Mosaic NRAS Q61R mutation in a child with giant congenital melanocytic naevus, epidermal naevus syndrome and hypophosphataemic rickets.

The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy). We speculate on the apparently rare association of CSHS with CMN compared with EN. We also report the favourable outcome of this patient at the age of 8 years after extensive neonatal curettage of the giant CMN and use of vitamin D and phosphate supplementation.

Effective secondary fracture prevention: implementation of a global benchmarking of clinical quality using the IOF Capture the Fracture® Best Practice Framework tool.

UNLABELLED: Fracture Liaison Services are the best model to prevent secondary fractures. The International Osteoporosis Foundation developed a Best Practice Framework to provide a quality benchmark. After a year of implementation, we confirmed that a single framework with set criteria is able to benchmark services across healthcare systems worldwide. INTRODUCTION: Despite evidence for the clinical effectiveness of secondary fracture prevention, translation in the real-world setting remains disappointing. Where implemented, a wide variety of service models are used to deliver effective secondary fracture prevention. To support use of effective models of care across the globe, the International Osteoporosis Foundation's Capture the Fracture® programme developed a Best Practice Framework (BPF) tool of criteria and standards to provide a quality benchmark. We now report findings after the first 12 months of implementation. METHODS: A questionnaire for the BPF was created and made available to institutions on the Capture the Fracture website. Responses from institutions were used to assign gold, silver, bronze or black (insufficient) level of achievements mapped across five domains. Through an interactive process with the institution, a final score was determined and published on the Capture the Fracture website Fracture Liaison Service (FLS) map. RESULTS: Sixty hospitals across six continents submitted their questionnaires. The hospitals served populations from 20,000 to 15 million and were a mix of private and publicly funded. Each FLS managed 146 to 6200 fragility fracture patients per year with a total of 55,160 patients across all sites. Overall, 27 hospitals scored gold, 23 silver and 10 bronze. The pathway for the hip fracture patients had the highest proportion of gold grading while vertebral fracture the lowest. CONCLUSION: In the first 12 months, we have successfully tested the BPF tool in a range of health settings across the globe. Initial findings confirm a significant heterogeneity in service provision and highlight the importance of a global approach to ensure high quality secondary fracture prevention services.

Herbal creams used for atopic eczema in Birmingham, UK illegally contain potent corticosteroids.

AIMS: To determine whether "herbal creams" reported as being effective for the treatment of childhood atopic eczema contained corticosteroids. METHODS: Patients attending the paediatric dermatology clinic at Birmingham Children's Hospital, April 2001 to March 2002, and who reported using "herbal creams" with good effect for atopic eczema were asked to submit the cream for analysis. Hydrocortisone, clobetasone butyrate, betamethasone valerate, and clobetasol propionate were analysed by HPLC. RESULTS: Twenty four creams from 19 patients, median (interquartile range) age 3.82 (0.69-7.98) years were analysed. All five creams labelled Wau Wa and the two labelled Muijiza cream contained clobetasol propionate. Thirteen of 17 unnamed creams contained corticosteroids: clobetasol proprionate (n = 4), clobetasol proprionate + hydrocortisone (n = 1), betamethasone valerate (n = 2), clobetasone butyrate (n = 3), and hydrocortisone (n = 2); there was an unidentified peak in one. Further analysis suggested Wau Wa cream contained approximately 20% proprietary Dermovate Cream in a paraffin base. No parents were aware that the creams contained steroid. CONCLUSIONS: The majority of herbal creams analysed illegally contained potent or very potent topical steroids. There is an urgent need for tighter regulation of herbal creams and for increased public education about the potential dangers of alternative therapies.

Five element acupuncture: treating body, mind, and spirit.

In the history of Chinese medicine, Five Elements was one of the major doctrines influencing not only acupuncture but all aspects of society. Through the system of correspondences, Five Element acupuncture provides a unique understanding of the connections between body, mind, and spirit in health and disease. Today the practice of Five Element acupuncture in the West has been further refined and differs in substantial ways from what is known as traditional Chinese medicine. The clinical application of the Five Element system provides an understanding of how the Taoist concept of the Laws of Nature can be used in modern society.

Spatially selective auditory responses in the superior colliculus of the echolocating bat.

