Human skin fibrosis: up-regulation of collagen type III gene transcription in the fibrotic skin nodules of lower limb lymphoedema.

OBJECTIVES: To investigate the cellular and molecular pathophysiology involved in the development of fibrotic skin of grade-3 lymphoedema patients with a focus on collagen types. METHODS: Fibrotic and normal skin biopsy samples obtained from grade-3 lymphoedema patients and normal individuals, respectively, were analysed by histopathology, quantitative real-time PCR and immunohistochemistry to examine collagen gene expression. RESULTS: Histopathologic analysis revealed epidermal changes such as orthokeratosis, hypergranulosis and irregular acanthosis in the skin biopsies. The thickened dermis contained nodules of haphazardly arranged thick collagen bundles. Real-time PCR data showed significant (P-value 0.0003) up-regulation of Collagen type I and type III gene transcripts in the fibrotic skin of patients resulting in 38.94-fold higher transcription of Collagen type III alpha-1 gene than of Collagen type I alpha-1 gene. Semi-quantification of the per cent of haematoxylin-DAB-stained area of immunohistochemistry images also showed significant (P < 0.0001) enhancement of both collagen proteins in the fibrotic skin of patients vs. normal human skin. CONCLUSIONS: Gene transcript analysis revealed significant up-regulation of Collagen type III vs. Collagen type I in fibrotic skin of limb nodules from patient biopsies. Histopathological and immunohistochemical analysis also revealed enhancement of Collagen types I and III in fibrotic vs. normal skin. The findings of this preliminary study indicate the potentially significant involvement of Collagen type III in the development of the fibrotic skin of grade-3 lymphoedema patients.

OBJECTIFS: Etudier la physiopathologie cellulaire et moléculaire impliquée dans le développement de la fibrose cutanée chez les patients atteints de lymphœdème de grade 3 en mettant l'accent sur les types de collagène. MÉTHODES: Des échantillons de biopsie cutanée fibrotique et normale obtenus respectivement de patients atteints de lymphœdème de grade 3 et d'individus normaux ont été analysés par histopathologie, par PCR quantitative en temps réel et par immunohistochimie pour examiner l'expression des gènes de collagène. RÉSULTATS: L'analyse histopathologique a révélé des changements épidermiques tels que l'orthokératose, l'hypergranulose et l'acanthose irrégulière dans les biopsies cutanées. Le derme épaissi contenait des nodules de faisceaux de collagène épais disposés au hasard. Les données de PCR en temps réel ont montré une régulation à la hausse significative (P = 0.0003) des transcrits des gènes de collagène de type I et III dans la peau fibrotique des patients, résultant en une transcription 38,94 fois plus élevée du gène alpha-1 du collagène de type III par rapport à celui du gène alpha-1 du collagène de type I. La semi-quantification du pourcentage de zone colorée à l'hématoxyline-DAB des images d'immunohistochimie a également montré une amélioration significative (P < 0.0001) des deux protéines de collagène dans la peau fibrotique des patients par rapport à la peau humaine normale. CONCLUSIONS: L'analyse de transcription génétique a révélé une régulation à la hausse importante du collagène de type III par rapport à celle du collagène de type I dans la peau fibrotique des nodules des membres provenant de biopsies de patients. L'analyse histopathologique et immunohistochimique a également révélé une amélioration du collagène de types I et III dans la peau fibrotique pa rapport à la peau normale. Les résultats de cette étude préliminaire indiquent l'implication potentiellement significative du collagène de type III dans le développement de la peau fibrotique des patients atteints de lymphœdème de grade 3.

Future Research Priorities for Morbidity Control of Lymphedema.

