Transdermal Delivery of Metoprolol by Electroporation

Electroporation, i.e., the creation of transient pores in lipid membranes leading to increased permeability, could be used to promote transdermal drug delivery. We have evaluated metoprolol permeation through full thickness hairless rat skin in vitro following electroporation with an exponentially decaying pulse. Application of electric pulses increased metoprolol permeation as compared to diffusion through untreated skin. Raising the number of twin pulses (300 V, 3 ms; followed after 1 s by 100 V, 620 ms) from 1 to 20 increased drug transport. Single pulse (100 V, 620 ms) was as effective as twin pulse application (2200 V, 1100 V or 300 V, 3 ms; followed after 1 s by 100 V, 620 ms). In order to investigate the effect of pulse voltage on metoprolol permeation, 5 single pulses (each separated by 1 min) were applied at varying voltages from 24 to 450 V (pulse time 620 ms). A linear correlation between pulse voltage and cumulative metoprolol transported after 4 h suggested that voltage controls the quantity of drug delivered. Then, the effect of pulse time on metoprolol permeation was studied by varying pulse duration of 5 single 100 V pulses from 80 to 710 ms (each pulse also separated by 1 min). Cumulative metoprolol transported after 4 h increased linearly with the pulse time. Therefore, pulse time was also a control factor of the quantity of drug delivered but to a lesser extent than the voltage at least at 100 V. The mechanisms behind improved transdermal drug delivery by electroporation involved reversible increased skin permeability, electrophoretic movement of drug into the skin during pulse application, and drug release from the skin reservoir formed by electroporation. Thus, electroporation did occur as shown by the increased transdermal permeation, on indicator of structural skin changes and their reversibility. Electroporation has potential for enhancing transdermal drug delivery.     

Response to symptoms of stroke in the UK: a systematic review

Background  

The English National Stroke Strategy suggests that there is a need to improve the response of patients and witnesses to the symptoms of acute stroke to increase rapid access to specialist care. We wished to review the evidence base regarding the knowledge, attitudes and behaviours of stroke patients, witnesses and the public to the symptoms of stroke and the need for an urgent response at the onset of symptoms.     

Improving Professional Practice in the Disclosure of a Diagnosis of Dementia: A Modeling Experiment to Evaluate a Theory-Based Intervention

Background  

Among health professionals, there is wide variation in the practice of disclosing a diagnosis of dementia to patients.     

Issues of recruitment and maintaining high response rates in a longitudinal study of older hospital patients in England--pathways through care study.

STUDY OBJECTIVES: To describe and discuss the methods used to recruit and maintain an unbiased sample of older discharged hospital patients in a study of the process and outcomes of hospital care. DESIGN: Prospective longitudinal interview study of consecutive patients admitted to hospital over a 12 month period and followed up for six months. Interviews took place in hospital five days after admission, at home 10 days after discharge, and six months after admission. SETTING: Six hospital locations: three in the north of England and three in the south. PARTICIPANTS: People aged 65 and over admitted to hospital with a new stroke or fractured neck of femur, their significant other, and nursing staff caring for them. MAIN RESULTS: Of 3105 patients referred to the study, 2111 were eligible and 1671 (79%) were recruited. Recruited stroke patients were younger than those not recruited and rates differed between locations for both stroke and fractured neck of femur. By six months after admission 25% had died. Outcome data were obtained for 85% of the surviving patients. Patients who died were older and frailer before admission. Among survivors, outcome data for stroke patients were less likely to be obtained for men, those more able initially, and those who were married. Response rates to each interview differed according to respondent types. Interviews were more likely to be obtained with significant others than patients. Patients who were not able to be interviewed were older and frailer; significant others were less likely to be interviewed if the patients were younger and more able. CONCLUSIONS: High response rates can be achieved with very frail older people if strategies are adopted to maintain their interest and if self reported data are supplemented by interviewing significant others.     

Ultrastructure and Cytochemical Detection of Alkaline Phosphatase in Long-Term Cultures of Osteoblast-like Cells from Rat Calvaria

Two methods of collecting osteoblast-like cells from newborn rat calvaria were tested, either placing individual glass fragments or tipping dense glass beads onto the endocranial surface of periosteum-free bone. Inoculated at high density, cells collected by using these two methods form large mineralized plates after three weeks of culture. The main purpose of our investigation was to analyze the progressive formation of this mineralized structure and to localize alkaline phosphatase activity. At the beginning of the culture, flattened cells gathered into multilayers and synthesized collagen fibers. Cells in the upper layer became rapidly cuboidal in shape and continued to secrete collagen at their basal pole, whereas other cells became progressively embedded in the extracellular matrix. The upper cells featured ultrastructural characters of osteoblasts, whereas the embedded cells resembled osteocytes. After two weeks, the matrix began to mineralize: crystals appeared on collagen fibers, on matrix vesicles, and on cell debris. During the first days of the culture, the alkaline phosphatase activity was localized on the plasma membranes and on the collagen fibers. Thereafter, only the upper cells and collagen fibers that were juxtaposed to these cells showed alkaline phosphatase activity. In addition, the presence of mineralized matrix prevented the reaction product from being visualized on collagen fibers. The ultrastructural analysis reveals large mineralized plates with a structure resembling that of bone in vivo. This culture appears to be an appropriate model to study bone formation and regulation. Received: 30 September 1995 / Accepted: 3 May 1996     

