New concept: "TARN friendly trauma reporting" (what radiologists say really does matter).

AIM: To establish if detailed review of trauma reports with reference to coding manual improved accuracy of ISS and to establish if demonstrated changes in coding affected performance and tariff payment. MATERIALS AND METHODS: A study was undertaken which gathered data from 6 months across the five trusts with information on imaging undertaken, mechanism of injury (MOI), Injury Severity Score (ISS), and injury descriptors was included. Patients with ISS near to a best practice tariff boundary of 9 and 16 (5-8 and 11-15) then had their imaging reviewed by the Radiology Department with direct reference to the ISS coding manual. Injuries were then re-coded and ISS recalculated. RESULTS: Over the 6-month period, 1,693 patients were admitted to the database from the five hospitals. One hundred and sixty-nine (9.9%) patients met the inclusion criteria for review. Thirty-five (20.7%) had a change in abbreviated (region specific) injury code, with 30 a change in the resultant ISS. Three had a decrease in ISS and 27 increased ISS with all 27 moving across an ISS best practice tariff and three moving across two payment tariff boundaries. With re-coding, there was a potential £15,000 of lost revenue from the major trauma centre (MTC) alone. CONCLUSION: Reporting with reference to ISS description improves the accuracy of ISS significantly. Radiologists improving the descriptions of specific injury patterns and adopting 'Trauma Audit and Research Network friendly' reporting strategies may improve data accuracy, performance, and payment of best practice tariffs to hospitals.

Alopecia areata: a review of disease pathogenesis.

BACKGROUND: Alopecia areata is a disorder that results in nonscarring hair loss. The psychological impact can be significant, leading to feelings of depression and social isolation. Objectives In this article, we seek to review the pathophysiological mechanisms proposed in recent years in a narrative fashion. METHODS: We searched MEDLINE and Scopus for articles related to alopecia areata, with a particular emphasis on its pathogenesis. RESULTS: The main theory of alopecia areata pathogenesis is that it is an autoimmune phenomenon resulting from a disruption in hair follicle immune privilege. What causes this breakdown is an issue of debate. Some believe that a stressed hair follicle environment triggers antigen presentation, while others blame a dysregulation in the central immune system entangling the follicles. Evidence for the latter theory is provided by animal studies, as well investigations around the AIRE gene. Different immune-cell lines including plasmacytoid dendritic cells, natural killer cells and T cells, along with key molecules such as interferon-γ, interleukin-15, MICA and NKG2D, have been identified as contributing to the autoimmune process. CONCLUSIONS: Alopecia areata remains incurable, although it has been studied for years. Available treatment options at best are beneficial for milder cases, and the rate of relapse is high. Understanding the exact mechanisms of hair loss in alopecia areata is therefore of utmost importance to help identify potential therapeutic targets.

Protocol guided bleeding management improves cardiac surgery patient outcomes.

BACKGROUND AND OBJECTIVES: Excessive bleeding is a risk associated with cardiac surgery. Treatment invariably requires transfusion of blood products; however, the transfusion itself may contribute to postoperative sequelae. Our objective was to analyse a quality initiative designed to provide an evidenced-based approach to bleeding management. MATERIALS AND METHODS: A retrospective analysis compared blood product transfusion and patient outcomes 15 months before and after implementation of a bleeding management protocol. The protocol incorporated point-of-care coagulation testing (POCCT) with ROTEM and Multiplate to diagnose the cause of bleeding and monitor treatment. RESULTS: Use of the protocol led to decreases in the incidence of transfusion of PRBCs (47·3% vs. 32·4%; P < 0·0001), FFP (26·9% vs. 7·3%; P < 0·0001) and platelets (36·1% vs. 13·5%; P < 0·0001). During the intra-operative period, the percentage of patients receiving cryoprecipitate increased (2·7% vs. 5·1%; P = 0·002), as did the number of units transfused (248 vs. 692; P < 0·0001). The proportion of patients who received tranexamic acid increased (13·7% to 68·2%; P < 0·0001). There were reductions in re-exploration for bleeding (5·6% vs. 3·4; P = 0·01), superficial chest wound (3·3% vs. 1·4%; P = 0·002), leg wound infection (4·6% vs. 2·0%; P < 0·0001) and a 12% reduction in mean length of stay from operation to discharge (95%: 9-16%, P < 0·0001). Acquisition cost of blood products decreased by $1 029 118 in the 15-month period with the protocol. CONCLUSIONS: The implementation of a bleeding management protocol supported by POCCT in a cardiac surgery programme was associated with significant reductions in the transfusion of allogeneic blood products, improved outcomes and reduced cost.

Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice.

BACKGROUND: Innate lymphoid cells (ILCs) play important roles in innate immunity and tissue remodeling via production of various cytokines and growth factors. Group 2 ILCs (ILC2s) were recently shown to mediate the immune pathology of asthma even without adaptive immunity. However, little is known about possible interactions between ILC2s and other immune cells. We sought to investigate the capacity of ILC2s to regulate effector functions of T cells. METHODS: We isolated ILC2s from the lungs of naïve mice. We cultured CD4(+) T cells with ILC2s in vitro and examined the functions of these cell types. The mechanisms were investigated using blocking antibodies and cells isolated from cytokine-deficient mice. For the in vivo study, we adoptively transferred ILC2s and CD4(+) T cells into Il7ra(-/-) mice and subsequently exposed the mice to ovalbumin and a cysteine protease. RESULTS: Lung ILC2s enhanced CD4(+) T-cell proliferation and promoted production of type 2 cytokines in vitro. The interaction between ILC2s and CD4(+) T cells involved costimulatory molecule OX40L and cytokine IL-4, which was mainly derived from ILC2s. Adoptive transfer of both ILC2 and CD4(+) T-cell populations, but not each population alone, into Il7ra(-/-) mice resulted in induction of a robust antigen-specific type 2 cytokine response and airway inflammation. CONCLUSION: Lung ILC2s function to promote adaptive immunity in addition to their established roles in innate immunity. This novel function of ILC2s needs to be taken into account when considering the pathophysiology of asthma and other allergic airway diseases.

Human biliary glycoprotein gene: characterization of a family of novel alternatively spliced RNAs and their expressed proteins.

Eight different human biliary glycoprotein (BGP) isoantigens, structurally related members of the carcinoembryonic antigen family, CD66/67 family, and immunoglobulin superfamily, are derived by alternative splicing from a single genomic transcription unit. Novel BGP isoforms have been identified by polymerase chain reaction amplification and by DNA sequencing of amplified cDNA segments. In addition to verifying previously documented BGPs, we describe four new forms, two of which have unusual nonimmunoglobulin exons contributed by inverted Alu repeats. Determination of the genomic DNA sequence encompassing most of the known extracellular and intracellular domains demonstrates that the translatable Alu-like sequences are encoded in bona fide exons. The third novel BGP isoform contains none of the extracellular disulfide-linked immunoglobulin-like domains typical of these molecules but retains N-terminal and intracellular domains, suggesting distinct functions for N-terminal versus other disulfide-linked domains. cDNAs coding for each identified isoform have been transfected into COS7 monkey cells, and the resulting polypeptides are heavily N glycosylated but can be deglycosylated to their expected primary sizes. Many of these deglycosylated forms can be correlated with unique patterns of BGP expression in different cell lines, while in granulocytes, some previously undescribed or alternatively modified forms may predominate. The BGP family represents a potentially large but unknown source of functional diversity among cells of epithelial and hematopoietic origin. The availability of a defined set of expressed of BGP cDNAs should permit critical definition of their function.

Hematopoietic stem cell mobilization with intravenous melphalan and G-CSF in patients with chemoresponsive multiple myeloma: report of a phase II trial.

