Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model.

Peptide immunotherapy (PIT) is a targeted therapeutic approach, involving administration of disease-associated peptides, with the aim of restoring antigen-specific immunological tolerance without generalized immunosuppression. In type 1 diabetes, proinsulin is a primary antigen targeted by the autoimmune response, and is therefore a strong candidate for exploitation via PIT in this setting. To elucidate the optimal conditions for proinsulin-based PIT and explore mechanisms of action, we developed a preclinical model of proinsulin autoimmunity in a humanized HLA-DRB1*0401 transgenic HLA-DR4 Tg mouse. Once proinsulin-specific tolerance is broken, HLA-DR4 Tg mice develop autoinflammatory responses, including proinsulin-specific T cell proliferation, interferon (IFN)-γ and autoantibody production. These are preventable and quenchable by pre- and post-induction treatment, respectively, using intradermal proinsulin-PIT injections. Intradermal proinsulin-PIT enhances proliferation of regulatory [forkhead box protein 3 (FoxP3(+))CD25(high) ] CD4 T cells, including those capable of proinsulin-specific regulation, suggesting this as its main mode of action. In contrast, peptide delivered intradermally on the surface of vitamin D3-modulated (tolerogenic) dendritic cells, controls autoimmunity in association with proinsulin-specific IL-10 production, but no change in regulatory CD4 T cells. These studies define a humanized, translational model for in vivo optimization of PIT to control autoimmunity in type 1 diabetes and indicate that dominant mechanisms of action differ according to mode of peptide delivery.

Hand dermatitis and lymphoedema.

Hand dermatitis is common, with lymphoedema of the hand and forearm a rare complication. The mechanism of lymphoedema in such cases is poorly understood, hence management can be challenging. To investigate the underlying mechanism of lymphoedema associated with hand dermatitis and outline recommendations for management, we identified all patients with lymphoedema associated with hand dermatitis referred to our lymphoedema service, a tertiary referral centre. Treatment outcome was assessed by telephone interview and through correspondence with primary physicians and therapists. In total, nine patients, six with bilateral and three with unilateral lymphoedema associated with hand dermatitis, attended our service over a 4-year period. Most had long-standing bilateral pompholyx eczema. Three patients reported no signs of infection prior to the onset of swelling. All patients had recurrent episodes of infection after the onset of swelling. Lymphoscintigraphy, when used, revealed a failure of small initial lymphatics of the hand to absorb and drain lymph to regional nodes. Prophylactic antibiotics together with aggressive management of the dermatitis, often with systemic therapy, were required to reduce swelling. Possible mechanisms for lymphoedema associated with hand dermatitis include obliterative lymphangitis from infection, an inflammatory effect of the dermatitis on local lymphatics or a constitutive weakness of lymph drainage exposed to chronic inflammation, or any combination of the three. Treatment is only successful once both infection and inflammation from the dermatitis are controlled.

Immortalization of epithelial progenitor cells mediated by resveratrol.

Within the hierarchy of epithelial stem cells, normal progenitor cells may express regulated telomerase during renewal cycles of proliferation and differentiation. Discontinuous telomerase activity may promote increased renewal capacity of progenitor cells, while deregulated/continuous telomerase activity may promote immortalization when differentiation and/or senescent pathways are compromised. In the present work, we show that resveratrol activates, while progesterone inactivates, continuous telomerase activity within 24 h in subpopulations of human Li-Fraumeni syndrome-derived breast epithelial cells. Resveratrol results in immortalization of mixed progenitor cells with mutant p53, but not human epithelial cells with wild type p53. Our results demonstrate the potential for renewing progenitor cells with mutant p53 to immortalize after continuous telomerase expression when exposed to certain environmental compounds. Understanding the effects of telomerase modulators on endogenous telomerase activity in progenitor cells is relevant to the role of immortalization in the initiation and progression of cancer subtypes.

Chlamydia testing in community pharmacies: evaluation of a feasibility pilot in south east London.

BACKGROUND AND OBJECTIVE: Chlamydia trachomatis infection is a common sexually transmitted infection with serious sequelae. Excellent access to testing, treatment and contact tracing are an essential part of strategies to control it. With traditional sexual health services over-stretched, community pharmacies are well placed to provide this service. They have the potential to improve access by offering chlamydia testing and treatment from high street venues with long opening hours. This study evaluated the feasibility and acceptability to users and pharmacists of this service in independent community pharmacies. METHOD: A chlamydia testing and treatment service was offered in three community pharmacies in two inner London boroughs for a 3-month pilot. Data on the feasibility and acceptability of the new service were collected via a survey of client experience, in-depth semistructured interviews with clients and pharmacists, and structured evaluation reports completed by professional patients paid to visit the pharmacies. RESULTS: 83 tests were taken with eight (9.5%) of these positive for C trachomatis. Of those tested, 94% (n = 73) were women and 71% (n = 56) were from ethnic minorities. 80 clients completed the questionnaires and 24 clients were interviewed. Most clients heard about the service from the pharmacist when requesting emergency contraception and 16% (n = 13) would not otherwise have been tested. Clients valued the speed and convenience of the service and the friendly, non-judgmental approach of the pharmacist. Confidentiality when asking for the service at the counter was suboptimal, and the pharmacist trained to deliver the service was not always available to provide it. CONCLUSIONS: Chlamydia testing and treatment in community pharmacies is feasible and acceptable to users. The service increases access among young women at high risk of sexually transmitted infection but not among young men.

