The filaggrin story: novel insights into skin-barrier function and disease.

Recent reports have uncovered the key role of the protein filaggrin in maintaining an effective skin barrier against the external environment. Loss-of-function mutations in the profilaggrin gene (FLG) are common and are present in up to 10% of the population. These mutations are the cause of the semi-dominant skin-scaling disorder ichthyosis vulgaris and are a major risk factor for the development of atopic dermatitis.

The impact of recent data on our understanding of the roles of COX-1 and COX-2 in gastrointestinal pathophysiology.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the world. In general, these agents have comparable efficacy and are well tolerated, although their use may be limited by their gastrointestinal (GI) tolerability. After the discovery of cyclo-oxygenase (COX)-1 and COX-2 isoforms, COX-1 was postulated to play a role in gastroprotection and COX-2 a role in inflammation and, as known, selective COX-2 inhibitors were developed in an attempt to reduce gastrointestinal toxicity while maintaining therapeutic efficacy.

Genetic diseases of junctions.

Tight junctions, gap junctions, adherens junctions, and desmosomes represent intricate structural intercellular channels and bridges that are present in several tissues, including epidermis. Clues to the important function of these units in epithelial cell biology have been gleaned from a variety of studies including naturally occurring and engineered mutations, animal models and other in vitro experiments. In this review, we focus on mutations that have been detected in human diseases.

CCL21 expression pattern of human secondary lymphoid organ stroma is conserved in inflammatory lesions with lymphoid neogenesis.

CCL21 is a homeostatic lymphoid chemokine instrumental in the recruitment and organization of T cells and dendritic cells into lymphoid T areas. In human secondary lymphoid organs (SLOs), CCL21 is produced by cells distributed throughout the T zone, whereas high endothelial venules (HEVs) lack CCL21 mRNA. A critical question remains whether the development of ectopic lymphoid tissue (ELT) in chronic inflammation recapitulates the features of SLOs.

Lymphoid tissue reactions in rheumatoid arthritis.

Frequently, the immune cell infiltrate of chronically inflamed tissues develops functional germinal centres and acquires structural features of secondary lymphoid organs. Ectopic lymphoid structures occur in peripheral tissues not only during autoimmune diseases but also in tumors (reactive infiltrate), chronic infections and graft rejection, indicating a strong link between lymphoid neogenesis and persistent antigen driven immune/inflammatory responses. There has been a renewed interest in ectopic lymphoid neogenesis, as better understanding of the mechanisms underpinning this process could contribute to elucidate the bio-pathological mechanisms involved in transition from acute-self resolving to chronic immunological aggression as well as identify novel therapeutic targets.

Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene.

Background: Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development.

The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1.

Lipoid proteinosis (OMIM 247100), also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoprotein extracellular matrix protein 1 (ECM1). ECM1 has since been shown to have several important biological functions.

Meta-analysis of genome-wide linkage studies in BMI and obesity.

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis.

Research Methods And Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry.

Unusual molecular findings in Kindler syndrome.

Kindler syndrome (KS) is a rare inherited skin disorder with blistering and poikiloderma as its main clinical features. It is caused by loss-of-function mutations in the C20orf42 (KIND1) gene which encodes kindlin-1, an actin cytoskeleton-focal contact-associated protein which is predominantly expressed in keratinocytes. We investigated the molecular basis of KS in a 16-year-old Indian boy who had additional clinical findings, including scleroatrophic changes of the hands and feet, pseudoainhum and early onset of squamous cell carcinoma on his foot.

Critical illness myopathy: further evidence from muscle-fiber excitability studies of an acquired channelopathy.

Recent studies have demonstrated acquired muscle inexcitability in critical illness myopathy (CIM) and have used direct muscle stimulation (DMS) techniques to distinguish neuropathy from myopathy as a cause of weakness in the critically ill. The mechanisms underlying weakness in CIM are incompletely understood and DMS is only semiquantitative. We report results from a series of 32 patients with CIM and demonstrate significant slowing of muscle-fiber conduction velocity (MFCV) and muscle-fiber conduction block during the acute phase of CIM, which correlates with prolonged compound muscle action potential (CMAP) duration, clinical severity, and course.

Botulinum toxin for detrusor overactivity and symptoms of overactive bladder: where we are now and where we are going.

Botulinum toxin (BTX) treatment for overactive bladder and detrusor overactivity is becoming increasingly recognized as an excellent therapeutic option for treating patients refractory to anticholinergic agents. Results from open-label studies have suggested that this therapy is effective in neurogenic and idiopathic detrusor overactivity, yet validating evidence from randomized, placebo-controlled trials has been unavailable. The exact mechanism of action of BTX in the bladder is controversial, although evidence suggests that apart from preventing the presynaptic release of acetylcholine from the parasympathetic innervation to the bladder, it might have an effect on sensory mechanisms.

Communication with older breast cancer patients.

An increasing proportion of patients with breast cancer are aged above 70 at the time of diagnosis and yet this particular age group has been underserved in terms of clinical research. Good communication between a doctor and a patient implies giving the advice and treatment most appropriate to that particular individual's needs, based upon their health and the tumor characteristics in the framework of their experience and belief system. Doctors need to be able to pick up both verbal and nonverbal cues and whenever possible to place the needs of the patient rather than her relatives as paramount.

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Using the ultrasound compression test for deep vein thrombosis will not precipitate a thromboembolic event.

