Aberrant splicing as potential modifier of the phenotype of junctional epidermolysis bullosa.

BACKGROUND: A lack or dysfunction of the anchoring protein laminin-332 in the basement membrane leads to the skin blistering disorder junctional epidermolysis bullosa (JEB). The mutation c.628G>A in the gene LAMB3 encoding the laminin ß3-chain is associated with generalized intermediate JEB; it may introduce an amino acid substitution (p.Glu210Lys) or disrupt splicing. OBJECTIVE: This retrospective study aimed at determining the effects of aberrant splicing on the JEB phenotype. METHODS: LAMB3 transcription was analysed in two siblings compound heterozygous for the LAMB3 mutations p.Glu210Lys and p.Arg635* with a diverging JEB phenotype from late childhood on. Laminin-332 levels in skin sections and in cultured keratinocytes were investigated by immunofluorescence staining. Real-time PCR was used to quantify LAMB3 expression in keratinocytes. RNA splice variants were identified by subcloning of a LAMB3 cDNA fraction and subsequent DNA sequencing. Structural models of laminin-332 helped to assess the impact of certain mutations on laminin-332 folding. RESULTS: Both siblings showed diminished LAMB3 expression. Laminin-332 was equally reduced in skin sections obtained during infancy but differed in keratinocytes isolated during adolescence. Although aberrant LAMB3 splicing with 26 variants was detected in both patients, splicing differed significantly: the full-length LAMB3 transcript harbouring the p.Glu210Lys mutation was found more often in the patient affected less severely (14/108 vs. 5/106 clones; P = 0.03). Structural modelling predicted that several deletions in LAMB3, but not the point mutation p.Glu210Lys, have an effect on laminin-332 folding and secretion. CONCLUSIONS: Differential LAMB3 mRNA splicing in the patients may explain the disparate JEB phenotype. By elucidating the regulation of laminin-332 gene expression, these findings may contribute to the development of therapeutic strategies for JEB and might help to understand phenotype modification by splice-site mutations in other hereditary diseases.

Nutritional and Functional Status in Geriatric Day Hospital Patients - MNA Short Form Versus Full MNA.

OBJECTIVES: The aims of this study were to determine the prevalence of malnutrition in patients of a geriatric day hospital using the Mini Nutritional Assessment short form (MNA-SF) and the full MNA, to compare both tools, and to examine the relationship between nutritional and functional status. DESIGN: Cross-sectional study. SETTING: Geriatric day hospital. PARTICIPANTS: 190 patients (72.1% female, median 80 years) aged 65 years or older. MEASUREMENTS: In consecutively admitted geriatric day hospital patients nutritional status was assessed by MNA-SF and full MNA, and agreement between both tools calculated by Cohen´s kappa. Basic activities of daily living (ADL), instrumental activities of daily living (IADL) and short physical performance battery (SPPB) were determined and related to MNA categories (Chi2-test, Mann-Whitney-U-test). RESULTS: 36.3 % and 44.7% of the patients were at risk of malnutrition, 8.9 % and 5.8 % were malnourished according to MNA-SF and full MNA, respectively. Agreement between both MNA forms was moderate (κ=0.531). No significant associations between MNA-SF and ADL, IADL and SPPB, and between full MNA and SPPB were observed. According to full MNA, the proportion of patients with limitations in ADL and IADL significantly increased with declining nutritional status (ADL: 2.1 vs. 8.2 vs. 18.2 %, p=0.044; IADL: 25.5 vs. 47.1 vs. 54.5 %, p=0.005) with a simultaneous decrease of the proportion of patients without limitations. Well-nourished patients reached significantly higher ADL scores than patients at risk of malnutrition (95 (90-100) vs. 95 (85-100), p=0.005) and significantly higher IADL scores than patients at risk or malnourished (8 (6-8) vs. 7 (5-8) vs. 6 (4-8), p=0.004). CONCLUSION: The high prevalence of risk of malnutrition and the observed association between functional status and nutritional status according to full MNA call for routine nutritional screening using this tool in geriatric day hospital patients.

[Is it possible to predict approval of medical rehabilitation by the extent of fatigue and subjective need for rehabilitation? Development, results and acceptance of a short screening]. / Lässt sich die Bewilligung einer Leistung zur medizinischen Rehabilitation mit dem Ausmass der Erschöpfung und der subjektiven Rehabilitationsbedürftigkeit vorhersagen? Entwicklung, Ergebnisse und Akzeptanz eines kurzen Screeningfragebogens.