Simple intervention to improve detection of child abuse in emergency departments.

PROBLEM: Child abuse is easily overlooked in a busy emergency department. DESIGN: Two stage audit of 1000 children before and after introduction of reminder flowchart. BACKGROUND AND SETTING: An emergency department in a suburban teaching hospital seeing about 4000 injured preschool children a year. KEY MEASURES FOR IMPROVEMENT: Number of records in which intentional injury was adequately documented and considered and the number of children referred for further assessment before and after introduction of reminder flowchart into emergency department notes. STRATEGIES FOR CHANGE: Nurses were asked to insert a reminder flowchart for assessing intentional injury into the notes of all children aged 0-5 years attending the department with any injury and to record the results of checking the child protection register. EFFECT OF CHANGE: Documentation of all eight indicators that intentional injury had been considered had increased in the second audit. Records of compatibility of history with injury and consistency of history increased from less than 2% to more than 70% (P<0.0001). More children were referred for further assessment in the second audit than the first, although the difference was not significant (6 (0.6%) v 14 (1.4%), P=0.072). The general level of awareness and vigilance increased in the second audit, even for children whose records did not contain the flowchart. LESSONS LEARNT: Inclusion of a simple reminder flowchart in the notes of injured preschool children attending the emergency department increases awareness, consideration, and documentation of intentional injury. Rates of referral for further assessment also increase.

Seasonal cold and circadian changes in blood pressure and physical activity in young and elderly people.

AIM: To test the hypothesis that there is no association between seasonal cold and the circadian responses of blood pressure, deep-body temperature and physical activity in healthy young and elderly men. METHODS: 25 healthy elderly (aged 70-82 years) and 21 young volunteers (aged 20-30 years) participated in a 3-year prospective cross-seasonal study. RESULTS: Ambulatory day-time blood pressures in the older men were higher in the winter than in the summer and higher in both seasons than in the young people. The seasonally related differences were associated with lower outdoor and indoor temperatures, lower body temperature and higher activity levels in the elderly group in the winter. The older but not the younger group had higher blood pressure and levels of physical activity at certain times of the day in the winter compared with the summer. CONCLUSION: Time-of-day winter increases in blood pressure in older people may be related to increased activity as well as to levels of ambient temperature. Although it is generally advantageous for older people to be physically active in order to prevent circulatory disease, there may be a rationale for advising that that they should avoid intense activity at certain times of the day, especially in the winter.

Seasonal cold, excursional behaviour, clothing protection and physical activity in young and old subjects.

Previous reports indicate that everyday excursional exposures may play a part in increased winter mortality (Donaldson et al 1997) and that the avoidance of cold stress is associated with low indices of cold related mortality in Europe (Eurowinter Group 1997). However, few prospective data have been reported on excursional data and risk factors for arterial disease. In a field study carried out on 21 young (mean age 23.5) and 24 elderly healthy subjects (mean age 73.6) there were no significant differences between winter and summer in the number or duration of outside excursions. Never the less, elderly subjects had significantly more clothing insulation (clo), both indoors and outdoors in the winter than in the summer (p < or = 0.001) and this was also the case for young subjects. The urine temperature of the elderly in the winter was significantly lower (p < or = 0.01) than in the summer but this was not seen in the young. Elderly physical activity was significantly higher in the winter than in the summer (p < or = 0.05) but not for the young. Thus, elderly subjects showed no material change in excursional behaviour in the winter, even though clothing protection was arguably inadequate in view of lower body temperature, accompanied by increased physical activity. Blood pressure was significantly higher in the winter (p < or = 0.01) in the elderly, though the extent to which activity levels contributed to this contrast is uncertain from these data.

Interrater and intrarrater reliability of the exeter dysphagia assessment technique applied to healthy elderly adults.