BACKGROUND: Innovation in the treatment of lower extremity lymphedema has received low priority from the governments and pharmaceutical industry. Advancing lymphedema is irreversible and initiates fibrosis in the dermis, reactive changes in the epidermis and subcutis. Most medical treatments offered for lymphedema are either too demanding with a less than satisfactory response or patients have low concordance due to complex schedules. A priority setting partnership (PSP) was established to decide on the future priorities in lymphedema research. METHODS: A table of abstracts following a literature search was published in workshop website. Stake holders were requested to upload their priorities. Their questions were listed, randomized, and sent to lymphologists for ranking. High ranked ten research priorities, obtained through median score, were presented in final prioritization work shop attended by invited stake holders. A free medical camp was organized during workshop to understand patients' priorities. RESULTS: One hundred research priorities were selected from priorities uploaded to website. Ten priorities were short listed through a peer review process involving 12 lymphologists, for final discussion. They were related to simplification of integrative treatment for lymphedema, cellular changes in lymphedema and mechanisms of its reversal, eliminating bacterial entry lesions to reduce cellulitis episodes, exploring evidence for therapies in traditional medicine, improving patient concordance to compression therapy, epidemiology of lymphatic filariasis (LF), and economic benefit of integrative treatments of lymphedema. CONCLUSION: A robust research priority setting process, organized as described in James Lind Alliance guidebook, identified seven priority areas to achieve effective morbidity control of lymphedema including LF. All stake holders including Department of Health Research, Government of India, participated in the PSP.

Yoga protocol for treatment of breast cancer-related lymphedema.

INTRODUCTION: Vaqas and Ryan (2003) advocated yoga and breathing exercises for lymphedema. Narahari et al. (2007) developed an integrative medicine protocol for lower-limb lymphedema using yoga. Studies have hypothesized that yoga plays a similar role as that of central manual lymph drainage of Foldi's technique. This study explains how we have used yoga and breathing as a self-care intervention for breast cancer-related lymphedema (BCRL). METHODS: The study outcome was to create a yoga protocol for BCRL. Selection of yoga was based on the actions of muscles on joints, anatomical areas associated with different groups of lymph nodes, stretching of skin, and method of breathing in each yoga. The protocol was piloted in eight BCRL patients, observed its difficulties by interacting with patients. A literature search was conducted in PubMed and Cochrane library to identify the yoga protocols for BCRL. RESULTS: Twenty yoga and 5 breathing exercises were adopted. They have slow, methodical joint movements which helped patients to tolerate pain. Breathing was long and diaphragmatic. Flexion of joints was coordinated with exhalation and extension with inhalation. Alternate yoga was introduced to facilitate patients to perform complex movements. Yoga's joint movements, initial positions, and mode of breathing were compared to two other protocols. The volume reduced from 2.4 to 1.2 L in eight patients after continuous practice of yoga and compression at home for 3 months. There was improvement in the range of movement and intensity of pain. DISCUSSION: Yoga exercises were selected on the basis of their role in chest expansion, maximizing range of movements: flexion of large muscles, maximum stretch of skin, and thus part-by-part lymph drainage from center and periphery. This protocol addressed functional, volume, and movement issues of BCRL and was found to be superior to other BCRL yoga protocols. However, this protocol needs to be tested in centers routinely managing BCRL.

Yoga for correction of lymphedema's impairment of gait as an adjunct to lymphatic drainage: A pilot observational study.

INTRODUCTION: Yoga used as a major component of integrative treatment protocol in 14 Indian village camps improved quality-of-life in 425 lymphatic filariasis patients. They experienced better mobility and reduced disability. This paper documents the gait abnormalities observed in lower limb lymphedema patients and the locomotor changes following integrative treatment. MATERIALS AND METHODS: Yoga postures were performed as explained by traditional yoga practice in two sessions: Before ayurvedic oil massage without compression bandages and after the massage with compression bandages. Each yoga posture lasted for 5 min and the whole session ended in 45 min. Throughout each session, we advised patients to do long, diaphragmatic breathing, concentrating on each breath. The flexion of joints was coordinated with exhalation and extension with inhalation. We educated the patients to do longer expiration than inspiration. RESULTS AND DISCUSSION: A total of 98 patients (133 limbs) attending the 6(th) month follow-up were evaluated. The most common gait abnormality was antalgic gait. Structural and functional abnormalities were observed in hip, knee and ankle joints. We found that yoga as an adjunct to other components in integrative treatment improved the gait problems. Long standing lymphedema caused altered gait and joint deformities. This was mostly due to inactivity causing muscle weakness and edema within and around the muscles. Both large and small limbs have shown significant volume reduction (P < 0.01) during follow-up after 6 months. CONCLUSION: There can be a mixed etiology for gait related problems in lymphedema patients. Further studies are recommended to understand the causes of deformities in lymphedema patients and an exact role of yoga.

Self care integrative treatment demonstrated in rural community setting improves health related quality of life of lymphatic filariasis patients in endemic villages.