Pudendal neuropathy and severity of incontinence but not presence of an anal sphincter defect may determine the response to biofeedback therapy in fecal incontinence

PURPOSE: It has been suggested that the severity of fecal incontinence, the presence of pudendal neuropathy, or an external anal sphincter defect does not preclude clinical improvement with biofeedback therapy. A discrepancy, however, is frequently found between subjective improvement and objective results after biofeedback therapy. Our aim was to assess whether severity of fecal incontinence, presence of pudendal neuropathy, or an external anal sphincter defect could influence the results of manometric parameters after biofeedback therapy in patients with fecal incontinence. METHODS: Biofeedback therapy was used to treat 27 patients with fecal incontinence (25 women; mean age, 53; range, 29–74 years), according to a strict protocol. Manometry, pudendal nerve terminal motor latency, and anal ultrasound were performed in all patients before biofeedback therapy. Manometric evaluation of external anal sphincter function was performed after the biofeedback sessions. RESULTS: Eight of 27 patients had a good clinical response to biofeedback, but with no significant difference in their mean amplitude and duration of squeeze pressure before and after biofeedback. There was no relationship between the clinical results of biofeedback therapy and the initial severity of fecal incontinence, pudendal neuropathy, or external sphincter defect. Patients with severe incontinence (incontinence to solids) and pudendal neuropathy failed to improve the amplitude and duration of their maximum voluntary contraction after biofeedback therapy. Patients with mild fecal incontinence (incontinence to flatus, liquids, or both) (P<0.04), without pudendal neuropathy (P<0.02), or with (P<0.05) and without (P<0.05) external sphincter defect improved their external anal sphincter function after biofeedback therapy. CONCLUSION: In patients with fecal incontinence, the severity of symptoms and pudendal neuropathy should be considered as two factors of poor prognosis of favorable manometric results after biofeedback therapy. Improvement, on the other hand, may be expected after biofeedback therapy despite an external anal sphincter defect.Presented at the XXIst congress of the Societé Internationale Francophone d'Urodynamique, Lisbon, Portugal, May 14 to 16, 1998.     

Outcomes following acute hospital care for stroke or hip fracture: how useful is an assessment of anxiety or depression for older people?

Objective. To investigate the association between severe life events and mental health outcomes following acute hospital care for older patients with acute stroke or fractured neck of femur. Design. Prospective longitudinal survey of stroke and hip fracture patients admitted to hospital from admission to 6-month follow-up. Setting. Six district general hospitals, three in the North and three in the South of England. Participants. 642 patients admitted to hospital with an acute stroke (268) or hip fracture (374) resident in a private household at 6 months follow-up. Main outcome measures. Hospital Anxiety and Depression Scale, cognitive items of the Survey Psychiatric Assessment Scale, Clackmannan Disability Scale, Severe Life Events Inventory, Wenger Social Support Network Typology. Results. 47% of 6-month survivors of stroke or hip fracture resident in private households had a possible psychiatric illness: dementia (13%), anxiety or depression (41%). 57% had severe or very severe disability and 48% experienced additional life events (17% two or more) after hospital admission. Severe disability was strongly associated with a higher prevalence of anxiety (p<0·0005) or depression (p<0·0001). Social contact was associated with a lower prevalence of anxiety (p<0·01) or depression (p<0·0001) and social support network type was strongly associated with depression (p<0·001) but not anxiety (p=0·096). Number of severe life events was associated with anxiety (p<0·001) but not depression (p=0·058). Conclusion. Disability is probably a more robust outcome measure than assessments of mental health for older people in uncontrolled studies. © 1998 John Wiley & Sons, Ltd.     

Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity

Aims/hypothesis

This case–control study was nested in a prospective birth cohort to evaluate whether the presence of enteroviruses in stools was associated with the appearance of islet autoimmunity in the Type 1 Diabetes Prediction and Prevention study in Finland.

Methods

Altogether, 1673 longitudinal stool samples from 129 case children who turned positive for multiple islet autoantibodies and 3108 stool samples from 282 matched control children were screened for the presence of enterovirus RNA using RT-PCR. Viral genotype was detected by sequencing.

Results

Case children had more enterovirus infections than control children (0.8 vs 0.6 infections per child). Time-dependent analysis indicated that this excess of infections occurred more than 1 year before the first detection of islet autoantibodies (6.3 vs 2.1 infections per 10 follow-up years). No such difference was seen in infections occurring less than 1 year before islet autoantibody seroconversion or after seroconversion. The most frequent enterovirus types included coxsackievirus A4 (28% of genotyped viruses), coxsackievirus A2 (14%) and coxsackievirus A16 (11%).

Conclusions/interpretation

The results suggest that enterovirus infections diagnosed by detecting viral RNA in stools are associated with the development of islet autoimmunity with a time lag of several months.