Multiple myeloma (MM) is an incurable hematologic malignancy for which autologous hematopoietic stem cell transplantation (HCT) is a standard therapy. The optimal method of stem cell mobilization is not defined. We evaluated intravenous melphalan (60 mg/m2), the most effective agent for MM, and G-CSF (10 microg/kg/day) for mobilization. End points were safety, adequacy of CD34+ collections, MM response, and contamination of stem cell components (SCC). In total, 32 patients were mobilized. There were no deaths or significant bleeding episodes; 14 patients (44%) required hospitalization for neutropenic fever. Median days of grade 3 or 4 neutropenia or thrombocytopenia were 7 (2-20) and 8 (3-17). Median mobilization days, CD34+ cells/kg and total leukaphereses were 16 (12-30), 12.1 million (2.6-52.8), and 2 (1-5) respectively. Four patients (12.5 %) failed to achieve the target of 4 million CD34+ cells/kg in five leukaphereses. Reduction in myeloma was seen in 11 patients (34%) with 3 (9%) achieving complete response; 15 (47%) maintained prior responses. Estimated MM contamination per SCC (N=48) was 0.0009% (range 0-0.1) and 0.21 x 10(4) cells per kg (range 0-41.2). Increased contamination was associated with increased patient age. This strategy for mobilization is feasible, frequently requires hospitalization and transfusion, and controls disease in most patients.

A single parameter, oxygenated hemoglobin, can be used to quantify experimental irritant-induced inflammation.

To quantify the dose-response relation of irritant-induced erythema, we examined inflammation in human skin after application of an irritant, using perpendicular polarized photography and diffuse reflectance spectroscopy as compared to clinical visual scoring. The ventral forearms of 11 healthy subjects were patch-tested for 24 h under occlusion in finn chambers with five concentrations of the irritant sodium lauryl sulfate. The tested sites and three control sites were evaluated clinically for erythema at 24, 48, and 72 h after occlusion, photographed using standard and perpendicular polarized photography, and measured by diffuse reflectance spectroscopy. All photographs were evaluated for erythema by three investigators. Diffuse reflectance spectra were analyzed, and changes in apparent oxyhemoglobin and deoxyhemoglobin concentrations were estimated. Clinical and photographic assessments of erythema yielded similar linear dose-response relations. A linear dose-response relation, with no minimum threshold, also was obtained for changes in the apparent oxyhemoglobin concentration with increasing irritant dose, whereas the apparent deoxyhemoglobin concentrations were unchanged with increasing dose. These results show that diffuse reflectance spectroscopy permits the characterization of irritant-induced inflammation in terms of a single parameter, the apparent concentration of oxyhemoglobin, and that irritant-induced inflammation primarily involves the capillaries and the superficial arterial plexus.

A useful modification of cDNA that enhances purification of recombinant protein.

With the availability of new and improved DNA vectors for producing large amounts of proteins by recombinant DNA technology, there is a growing need for efficient recovery of the desired protein, often from liters of culture medium. In this report, we describe a relatively simple modification of recombinant cDNA, that, in combination with immobilized metal affinity chromatography, is a rapid, inexpensive and highly effective method for enriching or purifying a desired protein.

The major secreted product of the whipworm, Trichuris, is a pore-forming protein.

The data presented here describe the first unequivocable characterization of a pore-forming protein in any helminth parasite. The excretory/secretory (E/S) material of the human whipworm T. trichiura contains a highly abundant protein of molecular mass 47 kDa (TT47); the murine model parasite, T. muris, contains a similarly abundant protein of molecular mass 43 kDa (TM43). When purified to homogeneity, these proteins induce ion-conducting pores in lipid bilayers. Antibodies raised against TM43 abolish channel activity. Pore formation in epithelial cell membranes may facilitate invasion of the host gut by Trichuris and enable the parasite to maintain its syncytial environment in the caecal epithelium. The observation that this activity may be inhibited by antibody opens a possible avenue for drug and vaccine development.

Molecular and functional characterization of a recombinant protein of Trichuris trichiura.

The pore-forming protein of the human whipworm, Trichuris trichiura, has been postulated to facilitate invasion of the host gut and enable the parasite to maintain its syncytial environment. The data presented here describe the first, to our knowledge, molecular characterization of a pore-forming protein in any helminth and provide a unique demonstration of the functional interaction between a parasite antigen and host molecules. Immunological screening of a T. trichiura cDNA library with T. trichiura infection sera identified a clone of 1.4 kB, the cDNA consisting of 1495 base pairs encoding a protein of 50 kDa. The sequence has a highly repetitive nature containing nine four-disulphide-bonded core domains. Structural prediction analyses reveals an amphipathic nature. TT50 induced pore formation in bilayers in a manner identical to that of the native protein. IgG antibody isolated from T. trichiura infection serum was observed to abolish channel activity.

