Rapid rest/stress regadenoson ungated perfusion CMR for detection of coronary artery disease in patients with atrial fibrillation.

Cardiovascular magnetic resonance (CMR) perfusion has been established as a useful imaging modality for the detection of coronary artery disease (CAD). However, there are several limitations when applying standard, ECG-gated stress/rest perfusion CMR to patients with atrial fibrillation (AF). In this study we investigate an approach with no ECG gating and a rapid rest/stress perfusion protocol to determine its accuracy for detection of CAD in patients with AF. 26 patients with AF underwent a rapid rest/regadenoson stress CMR perfusion imaging protocol, and all patients had X-ray coronary angiography. An ungated radial myocardial perfusion sequence was used. Imaging protocol included: rest perfusion image acquisition, followed nearly immediately by administration of regadenoson to induce hyperemia, 60 s wait, and stress image acquisition. CMR perfusion images were interpreted by three blinded readers as normal or abnormal. Diagnostic accuracy was evaluated by comparison to X-ray angiography. 21 of the CMR rest/stress perfusion scans were negative, and 5 were positive by angiography criteria. Majority results of the ungated datasets from all of the readers showed a sensitivity, specificity and accuracy of 80, 100 and 96%, respectively, for detection of CAD. An ungated, rapid rest/stress regadenoson perfusion CMR protocol appears to be useful for the diagnosis of obstructive CAD in patients with AF.

The role of radiation treatment in the management of eosinophilic pustular folliculitis.

We are reporting a rare chronic irritating, incapacitating skin condition that can be controlled by radiation treatment. We would like to add this case to the world literature.

Obesity and body fat distribution in the New Zealand population.

AIMS: To report the prevalence of obesity and body fat distribution in the New Zealand population and to determine if there is a trend to increasing obesity and changes in body fat distribution. METHODS: Body weight, height, two skinfolds (triceps and subscapular), and waist and hip circumferences were measured on 4,420 New Zealanders as part of the 1997 National Nutrition Survey (NNS97). These results are compared with data from the 1977 National Heart Foundation Survey (n=1,800) and the 1989 Life in New Zealand Survey (LINZ89) (n=3,300). RESULTS: 35% of the population (40.4% males, 30.1% females) were classified as overweight and a further 17% as obese (14.7% males, 19.2% females) in NNS97 compared to 32% overweight and 11% obese in LINZ89. Body weight and body mass index have increased in the last two decades. In addition, there has been an increasing trend towards central obesity as estimated by waist to hip ratio and subscapular to triceps ratio. CONCLUSIONS: The increase in body weight, obesity, central obesity, and the proportion of the population likely to exhibit health risk indicators presents an increasing health problem in New Zealand.

Force production in the rugby union scrum.

In this study, we examined the relationship between anthropometric, strength and power characteristics of rugby forwards, their body position when scrummaging, and their ability to apply force when scrummaging. Force applied to an instrumented scrum machine was measured for 56 players, both individually and as scrum packs. Measurements of body position for individuals were made by digitizing videotape records of the trials. Forty players subsequently had their anthropometry assessed and completed several strength and power tests. Body mass, each component of somatotype, maximal anaerobic power developed on a cycle ergometer, and isokinetic knee extension strength correlated significantly with individual scrummaging force. A regression model (P < 0.001) including body mass, mesomorphy, maximal anaerobic power and hip angle while in the scrummaging position accounted for 45% of the variance in individual scrummaging force. The packs that produced the largest scrummaging forces were, in general, characterized by a greater pack force to sum of individual force ratio than the packs producing lower forces. Our results emphasize the need for a scrum pack to develop technique and coordination as a unit to maximize scrummaging force.

Photofrin photodynamic therapy for treatment of AIDS-related cutaneous Kaposi's sarcoma.

OBJECTIVE: Kaposi's sarcoma, the most common malignancy in AIDS patients, often presents with painful cutaneous lesions that are difficult to treat effectively despite a wide variety of therapeutic approaches. We used photodynamic therapy in an attempt to provide effective palliative treatment for this disease. METHODS: Photodynamic therapy utilizes the activation by light of a photosensitizing drug that preferentially accumulates in tumor tissue such as Kaposi's sarcoma. We enrolled 25 patients who received 1.0 mg/kg of Photofrin 48 h before exposure to 100-400 J/cm2 of 630 nm light. RESULTS: Of the 348 lesions treated, 289 were evaluable: 32.5% had complete clinical response, 63.3% had partial clinical response and 4.2% were clinical failures. There was a strong correlation between response and light dose: 54% of lesions achieved a complete clinical response at optimum light dose (> 250 J/cm2). There was no correlation of response with CD4 cell count nor was there a change in CD4 cell count post-treatment. At 400 J/cm2 full field scabbing and necrosis occurred in 90% of the treated fields. Thus, the maximum tolerated dose was determined to be 300 J/cm2. At light doses of 250 J/cm2 and below the toxicities were limited to erythema and edema in the treatment field. Forty-three biopsies were taken 0.5 h to 4 months post-treatment. These showed little change in the B and T cell infiltrates identified. Kaposi's sarcoma cells disappeared post-treatment in certain lesions. CONCLUSION: Photofrin is effective palliative treatment for HIV-associated Kaposi's sarcoma.