OBJECTIVES: In earlier studies the lack of correlation between subjective need for rehabilitation of the applicant and the medically determined objective need for rehabilitation was reported again and again. The correlation between fatigue and subjective need for rehabilitation was not yet examined so far. Nevertheless fatigue is not defined sufficiently in the ICD, so interactions between chronic fatigue and somatic diseases are not taken into account appropriately. The following questions are considered: How high is the degree of chronic fatigue in insurees applying for rehabilitation? Is there a correlation between degree of fatigue and need for rehabilitation? Is it possible to predict approval of medical rehabilitation by fatigue and need for rehabilitation? How will insurees accept a screening accompanying their application for rehabilitation? METHOD: The study is based on data of 500 (response rate 85.6%) insurees of the pension insurance Braunschweig-Hannover, who had applied for medical rehabilitation between 1/2004 and 3/2004. The screening instrument included: scales on functional activity, mobility, social support, coping (IRES), the Chalder Fatigue Scale, SCL 14, Items concerning need for rehabilitation. As statistical methods t-, chi (2)-test, correlations, covariance-analysis and regression analysis are used. RESULTS: 70.2% of the patients claiming rehabilitation reported relevant clinical symptoms of chronic fatigue. There were no differences in age, work status, motivation, or expectations of returning to work, but differences in sex. Patients with chronic fatigue met more citeria of need for rehabilitation. But the approval of medical rehabilitation could not be predicted by fatigue and need for rehabilitation. Nevertheless the acceptance of the screening was high in the insurees. CONCLUSIONS: Patients with chronic fatigue met more criteria of need for rehabilitation. But the approval of medical rehabilitation could not be predicted by fatigue and need for rehabilitation. We assume that the reduction of activity and participation is associated with the degree of fatigue. It is discussed that the information an investigator may derive from a screening which is accepted by the insurees claiming medical rehabilitation will complete the collected clinical documents in a meaningful manner.

[Significance of the chronic fatigue syndrome in rehabilitation medicine--status and perspectives]. / Die Bedeutung des chronischen Erschöpfungssyndroms in der Rehabilitationsmedizin--Stand und Perspektiven.

It appears that from a clinical point of view chronic exhaustion or fatigue is an important factor in rehabilitation. This is, however, first of all a phenomenon that can be described as a function in accordance with the International Classification of Functioning, Disability and Health (JCF), caused by chronic illnesses or chronic excessive stress. The clinical and sociomedical ranking of chronic fatigue or exhaustion in respect of rehabilitation was discussed in the framework of a Workshop at the 12th Rehabilitation Science Colloquium, 2003 from the viewpoints of psychiatric rehabilitation, methodology, sociology and practical rehabilitation, and conclusions for future research were drawn. The definition of chronic fatigue is first of all mainly based on the feeling of chronic tiredness but also on phenomena of disturbed concentration, physical discomfort, headache and disorders of "drive" and mood. A psychiatric diagnosis linked with symptoms of chronic fatigue is neurasthenia, which is arrived at according to precisely defined criteria. Depressive disorder is one of the most important differential diagnoses in this sphere. Examinations by general practitioners revealed that about 90 % of the patients who had been diagnosed as suffering from psychovegetative disorders completely agreed with the diagnosis of neurasthenia. Neurasthenia resulted more often in work disability periods than disorders of somatisation and other psychosomatic diagnoses. Basing on the "IRES" scale "vital exhaustion", singular of even serious changes become evident in about 50 % to 90 % of the patients undergoing rehabilitation, depending on their individual range of indications. As was to be expected, the majority of pathologic findings concerns patients undergoing psychosomatic rehabilitation, since in such cases there is an overlapping with symptoms of psychosomatic diseases. It is, however, remarkable that also in somatically oriented orthopaedic rehabilitation symptoms of fatigue are seen in up to 50 % of the patients. Preliminary studies have shown that these symptoms can be definitely ameliorated within the rehabilitation framework, although pathological signs are still abundantly apparent in follow-up examinations. Markedly severe degrees of "vital exhaustion" and "vocational exhaustion" are also seen in rheumatology patients undergoing somatic rehabilitation. This agrees with case history details related by many female and male patients. Hence, it appears necessary to adapt rehabilitative intervention to both the psychovegetative and the medical behavioural aspects of this symptom. Scientific classification of the entire sphere of chronic fatigue in respect of rehabilitation requires classification of the relevant functions within the ICF framework. To this end it would be necessary to conduct patient inquiries within cross-sectional studies on the one hand and, on the other, a systematic consensus process among experts would have to be used for allocation to the relevant functions. This is the basis for development of suitable assessment tools for use in prospective studies in order to systematically evaluate the impact on functions and especially their effects on activities and participation.