When a bat approaches a target, it continuously modifies its echolocation sounds and relies on incoming echo information to shape the characteristics of its subsequent sonar cries. In addition, acoustic information about the azimuth and elevation of a sonar target elicits orienting movements of the head and pinnae toward the sound source. This requires a common sensorimotor interface, where echo information is used to guide motor behaviors. Using single-unit neurophysiological methods and free-field auditory stimulation, we present data on biologically relevant specializations in the superior colliculus (SC) of the bat for orientation by sonar. In the bat's SC, two classes of spatially tuned neurons are distinguished by their sensitivity to echoes. One population shows facilitated, delay-tuned responses to pairs of sounds, simulating sonar emissions and echoes. Delay tuning, related to encoding target range, may play a role in guiding motor responses in echolocation, because the bat adjusts its emissions with changes in target distance. The delay-facilitated response depends on the direction of stimulation and on the temporal relationship between the simulated emission and echo in the sound pair, suggesting that this class of neurons represents the location of a target in three dimensions. A second population encodes the target in two dimensions, azimuth and elevation, and does not show a facilitated response to echoes delivered from any locus. Encoding of azimuth and elevation may be important for directing head aim, and this class may function in transforming auditory spatial information into signals used to guide acoustic orientation.

Characterization of ear fluid isolates of Alloiococcus otitidis from patients with recurrent otitis media.

Nineteen isolates of Alloiococcus otitidis from ear fluid samples collected by tympanostomy from patients at four geographic locations were identified by phenotypic characterization and genetic relatedness. Initial growth of A. otitidis isolates occurred after 3 days at 37 degrees C on brain heart infusion (BHI) agar with 5% rabbit blood. Heavy growth occurred in BHI broth supplemented with 0.07% lecithin and 0.5% Tween 80 after 4 days of incubation. The isolates were gram-positive cocci that divided on an irregular plane and produced metabolic lactic acid, pyrrolidonyl arylamidase, and leucine aminopeptidase. These cocci grew sparsely in 6.5% NaCl-BHI broth, were asaccharolytic on both fermentative and oxidative bases, and were cytochrome negative by the iron-porphyrin test. The cellular fatty acid profile of A. otitidis was distinguished from those of related genera and characterized by major amounts ( > or = 14%) of 16:0, 18:2, 18:1 omega 9c, and 18:0 and smaller amounts of 14:0, 16:1 omega 7c, 17:0, and 18:1 omega 7c. Fifteen isolates demonstrated > 69% relatedness by DNA-DNA hybridization. Four isolates plus the original 15 were confirmed as A. otitidis by dot blot hybridization with a digoxigenin-labeled nucleotide probe specific for this species. The intergenic space between the genes coding for the 16S and 23S rRNAs of alloiococci was amplified by PCR, analyzed by restriction fragment length polymorphism, and determined to consist of three different genetic types. Although beta-lactamase negative, A. otitidis demonstrated intermediate levels of resistance to beta-lactams, including expanded-spectrum cephalosporins, and were resistant to trimethoprim-sulfamethoxazole and erythromycin.

Discrimination of jittered sonar echoes by the echolocating bat, Eptesicus fuscus: the shape of target images in echolocation.

1. Behavioral experiments with jittering echoes examined acoustic images of sonar targets in the echolocating bat, Eptesicus fuscus, along the echo delay or target range axis. Echo phase, amplitude, bandwidth, and signal-to-noise ratio were manipulated to assess the underlying auditory processes for image formation. 2. Fine delay acuity is about 10 ns. Calibration and control procedures indicate that this represents temporal acuity rather than spectral discrimination. Jitter discrimination curves change in phase when the phase of one jittering echo is shifted by 180 degrees relative to the other, showing that echo phase is involved in delay estimation. At an echo detectability index of about 36 dB, fine acuity is 40 ns, which is approximately as predicted for the delay accuracy of an ideal receiver. 3. Compound performance curves for 0 degrees and 180 degrees phase conditions match the crosscorrelation function of the echoes. The locations of both 0 degrees and 180 degrees phase peaks in the performance curves shift along the time axis by an amount that matches neural amplitude-latency trading in Eptesicus, confirming a temporal basis for jitter discrimination.

Antigenic stimulation during ultraviolet therapy in man does not result in immunological tolerance.

People receiving therapy with either 8-methoxypsoralen plus long wavelength ultraviolet radiation (PUVA) or medium wavelength ultraviolet radiation (UVB) have been studied to see whether their unresponsiveness to the contact sensitizer dinitrochlorobenzene (DNCB) is a form of immunological tolerance. It was confirmed that both PUVA and UVB therapy impair sensitization by DNCB:4/13 PUVA-treated and 9/29 UVB-treated psoriatic subjects became sensitized by a dose of DNCB which sensitizes 100% of untreated patients. Subjects unsuccessfully sensitized during PUVA therapy could subsequently be sensitized perfectly normally. Subjects unsuccessfully sensitized during UVB therapy showed slight impairment of subsequent sensitization which was not statistically significant, and which was probably a persistent effect of UVB exposure. In conclusion, the temporary unresponsiveness seen in human subjects exposed to antigens during PUVA or UVB therapy is not due to immunological tolerance.

