The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a rapidly progressive, lethal neuromuscular disorder, present from birth, which occurs almost exclusively in males. We have reviewed contemporary evidence of burden, epidemiology, illness costs and treatment patterns of DMD. This systematic review adhered to published methods with information also sought from the web and contacting registries. Searches were carried out from 2005 to June 2015. The population of interest was individuals with clearly defined DMD or their carers. RESULTS: Nine thousand eight hundred fifty titles were retrieved from searches. Fifty-eight studies were reviewed with three assessed as high, 33 as medium and 22 as low quality. We found two studies reporting birth and four reporting point prevalence, three reporting mortality, 41 reporting severity and/or progression, 18 reporting treatment patterns, 12 reporting quality of life, two reporting utility measures, three reporting costs of illness and three treatment guidelines. Birth prevalence ranged from 15.9 to 19.5 per 100,000 live births. Point prevalence per 100,000 males was for France, USA, UK and Canada, 10.9, 1.9, 2.2 and 6.1 respectively. A study of adult DMD patients at a centre in France found median survival for those born between 1970 and 1994 was 40.95 years compared to 25.77 years for those born between 1955 and 1969. Loss of ambulation occurred at a median age of 12 and ventilation starts at about 20 years. There was international variation in use of corticosteroids, scoliosis surgery, ventilation and physiotherapy. The economic cost of DMD climbs dramatically with disease progression - rising as much as 5.7 fold from the early ambulatory phase to the non-ambulatory phase in Germany. CONCLUSIONS: This is the first systematic review of treatment, progression, severity and quality of life in DMD. It also provides the most recent description of the burden, epidemiology, illness costs and treatment patterns in DMD. There are evidence gaps, particularly in prevalence and mortality. People with DMD seem to be living longer, possibly due to corticosteroid use, cardiac medical management and ventilation. Future research should incorporate registry data to improve comparability across time and between countries and to investigate the quality of life impact as the condition progresses.

Two days with a broken knife blade in the neck--an interesting case of Horner's syndrome.

A 25-year-old man presented to the Emergency department in a rural South African hospital after a left, submental neck stab with a knife. Examination was deemed unremarkable, and the patient was discharged, but re-attended 2 days later complaining of a painful, swollen neck. Further examination identified Horner's syndrome, and further investigation revealed that the blade of the knife had remained in the patient's neck. This was successfully removed in theatre. This case illustrates the importance of careful history, examination and diagnostic imaging in the management of penetrating neck injuries. Horner's syndrome can be easily missed in a busy Emergency department and may indicate life-threatening pathology in the context of neck trauma. The difficulties in assessing and managing this type of injury are discussed.

Two days with a broken knife blade in the neck--an interesting case of Horner's syndrome.

A 25-year-old man presented to the Emergency department in a rural South African hospital after a left, submental neck stab with a knife. Examination was deemed unremarkable, and the patient was discharged, but re-attended 2 days later complaining of a painful, swollen neck. Further examination identified Horner's syndrome, and further investigation revealed that the blade of the knife had remained in the patient's neck. This was successfully removed in theatre. This case illustrates the importance of careful history, examination and diagnostic imaging in the management of penetrating neck injuries. Horner's syndrome can be easily missed in a busy Emergency department and may indicate life-threatening pathology in the context of neck trauma. The difficulties in assessing and managing this type of injury are discussed.

Effect of exercise, training, circadian rhythm, age, and sex on insulin-like growth factor-1 in the horse.

Insulin-like growth factor-1 could be a useful marker in the horse for diagnostic, selection, or forensic purposes, provided its physiological regulation is well understood. The objective of this study was to investigate factors, such as acute exercise, fitness training, time of day, sex, and age, that may influence serum IGF-1 in normal, healthy horses. Throughout a 9-wk training program, 6 geldings maintained a mean (+/- SEM) IGF-1 concentration of 302 +/- 29 ng/mL. Moderate or high intensity exercise had no effect on IGF-1 concentrations, when pre- and postexercise values were compared. Over a 24-h period, there was some variation in IGF-1 concentrations but no clear diurnal rhythm. Concentrations of IGF-1 were measured in a large population of thoroughbred horses (1,880) on 3 continents. The population deviated slightly from a normal distribution (P < 0.001) because of large IGF-1 concentrations in 10 horses. The global mean IGF-1 concentration was 310 +/- 2.2 ng/mL, with a greater mean value (P < 0.001) in gonad-intact males (336 +/- 5.6 ng/mL) than in females (303 +/- 3.2 ng/mL) or geldings (302 +/- 3.2 ng/mL). However, the greatest IGF-1 concentrations observed for all stallions, mares, and geldings were 627, 676, and 709 ng/mL, respectively. In mares and geldings, IGF-1 concentrations showed a gradual decrease with advancing age (P < 0.001), but the effect was much less marked in stallions. This study confirms that IGF-1 concentrations are stable, compared with GH concentrations, in the horse and that a meaningful measure of IGF-1 status can be obtained from a daily serum sample.