Effects of sulfonylureas on the actions of insulin and insulin-mimickers: potentiation of stimulated hexose transport in adipocytes.

The sulfonylurea glyburide, a 'second-generation' oral hypoglycemic compound, was studied in vitro in order to determine its cellular mechanism of action in adipocytes prepared from cultured rat epididymal fat tissue. Glyburide treatment (1 microgram/ml) for 20 h did not alter insulin receptor number or affinity, or down-regulation by insulin. Biologic responses of these cells were measured in the presence of insulin or the oxidants Vitamin K5 and H2O2, which have insulin-like activity, but do not act through the binding portion of the receptor. 2-Deoxyglucose uptake was not significantly changed by exposure to glyburide alone. However, the sulfonylurea increased the insulin-stimulated or insulin-mimicker-activated uptake by approximately 30%. Insulin-stimulated glucose oxidation was also potentiated when glucose transport was rate limiting for metabolism. These findings extend our earlier observation that in adipose tissue the primary cellular mechanism of action of sulfonylureas is to potentiate insulin-stimulated hexose transport, and that this process may account for their hypoglycemic activity.

Dual activation of adenosine A1 and A3 receptors mediates preconditioning of isolated cardiac myocytes.

Ischemic preconditioning reduces post-ischemic myocardial injury by activating myocellular adenosine A1 receptors. Adenosine A3 receptors have also been implicated but there is no evidence for A3 receptors in cardiac myocytes. The aim of this study was to develop a model of preconditioning in isolated cardiac myocytes to evaluate the role of the adenosine A1 and A3 receptors in preconditioning-induced protection from ischemic injury. Reverse transcription polymerase chain reaction (PCR) was also employed to establish the presence of adenosine A3 receptors in these cells. In the preconditioning studies, ischemic injury was simulated by exposing isolated rabbit myocytes (placed in the cell chamber and paced at l Hz) to buffer containing (in mM) 2'-deoxyglucose (20), NaCN (1), Na (+)-lactate (20), KCl (10) at pH 6.6 (37 degrees C). Changes of diastolic and systolic cell length were monitored with an optical-video edge imaging system, and hypercontracture was assessed as an index of irreversible cell injury. Preconditioning (2 min brief ischemia and 15 min reperfusion) significantly reduced cell injury resulting from a subsequent prolonged ischemia (10 min) and reperfusion (15 min), as indicated by a reduction in the incidence of cell hypercontracture from 67 +/- 6% to 29 +/- 5% (P < 0.001). Preconditioning-induced cardioprotection was only partially blocked by a maximally effective concentration (100 nM) of the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (cell hypercontracture = 43 +/- 3%, P < 0.05 vs. control) but completely blocked by either the combination of DPCPX (100 nM) with the adenosine A1/A3 receptor antagonist DPCPX +8-(4-carboxyethylphenyl)-1,3-dipropylxanthine (BWA1433; 1 microM) or the non-selective adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8-SPT; 100 microM) (cell hypercontracture = 64 +/- 4%, 59 +/- 5%, respectively; P = NS vs. control). In non-hypercontractured myocytes, preconditioning also substantially enhanced the recovery of the contractile amplitude and, similarly, this effect was only partially blocked by DPCPX but completely blocked by either the combination of DPCPX with BWA1433, or 8-SPT. These studies suggest that preconditioning protects isolated cardiac myocytes from ischemic injury independent of other cell types, and that maximal preconditioning-induced cardioprotection requires activation of both adenosine A1 and A3 receptors. Reverse transcription-PCR using primers for the rabbit receptor provide evidence for the presence of adenosine A3 receptors in these cells.

The antipruritic effect of 5% doxepin cream in patients with eczematous dermatitis. Doxepin Study Group.