The purpose of this study was to evaluate the inter- and intrarater reliabilities of the Exeter Dysphagia Assessment Technique in a sample of elderly adults. This procedure uses noninvasive methods to record aspects of oral motor efficiency and synchronization of respiration during swallowing with the aid of specially developed equipment. Changes in the direction of nasal air flow, time of lip or tongue/spoon contact, and the time/frequency of swallow sounds are monitored and analyzed. Seventy records were evaluated independently by three trained assessors on three consecutive occasions. Interrater reliability was found to be good to very good for five of the respiratory variables assessed and moderate for the sixth. Interrater agreement was also very good for three of the timed oropharyngeal events assessed and moderate for the fourth. Intrarater reliability was very good for the same five respiratory variables and moderate for the sixth. Intrarater agreement was also very good for three of the timed oropharyngeal events and moderate for the fourth. Repeat evaluations of these records showed that agreement between and within raters concerning the sixth respiratory variable was improved substantially when the charts were examined in an enlarged form that provided improved resolution. We conclude that the majority of variables monitored by the Exeter Dysphagia Assessment Technique can be evaluated very reliably.

Leg cramps in the elderly: prevalence, drug and disease associations.

To determine the prevalence of leg cramps in elderly outpatients and their association any underlying diseases and concomitant drug intake, we conducted a cross-sectional study using an in-depth questionnaire. A total of 365 patients aged 65 years and over (mean 78.5 years) attending our outpatient clinic participated in the study. The prevalence of leg cramps was 50%. Cramps were commoner in females (56%) than in males (40%). Although reported to occur anytime throughout the 24 hours, cramps were most prevalent at night (62%). In many patients, leg cramps were a long-standing complaint: 20% had been suffering with them for more than 10 years, whereas only 9% of patients reported them first starting within the last six months. Only 73 (40%) sufferers had informed their practitioner; of these, 39 (53%) received treatment, of whom 26 gained benefit. Leg cramps were strongly associated with peripheral vascular disease (odds ratio 2.9, 95% CI 1.89-4.55, p < 0.00001), arthritis (odds ratio 2.26, 95% CI 1.48-3.45, p = 0.0001) and female gender (odds ratio 1.96, 95% CI 1.28-3.03, p = 0.002). Heart failure, hypertension, diabetes mellitus and stroke were not significantly associated. Except for a causal association with analgesic use, no positive association could be shown with any other class of drugs, including diuretics.

Differences in drug prescribing patterns in elderly parkinsonian patients identified at hospital admission.

In the period July 1984 to June 1993 a total of 4541 admissions to a Department of Medicine for the Elderly were investigated. Approximately 9% of the total were diagnosed to have parkinsonism. Full drug histories together with the available demographic and clinical data were investigated in order to identify differences in the prescribing patterns in this group compared to those of non-parkinsonian patients admitted during this time frame. There was a statistically significant lower incidence among the parkinsonian group for the prescribing of all cardiovascular drug groups, anticoagulants, hypoglycaemics, bronchodilators, and corticosteroids compared with non-parkinsonian patients. In contrast, the incidence of hypnotics, laxatives, antidepressants and antipsychotics were significantly higher.

Changes in prescribing patterns of oral hypoglycaemics in elderly patients, over a period of 10 years: matching with general practitioners' perceptions of their own prescribing.

A 10-year hospital admissions database had demonstrated a steep decline in the prescribing of chlorpropamide, and to a lesser degree, of glibenclamide, with tolbutamide, metformin and the most recently introduced oral hypoglycaemic, gliclazide, maintaining relatively uniform levels. Glipizide was the most popular emerging agent. Interviews with 20 general practitioners (GPs) revealed that 55% had a definite first choice agent with a priority order of gliclazide, tolbutamide and glibenclamide. For the remaining GPs without a sole preference, gliclazide (30%), glipizide (30%) and glibenclamide (20%) featured as their most commonly prescribed agents.

Dysphagia following strokes: clinical observations of swallowing rehabilitation employing palatal training appliances.

A retrospective study was undertaken to evaluate the progress of a group of dysphagic stroke patients for whom a dental prosthesis the Palatal Training Appliance (PTA), was used in the active rehabilitation of the swallowing mechanism. Patients selected were those who had sustained a stroke uncomplicated by other neurological illness, during one 12-month period, and whose dysphagia caused anxiety to the medical staff in the hospital ward. Thirty severely dysphagic stroke patients satisfied these criteria. The study recorded the duration and type of supplementary feeding required during hospitalization. Thirteen patients had evidence of aspiration before the PTA was fitted and 5 afterwards. Seven patients died, but only 1 was recorded as having a febrile illness which may have contributed to the death. At discharge, which averaged 10 weeks after admission, 22 of the 23 survivors were taking an adequate oral diet. It was also noted that almost half of the patients who wore dentures before the cerebrovascular event were unable to control them afterwards, adding to their neurological swallowing difficulties. The fitting of a PTA and correction of unstable dentures appeared to help both motivation and function. The results show an improvement in the rehabilitation of oral feeding compared with previous reports by other authors, who did not use the dental appliance. There did not appear to be any medical contraindication to its use.