The nature and circumstances of tackle injuries in rugby union.

This study describes the nature and circumstances of injury occurring in rugby union tackles (33% of 569 injury events) using data from the Rugby Injury and Performance Project (RIPP) and provides supplementary information on the nature of tackles involving injury from analysis of videotape of tackle injury events. The most common tackle injuries in the RIPP data were sprains/strains (41%) followed by haematomas/bruising (26%). The most frequently injured body sites were the head/neck/face (22%) and the knee (17%). The ball carrier and tackler were injured in tackles in similar proportions in both RIPP and New Zealand Rugby Football Union (NZRFU) video tackle incidents. Both players were most often in motion in the tackle at the time of injury with approximately 70% of injuries occurring when the injured player was running or diving/falling to the ground. Tackle injury was most often caused by impact with another player rather than impact with the ground. The use of protective padding may reduce the risk of impact injury. The majority of tackle injuries were associated with stopping tackles to the trunk which were from the front (63%), rather than from the side or behind. Thus consideration should be given to coaching strategies or to rule changes which reduce the likelihood or prohibit front-on tackles.

The role of agouti-related protein in regulating body weight.

Defects in signaling by leptin, a hormone produced primarily by adipose tissue that informs the brain of the body's energy reserves, result in obesity in mice and humans. However, the majority of obese humans do not have abnormalities in leptin or its receptor but instead exhibit leptin resistance that could result from defects in downstream mediators of leptin action. Recently, two potential downstream mediators, agouti-related protein (Agrp) and its receptor, the melanocortin-4 receptor (Mc4r), have been identified. Agrp and Mc4r are excellent candidates for human disorders of body weight regulation and represent promising targets for pharmacological intervention in the treatment of these disorders.

Physiological and anatomical circuitry between Agouti-related protein and leptin signaling.

Agouti-related protein (AGRP) is an orexigenic neuropeptide that acts via central melanocortin receptors, and whose messenger RNA (mRNA) levels are elevated in leptin-deficient mice. Fasting associated with a decline in circulating leptin normally causes a 15-fold elevation of hypothalamic Agrp mRNA levels but has no effect in leptin-deficient mice. Chronic hyperleptinemia associated with the tubby and Cpe(fat) mutations has no effect on Agrp mRNA levels, but short term leptin administration causes a 17% reduction of Agrp mRNA levels in nonmutant mice and a 700% reduction in leptin-deficient mice. In young nonobese animals, melanocortin receptor blockade associated with the Ay mutation causes complete resistance to leptin-induced weight loss. Dual in situ hybridization reveals that Agrp-expressing neurons in the medial portion of the arcuate nucleus constitute a subpopulation different from Pomc-expressing neurons, and that a significant proportion of Agrp-expressing neurons (10-25%) coexpresses the leptin receptor, Lepr-b. Immunocytochemistry confirms distinct locations of AGRP- and POMC-expressing cell bodies, but reveals an overlapping distribution of their terminal fields in the arcuate nucleus, the paraventricular hypothalamus, and the dorsomedial hypothalamus. These results suggest that in the fed state, AGRP is normally suppressed by leptin, and that release of this suppression during fasting leads to increased ingestive behavior.

Molecular pharmacology of Agouti protein in vitro and in vivo.

Agouti protein and Agouti-related protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxyterminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.

Photodynamic therapy for the treatment of nonmelanomatous cutaneous malignancies.

Photodynamic therapy (PDT) is a modality whose concept is not new to dermatologists. PDT has gained regulatory approval in the United States for the treatment of esophageal and lung malignancies. The field has grown over the last decade, and now phase II/III clinical trials using second generation drugs for the treatment of nonmelanoma skin cancers, palliation of metastases to the skin, and Kaposi's sarcomas have been introduced. These new sensitizers tend to reduce the one side effect of PDT, namely persistent generalized cutaneous photosensitivity. PDT has shown efficacy in (1) patients who have failed conventional therapies, and for whom local treatment options are limited (2) patients in whom surgery would result in cosmetic disfigurement, and (3) patients prone to developing multiple lesions as in Gorlins syndrome. Dosimetry is based on well-understood treatment matrices that have optimized light delivery with known photosensitizer administrations. The advantages of PDT for cutaneous malignancies include the ability to treat numerous lesions in one setting, in a noninvasive manner without any apparent concern for the development of carcinogenicity.