BACKGROUND AND DESIGN: Eczematous dermatitis is commonly characterized by intense pruritus. Current treatment modalities for this condition, regardless of its cause, are primarily directed at blunting the cutaneous inflammatory response and thereby providing relief of pruritus. To expand on our previous findings in atopic dermatitis, the present multicenter double-blind trial was conducted to evaluate the safety and antipruritic efficacy of 5% doxepin hydrochloride cream in patients with lichen simplex chronicus (n = 136), nummular eczema (n = 87), or contact dermatitis (n = 86). A total of 309 patients with moderate to severe pruritus were randomly assigned to apply either doxepin cream (n = 154) or vehicle cream (n = 155) to eczematous areas four times per day for a period of 7 days. Efficacy was assessed using a pruritus severity rating scale, a Physician's Global Evaluation for pruritus relief, and a Visual Analogue Scale for pruritus relief. RESULTS: Twenty-four hours after initiation of treatment, and continuing throughout the remainder of the study, patients treated with doxepin cream experienced significantly greater pruritus relief than did vehicle-treated patients as determined by all efficacy parameters (P < .002). Sixty percent of doxepin-treated patients experienced pruritus relief within 24 hours. The response rate increased to 84% by conclusion of the study. As judged by significant changes (P < or = .05) occurring in at least one assessment of efficacy, doxepin cream provided pruritus relief in all forms of eczematous dermatitis that were examined. The study medication was well tolerated. The two most common adverse effects, stinging at the site of application and drowsiness, were usually transient and mild to moderate in severity. CONCLUSION: Topical application of doxepin provides significant antipruritic activity with a favorable safety profile, suggesting a role for doxepin cream in the symptomatic treatment of pruritus associated with eczematous dermatitis.

The future of Medicare. Their plans, your practice, Medicare reform, and how it will affect the practice of dermatology.

The future of Medicare will be determined by patient demands, government action, and physician reactions. The federal government has always had the authority to design the Medicare program, but in the past physicians have had control over its implementation. While it is impossible to accurately predict the future, past and present reform efforts shed considerable light on directions the Medicare program will take and the impact Medicare will have on the science and practice of dermatology. It is important to understand these historic trends and the changes they foster to position ourselves to avoid threats and benefit from opportunities that will arise for the science and practice of dermatology.

Treatment of alopecia areata with dinitrochlorobenzene.

Persistent refractory alopecia areata in 26 patients was treated topically with dinitrochlorobenzene (DNCB). Sixteen patients have had excellent regrowth of hair; three patients could either not be initially sensitized or an adequate allergic contact dermatitis on the scalp did not develop. Two patients discontinued therapy within two months; hair growth did not develop in five patients despite an adequate trial. Augmentation of the T-lymphocyte pool via DNCB sensitization and challenge may become effective therapy for some patients with severe alopecia areata.

Dyskeratosis congenita in a girl simulating chronic graft-vs-host disease.

Dyskeratosis congenita (DCG) is a rare genodermatosis characterized primarily by reticular hyperpigmentation of the skin, dystrophy of the nails, and leukoplakia. It is frequently associated with Fanconi-type pancytopenia. Although DCG has a male predisposition, it has been reported in several female patients. We encountered a case of DCG occurring in a girl whose clinical features simulated chronic graft-vs-host disease (GVHD). Because DCG and chronic GVHD share several clinical and histologic features, physicians should always examine a patient for possible DCG whenever a diagnosis of chronic GVHD is considered. In addition, the similar manifestations of the two disorders suggest a similar pathogenesis on a cellular level in the immunologic system.

American Academy of Dermatology guidelines of care. Development and process.

Medical practice guidelines are being developed at an accelerating pace, in all areas of medicine, for a wide range of uses. The field of practice guideline development is not new, but a number of important economic and health care issues have renewed interest in their creation. In 1987, in response to many of these issues, the American Academy of Dermatology took a leadership role and began a process designed to develop guidelines for disease entities treated by dermatologists. The result was a set of clinical practice guidelines and the most comprehensive dermatology guideline development processes to date. Herein we describe the guideline development process in its current, refined form and discuss some of its unique and important characteristics. New applications of guidelines, outside of clinical practice improvement, have made their development controversial. Nevertheless, it is important for the medical profession to lead in this effort, and the American Academy of Dermatology continues to explore ways to refine and update its guidelines to reflect the latest medical science and technology.

Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of photodamaged skin. A double-blind vehicle-controlled clinical trial.