The use of capsaicin cream in a case of erythromelalgia.

We present a case of erythromelalgia in a 68 year old lady who responded, within 48 hours, to a twice daily topical application of capsaicin cream 0.025%. Capsaicin cream was stopped after 2 months, and 6 months later the patient continued to have the symptomatic relief she experienced initially.

Subcutaneous apomorphine infusion in Parkinson's disease: does it have a role?

Apomorphine is a potent dopamine agonist at both D1 and D2 receptors and has been used successfully for treating the 'on/off' phenomenon in Parkinson's disease. We report our experience with apomorphine in treating the 'on/off' phenomenon in L-dopa responsive idiopathic Parkinson's disease. Thirteen such patients were commenced on apomorphine infusions. Their mean age was 69 (range 53-80) years and the mean duration of the disease was 15 (range 6-28) years. The clinical response to apomorphine was good in four patients, fair in two, unchanged in five and worse in two. Activities of daily living improved in six, were unchanged in five and worse in two. When the response was poor or showed no change, apomorphine was discontinued. In addition, apomorphine was also discontinued in three patients who had had a fair/good response but suffered side effects of hallucinations, delusions and psychosis, lack of cooperation or found the pump inconvenient. Apomorphine was continued in only three patients out of 13.

The synchronization of respiration and swallow sounds with videofluoroscopy during swallowing.

Simultaneous recording of adult subjects sipping small amounts of fluid from a cup have been obtained by videofluoroscopy together with feeding respiratory patterns and swallow sounds from the Exeter Dysphagia Assessment Technique (EDAT). These allowed visual representations of respiration and swallow sounds to be superimposed on a videofluoroscopy recording using a split-screen technique. Sequentially numbered, 1/50 sec, half-frame photographic prints were examined and schematic drawings of the relevant radiographs were made. These were superimposed on to the actual EDAT printed chart of the same swallow event, their exact time relationship with respiration and cervical swallow sounds being preserved. The results allow events in the barium videofluoroscopy to be related to events in the feeding respiratory pattern and swallow sounds recorded by EDAT.

Parkinson's disease: the spectrum of disabilities.

The needs of people with Parkinson's disease (PD) go beyond the purely medical domain and often require collaborative management. A Panel Discussion at the "Hither neurology" Symposium included neurologists, a speech therapist, a geriatrician and a sociologist. Their discussion highlighted certain aspects of the disability and disadvantage associated with PD. The starting point was a video recording, "Parkinson's Disease: the personal view", in which the contributors were patients and carers. Topics covered included counselling at the time of diagnosis; subsequent access to clinics and to neurological advice; access to therapy; support in the community; fluctuating disability associated with "on-off" phenomena; driving; and sexual problems.

Chromosome and DNA analyses of rat 13762NF mammary adenocarcinoma cell lines and clones of different metastatic potentials.

Chromosome morphologies revealed by Giemsa-banded karyotypes and chromosome numbers were compared between parental tumor-, lymph node- and lung metastasis-derived rat 13762NF mammary adenocarcinoma cell lines and clones having different spontaneous metastatic potentials. Although chromosome numbers in the cell lines and clones generally correlated with DNA content by flow cytometry, ploidy did not correlate with spontaneous metastatic potentials. Chromosome number and DNA content drifted during prolonged in vitro growth in each of the cell lines and clones. Common chromosome rearrangements were found, confirming a common origin for all the cell lines and clones, and the frequency and appearance of the individual marker chromosomes fluctuated during in vitro growth. Karyotypic analyses revealed that the markers coinciding with phenotypic drift in spontaneous metastatic potential and other biological properties of parental tumor-derived clones MTC and MTF7 and lung metastasis-derived clone MTLn3 involved chromosomes 3, 4, 5, 6, and 8. Clone MTC exhibited a shift in several markers and an increase in metastatic potential at passage T20, while clone MTF7 displayed a lesser spontaneous metastatic potential at high passage (T34) concomitant with an increase in the frequency of certain marker chromosomes. Lung metastasis-derived clone MTLn3 also exhibited a shift in some marker chromosomes, colonization preference and metastatic potential to lung and lymph nodes at high tissue culture passages. The changes in marker chromosomes during in vitro passage of clones MTC and MTLn3 suggested the presence of at least two cell subpopulations which could be responsible for the observed shift in spontaneous metastatic properties. Karyotypic features of the 13762NF cell lines and clones indicate that subtle cytogenetic changes, in contrast to gross chromosomal abnormalities, may be more important in determining metastatic phenotype.