Protective headgear in rugby union.

This article interprets the studies performed on the use of headgear in sport which relate to rugby. The design and testing of helmets and their effective use for protection in sport in general appears to be well documented. This is not the case for the use of protective headgear in rugby. Nevertheless, some conclusions and recommendations are warranted. Protection from the range of impacts that can arise through participation in contact sports does not seem to be attainable by using protective helmets or protective rugby headgear. However, the use of headgear is recommended for protection against lacerations and abrasions and to provide a limited protection from injury caused by impact. Referees should discourage the use of protective headgear, to manipulate an opponent by using the rules to eliminate such behaviour. Coaches, athletes and administrators must be committed to the practice of safe performance skills, for example, by not using the head as an implement and not targeting the headgear of the opposing player. Further research is required to determine the effectiveness of protective headgear in reducing the risk of injury in rugby, whether the use of headgear places a player at a greater risk of injury through altered behaviour and the reasons why players currently choose not to wear headgear.

Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo.

Agouti protein and Agouti-related protein (Agrp) are paracrine-signaling molecules that normally regulate pigmentation and body weight, respectively. These proteins antagonize the effects of alpha-melanocyte-stimulating hormone (alpha-MSH) and other melanocortins, and several alternatives have been proposed to explain their biochemical mechanisms of action. We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity. In melanophores, Agouti protein has no effect in the absence of alpha-MSH, but its action cannot be explained solely by inhibition of alpha-MSH binding. In 293T cells, expression of the Mc1r confers a specific, high-affinity binding site for HA-Agouti. Binding is inhibited by alpha-MSH, or by Agrp, which indicates that alpha-MSH and Agouti protein bind in a mutually exclusive way to the Mc1r, and that the similarity between Agouti protein and Agrp includes their binding sites. The effects of Agouti and the Mc1r in vivo have been examined in a sensitized background provided by the chinchilla (Tyrc-ch) mutation, which uncovers a phenotypic difference between overexpression of Agouti in lethal yellow (Ay/a) mice and loss of Mc1r function in recessive yellow (Mc1re/Mc1re) mice. Double and triple mutant studies indicate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. These results resolve questions regarding the biochemical mechanism of Agouti protein action, and provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein or Agrp function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.

Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.

Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation. Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.

Effects of recombinant agouti-signaling protein on melanocortin action.

Mouse agouti protein is a paracrine signaling molecule that has previously been demonstrated to be an antagonist of melanocortin action at several cloned rodent and human melanocortin receptors. In this study we report the effects of agouti-signaling protein (ASIP), the human homolog of mouse agouti, on the action of alpha-MSH or ACTH at the five known human melanocortin receptor subtypes (hMCR 1-5). When stably expressed in L cells (hMC1R, hMC3R, hMC4R, hMC5R) or in the adrenocortical cell line OS3 (hMC1R, hMC2R, hMC4R), purified recombinant ASIP inhibits the generation of cAMP stimulated by alpha-MSH (hMC1R, hMC3R, hMC4R, hMC5R) or by ACTH (hMC2R). However, dose-response and Schild analysis indicated that the degree of ASIP inhibition varied significantly among the receptor subtypes; ASIP is a potent inhibitor of the hMC1R, hMC2R, and hMC4R, but has relatively weak effects at the hMC3R and hMC5R. These analyses also indicated that the apparent mechanism of ASIP antagonism varied among receptor subtypes, with characteristics consistent with competitive antagonism observed only at the hMC1R, and more complex behavior observed at the other receptors. ASIP inhibition at these latter receptors, nonetheless, can be classified as surmountable (hMC3R, hMC4R and hMC5R) or nonsurmountable (hMC2R). Recombinant ASIP also inhibited binding of radiolabeled melanocortins, [125I-Nle4, D-Phe7] alpha-MSH and [125I-Phe2, Nle4]ACTH 1-24, to the hMCR 1-5 receptors, with a relative efficacy that paralleled the ability of ASIP to inhibit cAMP accumulation at the hMC1R, hMC2R, hMC3R, and hMC4R. These results provide new insight into the biochemical mechanism of ASIP action and suggest that ASIP may play an important role in modulating melanocortin signaling in humans.

Trampoline injury in New Zealand: emergency care.