[Relevance of a performance capacity model for uniform and standardized performance diagnostics]. / Die Relevanz eines Leistungsfähigkeitsmodells für eine einheitliche und standardisierte Leistungsdiagnostik.

To obtain a standardized method for performance capacity assessment in social medicine reference to a generally accepted model of performance capacity is necessary. Further, such a model enables description of the effects of chronic disease on performance capacity. This article describes how the term "performance capacity" can be reduced to operational basal parameters by a hierarchic breakdown, with the domain "physical performance capacity" having the most complex structure. Furthermore the construction of a graduation according to work-load taxonomies for every parameter is shown. The collection of data on the level of basal parameters is essential to assess the concrete performance capacity. To apply the model as a basis for estimating the effects of chronic disease, graduated disease features have to be created. The benefit of the procedure described lies in increased transparency of the decision process. Hence, performance capacity assessment will gain reliability and objectivity.

[Results of a 1-year follow-up study of neighborhood ambulatory aftercare after inpatient psychosomatic rehabilitation]. / Ergebnisse der 1-Jahres-Katamnese einer ambulanten wohnortnahen Nachsorge nach stationärer Psychosomatischer Rehabilitation.

Attention has been repeatedly drawn to the necessity to support patients after psychosomatic rehabilitation with their transfer of skills acquired during their stay at the interface between their inpatient treatment and their reintegration into everyday life. The authors' concept of the outpatient aftercare was already introduced in an earlier paper. This article presents the results of the one-year follow-up. A comparison with a control group revealed a further reduction of patients' depression. In contrast to the control group, the reduction in fear and discomfort already achieved during inpatient rehabilitation remained stable. At the same time the ability to cope with everyday life was expanded. Compared with the control group the participants of the aftercare could reduce the absence from work, days spent in hospital and visits to the doctor more than twice as much. Methodological problems of the design of the study are critically discussed.

Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group.

PURPOSE: To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. PATIENTS AND METHODS: Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). RESULTS: Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, -3.4%, +4.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. CONCLUSION: In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.

[Requirements for graduates of training courses from the viewpoint of various specialty fields]. / Anforderungsprofil der Absolventen der Aufbaustudiengänge aus der Sicht unterschiedlicher Arbeitsfelder.

Against the background of rehabilitation as practised within the legal German framework of statutory and compulsory old age pension insurance--this rehabilitation scheme having developed continually, getting more and more differentiated for the last 40 years--we welcome the post-graduates of the specialised training curriculae in Public Health. The post-graduates are expected not only to acquire differentiated knowledge of the various spheres of activities of the different statutory social insurance and welfare bodies, but also to possess so to say a "sixth sense" regarding the "quality" of the individual spheres. Governed by the concepts of economy of means, triftiness and efficiency it is always imperative to ensure that the best possible care is offered to an individual in need and to plan further developments. The postgraduate must therefore be capable of becoming integrated within a team and to appreciate the expectations of members of other professions in order to eventually participate in creating feasible solutions within the framework of the hierarchically preferential demands inherent in the various spheres.

The role of radiotherapy in carcinoma of the thoracic oesophagus: an audit of the Mount Vernon experience 1980-1989.

All 244 patients with carcinoma of the thoracic oesophagus registered at the Mount Vernon Centre for Cancer Treatment during the decade from 1 January 1980 to 31 December 1989 have been audited. We have made a detailed analysis of 110 (45%) with localized disease considered unsuitable for surgery, who completed treatment solely by radiotherapy. The median survival of this group of patients was 8.2 months (range 0.2-54 months). Dysphagia was improved by radiotherapy in 77.3% of cases, the median duration of relief was 24 weeks (range 0-208 weeks) and was maintained until death in 40%. Life table analysis showed that radical compared with less than radical regimens of radiotherapy gave significantly superior relief of dysphagia. This result is unlikely to be due to case selection.

Experience with CHART.