This study assessed impact of community based self care integrative treatment provided through mass camps in villages of three districts of Kerala, India endemic for lymphatic filariasis (LF). Two most endemic Primary Health centres (PHCs) were selected from each of the three districts, where maximum concentration of LF patients is recorded. Fourteen one day LF camps, each attended by 30-40 patients were conducted. Trained Accredited Social Health Activists encouraged LF patients to attend camps. Skin wash and drying, care of bacterial entry points using dermatology drugs, and simple yoga and breathing exercises were demonstrated in these camps. Patients were advised to continue these self care activities daily at home for six months. The quality of life (QoL) of LF patients was determined for Indian life style domains using validated and pretested specific questionnaire (LF-specific QoL questionnaire-LFSQQ). It addressed conditions and state of individuals with reference to LF. The questionnaire had 7 domains and each domain consisted of a series of questions with likert scale (no problem, mild, moderate, severe, most severe). 446 patients attended one day camps to get training on integrative self care treatment. 425 patients (95.3%) were followed up after six months and QoL was reassessed. Each patient's QoL in mobility, self care, usual activity, pain and discomfort and social relationship significantly improved (P value <0.01). Psychological health showed no significant change. The disease burden, for the purpose of the study was measured by asking questions about history of painful redness, swelling and cellulitis of legs (filarial fever), foul smell (odor), itching (eczema/discharge from limb), wound (non healing ulcer) and weight/size of the limb. The difference in disease burden as recorded during the sixth month follow up was measured using dependent t test, reduced significantly (P value <0.01) in 409 (96.2%) patients. 103 (24.2%) patients experienced fever during follow up. Severity of inflammatory episodes reduced from severe problem to no problem, after six months of home based self care. There was significant relation between treatment regularity and QoL status (P value=0.003). The community based one day camps that trained LF patients on skin care and daily yoga and breathing practices improved QoL.

Conducting literature searches on Ayurveda in PubMed, Indian, and other databases.

BACKGROUND: Literature searches for articles on Ayurveda provide special challenges, since many of the Indian journals in which such articles appear are not indexed by current medical databases such as PubMed and Cochrane Central Register of Controlled Trials. AIM: The aim of this study was to develop a comprehensive search strategy on Ayurveda topics and to map the existing databases containing Ayurveda journal publications. METHODS: We have developed a literature search procedure that can recover the great majority of articles on any given topic associated with Ayurveda. RESULTS: Our system is formulated in an easily reproducible fashion that all researchers can use. Using the keywords related to Ayurveda and vitiligo, we searched 41 databases that may contain complementary and alternative medicine publications. Only 11 databases yielded results; PubMed contained 9 articles. Each of 14 other databases named in our search procedure averaged 23 articles. International Bibliographic Information of Dietary Supplements, for example, gave 22, of which 1 satisfied our eligibility criteria. "Annotated Bibliography of Indian Medicine" gave 47, of which 7 satisfied eligibility criteria. CONCLUSIONS: This article proposes guidelines enabling comprehensive searches to locate all types of Ayurvedic articles, not necessarily only randomized controlled trials.

A protocol for systematic reviews of Ayurveda treatments.

This protocol is intended primarily for Ayurveda doctors who wish to take up systematic reviews along with an expert who has experience in doing such reviews. We have structured this protocol by incorporating the principles of patient treatment in Ayurveda, within the Cochrane framework, using Vitiligo as a model. The treatment section provides a comprehensive list of classical medicines used in the treatment of the disease. This will help in increasing the search terms. Such a list also helps to determine the needs of individualized treatment principles used in the trial and to assess the confounding factors. The search strategy includes an extensive listing of eastern data bases and hand searching. In Ayurveda, the titles of articles are not in the Population, Intervention, Control, and Outcome (PICO) pattern and sometimes the title and methodology do not tally. Therefore, a search of all types of studies is necessary to pool all the relevant publications. A data extraction form is proposed for use in assessing the quality of Ayurvedic studies. The form provides a template for performing evidence reviews of Ayurvedic interventions.

Evidence-based approaches for the Ayurvedic traditional herbal formulations: toward an Ayurvedic CONSORT model.

This paper considers the problem of evaluating multimodal integrative medicine treatments for complex pathologic conditions. The example is given of evaluation of highly successful treatments of lymphedema using Ayurvedic and Yoga medicine practices together with modern medicine. For a framework to evaluate such a complex intervention, we base our proposal on Consolidated Standards of Reporting Trials (CONSORT) guidelines.