OBJECTIVE: To examine trampoline related injuries resulting in emergency department attendance. METHODS: Cases were identified by searching free text descriptions of the circumstances of injury contained in the records of the emergency department of a large city hospital. RESULTS: 114 cases were identified for a 12 month period, giving an incidence rate of 108 per 100,000 population per year (95% confidence interval = 89 to 129) compared with 9.3 hospital admissions per 100,000 population per year (95% confidence interval = 8.3 to 10.4) for a corresponding period reported in earlier research from New Zealand. This suggested that for every one hospital admission there are approximately 12 emergency department attendances. Of the cases, 95% were aged less than 20 years. As for the earlier research, falls from the trampoline to the surrounding surface were the commonest cause of injury. In the present study, sprains and strains were the commonest type of injury (40%), and the body site most frequently involved was the lower limb (46%). CONCLUSIONS: The findings support the conclusion from earlier research that although existing trampoline standards address many of the issues relating to trampoline safety, the need remains for measures to reduce the impact of falls from the trampoline to the ground surface and to prohibit the use of trampolines as unsupervised "play equipment".

Susceptibility to amiodarone-induced pulmonary toxicity: relationship to the uptake of amiodarone by isolated lung cells.

In previous studies, we showed that Fischer rats fed 175 mg/kg of amiodarone accumulated large amounts of drug and metabolite in the lung and developed pulmonary toxicity, whereas Wistar rats fed the same drug dose had significantly less amiodarone in the lung and did not develop pulmonary inflammation. The present study was designed to determine whether this difference in susceptibility between the strains was related to differences in uptake of amiodarone by lung cells. We found that isolated mixed lung cells of Fischer rats sequester significantly more drug than cells from Wistar rats. This difference in uptake cannot be due to drug metabolism because the lung is not capable of metabolizing amiodarone. We also found that the alveolar macrophage is one of the cell types in the mixed cell population that is partially responsible for the difference in drug uptake and that fibroblasts and type II pneumocytes are not involved. In addition, despite the fact that there was no difference in drug uptake, we found that fibroblasts isolated from Fischer rats were more susceptible to amiodarone-induced cytotoxicity than were Wistar fibroblasts. We conclude that genetic differences in lung drug sequestration and possibly the sensitivity to cytotoxicity may explain differences in susceptibility to amiodarone-induced pulmonary toxicity.

The New Zealand rugby injury and performance project. III. Anthropometric and physical performance characteristics of players.

OBJECTIVE: To investigate the anthropometric and physical performance characteristics of New Zealand rugby players of different ages and both sexes. METHODS: 356 rugby players (264 male, 92 female) took part in the study during a single season. Playing grade ranged from schoolboys and schoolgirls to senior men and women. Assessment of height, weight, neck circumference, and somatotype was performed before the competitive rugby season. A battery of six physical performance assessments was completed after the anthropometry. Analysis of variance was used to examine differences in these variables between field positions and grades. RESULTS: Significant differences between forwards and backs on anthropometric and physical performance variables were apparent at all grades assessed. In terms of anthropometric characteristics, forwards of a given grade were generally taller, possessed greater body mass, and were more endomorphic and less ectomorphic than backs of the same grade. The backs tended to perform better on physical performance measures than forwards, being more aerobically fit, faster, more agile, and possessing a higher degree of muscular endurance. Differences in anthropometry and physical performance attributes were also apparent between players from the various grades. The players at higher levels were generally larger, and performed better on tests of physical performance than the players at lower levels. These differences were found in both sexes. CONCLUSIONS: The greater body mass of the forwards allows them to obtain greater momentum than the backs when sprinting. The ability to obtain greater momentum is important in the body contact phases of the game. Forwards may compromise their aerobic fitness and speed to some extent in order to maintain a high body mass. The anthropometric and physical performance characteristics of players appear to reflect the demands placed on them by the sport.

Structure and function of ASP, the human homolog of the mouse agouti gene.

The mouse agouti coat color gene encodes a novel paracrine signaling molecule whose pulsatile expression produces a characteristic pattern of banded pigment in individual hairs. Several spontaneous agouti alleles produce adult-onset obesity and diabetes, and have provided important single-gene animal models for alterations in energy metabolism. Utilizing linkage groups conserved between mice and humans, we have cloned the human homolog of the mouse agouti gene from a human chromosome 20 yeast artificial chromosome known to contain S-adenosyl homocysteine hydrolase (AHCY). The human agouti gene, named Agouti Signaling Protein (ASP), encodes a 132 amino acid protein, the mRNA for which is expressed in testis, ovary, and heart, and at lower levels in liver, kidney, and foreskin. As predicted by the interactions of mouse agouti with the extension gene (which encodes the melanocyte receptor for alpha-melanocyte stimulating hormone [alpha-MSH]), expression of ASP in transgenic mice produces a yellow coat, and expression of ASP in cell culture blocks the alpha-MSH-stimulated accumulation of cAMP in mouse melanoma cells. The localization of ASP relative to other loci on chromosome 20 excludes it as a candidate for the MODY1 locus, a gene responsible for one form of early-onset non-insulin-dependent diabetes mellitus or maturity-onset diabetes of the young. The expression of ASP in human tissues suggests a function for agouti homologs in species that do not exhibit the characteristic phenotype of banded hairs.