Recovery of cutaneous immune responsiveness after PUVA therapy.

We studied sensitization to dinitrochlorobenzene (DNCB) in psoriatic patients before, during and 2, 4, and 6 weeks after a course of photochemotherapy (PUVA). The inhibition of sensitivity observed during PUVA was completely reversed after 6 weeks. Thus the PUVA-mediated inhibition of cutaneous immune responsiveness is of short duration. However, whether there are long-term sequelae remains to be established.

Behavioral audiograms of the bullfrog (Rana catesbeiana) and the green tree frog (Hyla cinerea).

Reflex modification was used in a psychophysical technique to measure absolute auditory sensitivity of two species of anurans. Behavioral audiograms for these animals reveal that the bullfrog can detect sounds from 100 Hz to 3.2 kHz and the green tree frog from 100 Hz to 5 kHz. The shape and the sensitivity of these behavioral audiograms are similar to those of neural evoked-response audiograms of these animals. Absolute auditory sensitivity of anurans is only partially related to the spectral composition of their species-specific vocalizations.

Frequency-pulsed electron capture gas-liquid chromatographic analysis of metabolites produced by Clostridium difficile in broth enriched with amino acids.

Clostridium difficile strain CDC A-567 was cultured in Trypticase (BBL Microbiology Systems)-yeast-salt broth supplemented with 0.2% L-leucine, L-norleucine, L-isoleucine, L-tyrosine, or L-tryptophan. Four extractions were done on the spent medium, three at pH 2 and one at pH 10, using CHCL3 or ether. Derivatizations were done with trichloroethanol, heptafluorobutyric anhydride, and heptafluorobutyric anhydride-ethanol. All samples were analyzed with frequency-pulsed electron capture gas-liquid chromatography. A dedicated computer was used to assist in data analysis. C. difficile produced both short-chain and aromatic acids in Trypticase-yeast-salt broth; hydroxy acids were also detected. p-Cresol, indoleacetic acid, 4-methylthio-2-hydroxybutyric acid, and some unidentified alcohols were observed. The basic chloroform extraction contained cadaverine and putrescine. Leucine, norleucine, and isoleucine influenced the production of C5 and C6 acids and alcohols. L-Tyrosine underwent successive degradation to produce p-cresol and aromatic acids as final products. Tryptophan increased the production of indoleacetic, indolepropionic, and indolebutyric acids. Isocaproic acid was produced in relatively high concentrations regardless of medium substitution. The consistent production of iC6 under various substrate conditions indicates that the production of this compound might be consistent enough in vitro to form the basis of a rapid test for detection of C. difficile in stool specimens by frequency-pulsed electron capture gas-liquid chromatography.

Quantitation of sensitization and responsiveness to dinitrochlorobenzene in normal subjects.

Dinitrochlorobenzene (DNCB) has been used widely to assess cell-mediated immunity in man. However, previous workers have evaluated response qualitatively and subjectively. Such methods cannot elucidate the quantitative relationships between stimulus and response essential to an understanding of the functional components of the system. We have developed quantitative techniques to explore the dose-response relationships of both afferent and efferent limbs of the response, and used this method to examine changes in reactivity to DNCB after exposure to UV radiation and in people with contact allergies.

Impaired contact hypersensitivity in untreated psoriasis and the effects of photochemotherapy and dithranol/UV-B.

Cell mediated immune reactivity was studied in eighty-five psoriasis patients and twenty-five healthy controls by an improved (quantitative) method for measuring contact hypersensitivity to 2,4 dinitrochlorobenzene (DNCB). Patients were sensitized with 50 micrograms DNCB, the lowest dose found to sensitize all healthy subjects. Responses to epicutaneous challenge with a series of concentrations of DNCB were measured as volumes calculated from diameter and thickness and the various groups were compared by the differences in the log dose-response curves. Patients with untreated psoriasis were less responsive than healthy controls; responses were less still in patients treated with dithranol/UV-B/tar and they were least of all in patients treated with photochemotherapy with 8-methoxypsoralen and UV-A (PUVA), particularly in those who pigmented least. Sensitization and challenge at different stages of treatment showed that both induction and elicitation of sensitization were impaired by PUVA. The possible relationship of these changes to DNCB metabolism, Langerhans cell damage and a decrease in circulating T cells is discussed. Although the clinical significance of the findings is unknown, treatment with dithranol/UV-B/tar has proved safe over many years of use.