OBJECTIVE: To evaluate the efficacy and tolerability of 2 widely used topical alpha-hydroxy acids at low concentrations, 8% glycolic acid and 8% lactic (L-isoform) acid creams, in the treatment of photodamaged skin. DESIGN: A single-center, 22-week, double-blind, vehicle-controlled, randomized clinical trial assessed the overall severity of photodamage on the faces and forearms of volunteers, based on 7 individual clinical components of cutaneous photodamage. SETTING: The study was performed in an outpatient clinical research unit at the Massachusetts General Hospital, Boston. PATIENTS: Seventy-four women, aged 40 to 70 years, with moderately severe photodamaged facial skin were enrolled in the study. One subject withdrew from the study early because of skin irritation, and 6 subjects withdrew from the study for personal reasons. INTERVENTIONS: Glycolic acid, L-lactic acid, or vehicle creams were applied twice daily to the face and outer aspect of the forearms. MAIN OUTCOME MEASURES: Improvement in alpha-hydroxy acid-treated photodamaged skin as determined by patient self-assessments and physician evaluations of efficacy and irritancy. RESULTS: The percentage of patients using either 8% glycolic acid or 8% L-lactic acid creams on the face achieving at least 1 grade of improvement (using a scale from 0 through 9) in overall severity of photodamage was significantly greater than with the vehicle cream (76% glycolic acid, 71% lactic acid, and 40% vehicle; P < .05). On the forearms, after 22 weeks, treatment with glycolic acid cream was superior to the vehicle in improving the overall severity of photodamage and sallowness (P < .05). L-Lactic acid cream was significantly superior to the vehicle in reducing the overall severity of photodamage (P < .05), mottled hyperpigmentation (P < .05), sallowness (P < .05), and roughness on the forearms (P < .05) at week 22. CONCLUSIONS: Topical 8% glycolic acid and 8% L-lactic acid creams are modestly useful in ameliorating some of the signs of chronic cutaneous photodamage. These agents are well tolerated and available without prescription.

The safety and efficacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis.

OBJECTIVE: To determine the safety and efficacy of topically applied tazarotene gel in the treatment of mild to moderate psoriatic plaques. DESIGN: Two multicenter, double-blind, randomized studies of 6- and 8-week duration, with an 8-week follow-up in the second study. SETTING: Medical center outpatient dermatology services. PARTICIPANTS: One hundred fifty-three adults with 2 bilateral target plaques on the trunk, legs, or arms. INTERVENTIONS: Vehicle gel or 0.01% and 0.05% tazarotene gel administered twice daily to 45 patients (study A), or 0.05% and 0.1% tazarotene gel administered either once or twice daily to 108 patients (study B). MAIN OUTCOME MEASURES: Treatment success and plaque elevation, scaling, and erythema vs time. RESULTS: The 0.01% tazarotene gel showed minimal efficacy. Applications of 0.05% and 0.1% tazarotene gels administered once or twice daily, resulted in significant improvements in plaque elevation, scaling, erythema, and overall clinical severity as early as 1 week. Treatment success rates (defined as > 75% improvement from baseline) were 45% with 0.05% tazarotene gel vs 13% with vehicle gel after 6 weeks of treatment (P < .05; study A) and ranged from 48% to 63% with the various tazarotene treatment regimens after 8 weeks of treatment (study B). These improvements were evident at the 8-week follow-up. Treatment-related adverse effects were generally limited to mild or moderate local irritation and were less frequent with the treatment regimen administered once daily. CONCLUSION: The 0.05% and 0.1% tazarotene gels demonstrated significant efficacy in the treatment of mild to moderate psoriatic plaques that persisted after cessation of treatment.

Effect of amygdalectomy on habituation and CER in rats.

Amygdalectomized, Sham operates and unoperated rats received 20 habituation trials followed by CER training during which the habituation stimulus was made a CS for 10 CS-UCS pairings. Although no reliable differences in rate of magnitude of habituation as measured by suppression ratio magnitudes and ITI durations were apparent between any groups, these same measures indicated that substantial deficits in conditioned suppression were produced by bilateral amygdalectomy. In addition the lesion produced a reliable deficit in unconditioned suppression and a slight but reliable reduction in the number of ccs of water consumed in a 24 hour period. These results are more consistent with the hypothesis that amygdalectomy interferes with the arousal of fear than with the proposals that this lesion produces deficits in habituation or in response inhibition.