Continuous, hyperfractionated, accelerated radiotherapy (CHART) has been used at the Mount Vernon Cancer Treatment Center since January 1985. Patients with head and neck tumors and those with locally advanced non-oat cell carcinoma of the bronchus have formed the large majority of the 263 patients treated. Early reactions in the mucosae of the mouth and pharynx have been pronounced, but all have healed, while those in the skin have been less severe than with conventional radiotherapy. An unexpected late morbidity was radiation myelitis in four patients, but in other tissues including the skin, mucosae, the connective tissues, and the salivary glands, late changes appear reduced compared to those after conventional radiotherapy. In 92 patients with squamous cell carcinoma of the major sites in the head and neck region, of whom 71 were in Stages T3 and T4, a complete regression at the primary site and nodes was achieved in 90%. This can be compared with 62% in similar patients previously treated with curative intent at Mount Vernon between 1980 and 1985; the difference was maintained in follow-up (p = 0.003). Of 76 assessable patients with non-oat cell carcinoma of the bronchus, a complete radiological response has been achieved in 40%, compared to 12% in a retrospective group; again the difference has been maintained in follow up (p = 0.0001). A 1-year survival of 60% can be compared to 40% in the retrospective group and a 2-year survival of 29% compared to 12% (p = 0.01). With a reduction of permitted dose to the spinal cord, CHART gives promise for improvement in tumor control and a reduction in late morbidity. These promising results have led to multi-center randomized controlled clinical trials in carcinoma at the head and neck and in non-oat cell carcinoma of the bronchus. In these studies, CHART is being compared with conventional fractionated radiotherapy.

An audit of head and neck cancer treatment in a Regional Centre for Radiotherapy and Oncology.

All patients with head and neck cancer attending the Regional Centre for Radiotherapy and Oncology at Mount Vernon hospital during the 8-year period from 1 January 1980 to 31 December 1987 have been included in this review. The 545 patients presenting a new primary carcinoma without evidence for metastasis outside the locoregional area, who were treated primarily by radiotherapy are the subject of this present audit. The characteristics of the patients, of the tumours and of the treatment given have been related to outcome. Early tumours (T1 and T2 which were node-negative) showed a complete response (CR) rate of 94% whereas more advanced tumours (T1 and T2 with palpable lymph nodes) showed a CR of 59%. The probability of local tumour control at 5 years was 77% in those without nodes and 20% in those with nodes. For more advanced disease (T3 and T4 tumours), initial CR was 72% in node-negative disease and 32% when the nodes were positive. At 5 years, the probability of local tumour control fell to 37% and 0 respectively. CR, freedom from recurrence and survival were statistically significantly related to T stage, N stage and site of primary tumour. The results compare favourably with those reported by other institutions. The development of medical audit and its influence on treatment policy are considered.

Who gets radiotherapy?

This study investigated the use of radiotherapy for patients perceived to be unsuitable for curative therapy. Patients were grouped according to whether their cancer was considered curable or incurable and whether they received radical or palliative schedules of radiotherapy. The latter group was further evaluated to clarify current practice, to examine the problems in establishing guidelines for treatment and as a basis for prospective audit. Results confirmed that therapy guidelines within the unit were in line with national practice. Changes in standard therapy were proposed in view of resource limitations and recent results from other surveys. A second audit in 1989, together with a formal costing exercise, showed a reduction in the median number of fractions per course in both patient groups. This study suggests that palliative radiotherapy was used selectively for patients likely to receive significant benefit, and that consensus management was practised, and influenced, by informal internal audit. Results highlighted decision-making problems in the management of advanced non-metastasised cancer; confirmed doubts about the advisability of establishing rigid guidelines in palliative therapy; and clarified some of the difficulties in conducting meaningful cost-benefit analyses in this area.

Continuous hyperfractionated accelerated radiotherapy in locally advanced carcinoma of the head and neck region.

Shortening of the overall duration of radiotherapy would reduce the possibility repopulation of tumor during treatment. Most clinical trials of such accelerated radiotherapy have incorporated a split course to improve normal tissue tolerance. Any interruption, however, even for the week-end, may allow repopulation to occur. A scheme of radiotherapy has been used during which treatment was given 3 times per day on each of 12 consecutive days without interruption for the week-end. In a pilot study a significant improvement in survival and local tumor control has been achieved in 48 patients with head and neck tumors when comparison was made with a previously treated group. A randomized controlled clinical trial is planned.

Radiotherapy employing three fractions on each of twelve consecutive days.

In order to achieve the greatest advantage of accelerated hyperfractionated radiotherapy, treatment has been given 3 times each day for 12 consecutive days without a rest period. A total tumour dose of 50.4 Gy was well tolerated in a series of 38 patients with bronchial, head and neck and oesophageal carcinomas. A further 14 patients have now received an elevated dose of 54 Gy, again with satisfactory tolerance. The tumour responses at all these sites have been very promising and further work is proceeding.