Confirmed Datura poisoning in a horse most probably due to D. ferox in contaminated tef hay.

Two out of a group of 23 mares exposed to tef hay contaminated with Datura ferox (and possibly D. stramonium) developed colic. The 1st animal was unresponsive to conservative treatment, underwent surgery for severe intestinal atony and had to be euthanased. The 2nd was less seriously affected, responded well to analgesics and made an uneventful recovery. This horse exhibited marked mydriasis on the first 2 days of being poisoned and showed protracted, milder mydriasis for a further 7 days. Scopolamine was chemically confirmed in urine from this horse for 3 days following the colic attack, while atropine could just be detected for 2 days. Scopolamine was also the main tropane alkaloid found in the contaminating plant material, confirming that this had most probably been a case of D. ferox poisoning. Although Datura intoxication of horses from contaminated hay was suspected previously, this is the 1st case where the intoxication could be confirmed by urine analysis for tropane alkaloids. Extraction and detection methods for atropine and scopolamine in urine are described employing enzymatic hydrolysis followed by liquid-liquid extraction and liquid chromatography tandem mass spectrometry (LC/MS/MS).

Surveillance of noise exposure in the Danish workplace: a baseline survey.

AIMS: To evaluate an epidemiological approach to a national noise hazard surveillance strategy, and report current exposure levels in the Danish workplace. METHODS: A study base of 840 companies in 10 selected high risk industries in the largest county in Denmark was identified from a national register. Noise exposure was measured among manual workers recruited from a random sample of workplaces in each industry. For reference, financial companies and a sample of residents were investigated according to the same protocol. The A-weighted equivalent sound level (L(Aeq)) for a full shift was measured by portable dosimeters worn by 830 workers employed at 91 workplaces (67% of 136 eligible companies). RESULTS: The epidemiological design proved feasible and established a baseline for future noise surveillance. Substantial resources were needed to motivate workplaces to enlist and the final participation rate was less than optimal (66.9%). The L(Aeq (8)) values in the selected industries were highly elevated (mean 83.7 dB(A) (95% CI 83.3 to 84.1) in comparison with residents and office workers (mean 69.9 dB(A), 95% CI 68.8 to 71.0). Some 50% of the workers were exposed to more than 85 dB(A) and some 20% to more than 90 dB(A) in several industries. CONCLUSION: Noise levels in Danish high risk industries remain high. A substantial proportion of workers are exposed to noise levels above the current threshold limit of 85 dB(A). Ongoing surveillance of noise exposure using full shift dosimetry of workers in random samples of workplaces most at risk to high noise levels may help reinforce preventive measures. Such a programme would benefit from compulsory workplace participation.

[Stability of osteosyntheses for condylar head fractures in the clinic and biomechanical simulation]. / Stabilität der Osteosynthese bei Gelenkwalzenfrakturen in Klinik und biomechanischer Simulation.

BACKGROUND: Fractures of the condylar head are traditionally managed by closed techniques, despite a considerable rate of dysfunctional problems. PDS pin osteosynthesis (presented by Rasse 1992) via a preauricular approach failed to become established as a standard procedure due to a lack of stability. Alternatively, mini- or microplating, as performed in our patients (101 condylar head fractures between 1993 and 2000), showed high-grade limitations of translatory movements in about 30% due to scarification after loosening of osteosynthesis materials. The aim of this study was to establish an efficient procedure for achieving a functionally stable and atraumatic osteosynthesis. METHODS: For the definition of a suitable procedure, models of the mandible (standardized fractures, types A, B, and C) were osteosynthesized (six samples for each type of fracture and type of screw), each with three PDS pins, 2.0 mm resorbable, 2.0 cortical, 1.7 and 1.2 mm small fragment screws, and exposed to increasing loads in centric (0-20-35 mm opening) and eccentric (35 mm opening) condylar positions. A computerized biomechanical test stand allowed a dynamic simulation of chewing forces (16 hydraulic drives). The resulting fracture gaps were measured without contact by a motion capture system. RESULTS: Within physiological limits, only 1.7 small fragment and 2.0 mm cortical screws were able to bear occlusal loadings up to 200 N (1.2 mm small fragment screws up to 150 N, resorbable 2.0 mm screws up to 100 N, and PDS-pins up to 50 N). In a pullout experiment (condylar spongious bone of young pigs, aged 4-6 months), 1.7 mm small fragment screws showed superior retention. A consecutively developed small fragment screw-system has been applied clinically in 74 condylar head fractures (58 patients). After removal of osteosynthesis material, 41 of 49 TM joints have so far shown complete restitution. CONCLUSIONS: The newly developed osteosynthesis system using a retroauricular approach based on 1.7 mm small fragment screws makes maxillomandibular immobilization unnecessary. The extra-articular position of the screw heads prevents scar-induced articular limitations. Preexisting degenerative alterations of the TMJ soft tissues, however, will affect functional results adversely.

