataract extraction     

When poor solubility becomes an issue: From early stage to proof of concept

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8–12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.