A short cut review was carried out to establish whether patients with deep vein thrombosis (DVT) are at risk of embolism during ultrasound compression testing. No papers were found that directly answered the clinical question. The clinical bottom line is that currently there is no evidence to suggest that compressing vessels in order to identify a DVT could cause an embolic event.

The effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.

Background: The pathogenesis of NSAID-induced enteropathy may involve dual inhibition of the cyclooxygenase (1 and 2) and a topical effect with sequential increased intestinal permeability, development of inflammation and ulcers. It has been suggested that nitric-oxide donating drugs cause significantly less gastrointestinal injury by counteracting for NSAID-induced reductions in blood flow.

Aims: To compare the effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.

The role of fibroblasts in tissue engineering and regeneration.

Fibroblasts are mesenchymal cells that can be readily cultured in the laboratory and play a significant role in epithelial-mesenchymal interactions, secreting various growth factors and cytokines that have a direct effect on epidermal proliferation, differentiation and formation of extracellular matrix. They have been incorporated into various tissue-engineered products such as Dermagraft (Advanced BioHealing, La Jolla, CA, U.S.

Dose and Frequency of Administration of Interferon-beta Affect its Efficacy in Multiple Sclerosis.

Data reviewed in this article demonstrate that both interferon-beta-1a (IFNbeta-1a) and interferon-beta-1b (IFNbeta-1b) show a dose-response relationship in multiple sclerosis at current clinical doses. Moreover, the efficacy of these therapies is probably dependent on their frequent administration to maintain optimal levels of biological effect. These results differ from the conclusions of a recent review of data comparing two doses of IFNbeta-1a, given intramuscularly once weekly, that showed no difference in efficacy between the two doses.

Randomized double-blind trial of treatment of vitiligo: efficacy of psoralen-UV-A therapy vs Narrowband-UV-B therapy.

Objective: To compare the efficacy of oral psoralen-UV-A (PUVA) with that of narrowband-UV-B (NB-UVB) phototherapy in patients with nonsegmental vitiligo.

Design: Double-blind randomized study.

Setting: Phototherapy unit in a university hospital.

Cervical cerclage: a review.

Cervical cerclage is a common prophylactic intervention that has been used in the management of second trimester loss for several decades, yet it remains one of the more controversial surgical interventions in obstetrics. The diagnosis of cervical insufficiency is notoriously difficult to make, and is usually a retrospective one based on a history of recurrent second trimester loss (or early preterm delivery) following painless cervical dilatation in the absence of contractions, bleeding, or other causes of recurrent pregnancy loss. This article reviews the current literature regarding the efficacy of transvaginal cerclage (in both an elective and emergency setting), therapeutic cerclage (whereby a suture is inserted on the basis of ultrasound evidence of cervical shortening) and transabdominal cerclage.

Maimonides: an early but accurate view on the treatment of haemorrhoids.

Moses Maimonides was not only one of the most influential religious figures of the middle ages, but also a pioneer in a wide variety of medical practices. A brief history of his life, and what is known about his medical education, is given here. His paper on haemorrhoids is summarised, as well as a review of the current understanding of the pathogenesis, prevention and treatment of this common condition.

The teaching of surgery in the undergraduate curriculum. Part II--Importance and recommendations for change.

In the past decade, the teaching of surgery in the undergraduate curriculum has undergone considerable changes in quantity, mode and method of delivery. This is a result of the radical reforms of higher education, the health service and the undergraduate medical curriculum. The changes are complex and require us to ask the questions: how important is the teaching of surgery in the modern medical undergraduate curriculum and is there a need for change? We aim to tackle these questions and propose practical action which medical schools can take to ensure that they deliver effective surgical teaching within the modern medical curriculum and health service.

Why do orthopaedic surgeons ignore the medial patellofemoral ligament?

The medial patellofemoral ligament (MPFL) is a condensation of the medial capsule of the knee joint. In the past two decades dissection studies have shown that it extends from the superomedial border of the patella to the femoral epicondyle, at or immediately above the adductor tubercle. MRI and operative studies have revealed that it is almost invariably damaged by lateral patellofemoral dislocation.

Preoperative anthropometric analysis of the cleft child's face: a comparison between groups.

This study examines the facial surfaces of different groups of cleft babies aged up to eleven months, prior to any corrective surgery, with the aim of identifying and assessing differences in their facial morphology. Measurements of standard anthropometric landmarks were made on plaster casts taken pre-operatively of the faces of babies presenting for surgical correction of lip and palate deformities. Periorbital and mid face measurements show no difference between control and cleft groups.

An audit and comparative analysis of the kidney transplantation programme in Burma.

Background: The first renal transplant operation to be carried out by a Burmese transplant team was undertaken at the Yangon General Hospital, Burma on the 8th of May 1997. Since then 21 further kidney transplantations have been performed in hospitals in Yangon (Rangoon) and Mandalay. Burma was renamed as Myanmar in 1989.

Cold air and exercise challenge -- influence of minute ventilation.

Exercises testing and cold air challenges are frequently used to assess airway hyperresponsiveness (AHR), but different goals are set for the two tests. We, therefore, wished to determine whether cold air and exercise challenge testing yielded similar responses and if any differences were due to differences in the maximum minute ventilation achieved. Twenty asthmatic subjects each performed a cold air (CACh) and an exercise (EXCh) challenge.