Oxygen and carbon dioxide kinetic challenges for thermophilic mineral bioleaching processes.

Agitated bacterial tank bioleaching reactors are currently sparged with air to satisfy both oxygen and CO(2) requirements of microbial cells. Under high-sulphide loading conditions, as is the case with high-grade metal sulphide concentrates, the microbial and chemical demand for oxygen is significantly increased during the bioleaching process. Sparging with enriched oxygen gas may offer an alternative process option to increased agitation and sparged aeration, to overcome the mass transfer difficulties at elevated temperatures where thermophilic Archaea, rather than Bacteria, are used. In the case of air sparging, the DO (dissolved oxygen) concentration in tank reactors could not be increased to a point where it would become inhibitory due to the limited oxygen content of air (20.9% O(2)). The use of enriched oxygen in such reactors at large scale does, however, pose its own set of process risks. The first aim of this investigation was, therefore, to determine the effects of various DO concentrations, in both the limiting and inhibitory ranges, on the microbial activity of Sulfolobus sp. U40813, a typical thermophilic mineral-leaching archaeon. Secondly, the effect of CO(2) concentration on the rate of ferrous iron oxidation was investigated. Both the oxygen and CO(2) kinetics were examined in controlled batch cultures at 78 degrees C, using ferrous sulphate and potassium tetrathionate as energy sources. The optimal DO concentration for iron oxidation was found to be between 1.5 and 4.1 mg.l(-1). The use of elevated DO concentrations (above 4.1 mg.l(-1)) inhibited the ferrous oxidation rates. The optimal gas CO(2) concentration for ferrous iron oxidation was found to be in the range 7-17% (v/v). The iron oxidation rates were, however, severely limited at CO(2) concentrations less than 7%, indicating that the CO(2) supply was limiting in this range and inhibited the microbial growth rate.

Evidence of clonality in chronic neutrophilic leukaemia.

BACKGROUND: Chronic neutrophilic leukaemia (CNL) is a rare myeloproliferative disorder of elderly patients characterised by sustained neutrophilia and splenomegaly. The diagnosis of CNL requires the exclusion of BCR/ABL positive chronic myelogenous leukaemia (CML) and of leukaemoid reactions (LRs). The differentiation between CNL and LR is problematic because both conditions share similar morphological features; it is also important because patients with CNL generally have a poor prognosis. AIMS: To determine whether CNL and LR could be distinguished on the basis of different clonality patterns. METHODS: Blood samples from 52 women were studied using the human androgen receptor gene assay (HUMARA). RESULTS: Monoclonality was found in the neutrophils in all 17 patients with different myeloproliferative syndromes (MPSs), including those with CNL. In four of the patients with CNL, autologous T cells were also monoclonal, suggesting that they belonged to the neoplastic clone. This finding was in contrast to other MPSs in which T cells were almost always polyclonal. Of nine patients with clinically suspected LR, the neutrophils of five were polyclonal, whereas three patients had monoclonal neutrophils, suggesting that they might be in the process of developing an MPS. Among 26 healthy blood donors, 20 had polyclonal neutrophils and five showed skewed clonality patterns. One case of LR and one normal blood donor were scored "not informative" at the HUMARA locus. CONCLUSIONS: Clonality studies of blood neutrophils using HUMARA aid in distinguishing female patients with monoclonal CNL from those with LR. For the diagnosis of CNL, monoclonality of the neutrophils should be demonstrated whenever possible.

Administration of bovine, porcine and equine growth hormone to the horse: effect on insulin-like growth factor-I and selected IGF binding proteins.

This study investigated the biochemical effects of administration of three types of recombinant growth hormone (GH; somatotropin) to the Thoroughbred horse. Equine or bovine or porcine GH was administered at a recommended dosage to 3-5-year old Thoroughbred geldings, for up to 21 days. It was shown that, in addition to equine GH, bovine and porcine GH were active in the horse; however, porcine GH caused injection-site reactions that were so serious that administration had to be terminated. The concentrations of a range of GH-related serum protein markers were determined before, during and after the administration period. Because of the short half-life of GH itself, the objective was to identify GH-related markers that showed changes in concentration and which could be used as indicators of the abuse of these hormones. Among the possible markers identified, serum total insulin-like growth factor (IGF)-I was shown to be the most promising, increasing to 270% of the basal concentration for equine GH administration. After GH administration, IGF-I took longer to attain baseline concentrations than the time required for GH concentrations to recover to normal. The concentration obtained from the administration significantly exceeded natural concentrations for IGF-I, as was determined from a population of more than 2000 Thoroughbred horses in three continents. The concentrations of serum free IGF-I and IGF binding protein 3 (IGFBP-3) were also shown to be significantly affected by equine and bovine GH.

Development of respirometry methods to assess the microbial activity of thermophilic bioleaching archaea.

Respirometry methods have been used for many years to assess the microbial activity of mainly heterotrophic bacteria. Using this technique, the consumption of oxygen and evolution of carbon dioxide for heterotrophic carbon catabolism can be used to assess microbial activity. In the case of autotrophic bioleaching bacteria, carbon dioxide is used as a carbon source resulting in the consumption of both oxygen and carbon dioxide. The use of such respirometry techniques at high temperatures (up to 80 degrees C) for the investigation of bioleaching Archaea, however, poses particular difficulties. At these elevated temperatures, the solubility of oxygen into the liquid phase is particularly poor. This work details specific methods by which high temperature constraints are overcome while monitoring the activity of thermophilic Archaea using a Micro-Oxymax respirometer (Columbus Instruments). The use of elevated headspace oxygen concentrations, in order to overcome low oxygen solubility, is demonstrated as well as the effect of such elevated oxygen concentrations on microbial oxygen consumption rates. The relative rates of oxygen and carbon dioxide consumption are also illustrated during the oxidation of a chalcopyrite concentrate. In addition, this paper details generic methods by which respirometry data can be used to quantify inhibitory effects of a compound such as Na(2)SO(4). The further use of such data in predicting minimum hydraulic reactor retention times for continuous culture bioleaching reactors, as a function of concentration of potentially inhibitory compounds, is also demonstrated.

Gardner's syndrome--the importance of early diagnosis: a case report and a review.

Gardner's syndrome (familial polyposis coli) is a genetic condition characterised by colonic polyps that carry a 100% risk of malignancy if untreated. Early diagnosis, in which an astute and knowledgeable dentist can play an essential role, is therefore of paramount importance. The presence of multiple unerupted teeth provides the dentist with a major pointer to the possible presence of this disease, which may be provisionally diagnosed on the detection of two other obvious features, namely osteomas and cutaneous lesions. This fact is clearly illustrated by the accompanying case report. Extracolonic manifestations increase the morbidity and make treatment more difficult. The presence of large desmoid tumours may be a serious complicating factor. Gardner's syndrome may be accompanied by adenomas of the stomach and duodenum and very rarely by malignant tumours of the central nervous system. Regular surveillance by means of colonoscopies must be carried out on all individuals suspected of having the disease in order to implement timeous life-saving prophylaxis.

Investigations of intermediate host specificity help to elucidate the taxonomic status of Trichobilharzia ocellata (Digenea: Schistosomatidae).

The avian schistosomatid Trichobilharzia ocellata plays an important role as causative agent of cercarial dermatitis of humans in Europe. In order to improve the taxonomic knowledge on this parasite, studies of miracidial chemo-orientation as well as experimental infections of different snail species were conducted using strains of T. ocellata and T. franki. Both schistosomes exhibited a high intermediate host specificity. The miracidia clearly preferred the SCW (snail-conditioned water) of the respective natural intermediate host to SCW of other sympatric snail species. T. ocellata proved to be capable of infecting Lymnaea stagnalis and Stagnicola palustris, but could not develop in Radix ovata or R. auricularia. T. franki established an infection in specimens of R. auricularia and R. ovata, but not in L. stagnalis or S. palustris. The results imply that the intermediate host spectrum of T. ocellata is limited to L. stagnalis and S. palustris. Findings of T. ocellata (or Cercaria ocellata) that originated from snails of the genus Radix are likely to have actually belonged to species such as T. franki or T. regenti. The assumption that T. szidati is synonymous to T. ocellata is also discussed.

Growth hormone abuse in the horse: preliminary assessment of a mass spectrometric procedure for IGF-1 identification and quantitation.

Previous studies have shown that insulin-like growth factor 1 (IGF-1) is a promising marker for the detection of growth hormone (GH) abuse in the horse. The significant increases observed with GH administration in comparison to natural levels imply the possibility of setting a threshold level for IGF-1 that would be indicative of GH abuse. Although an immunoradiometric assay (IRMA) has been identified as a reliable screening method, a more specific IGF-1 quantification method needs to be developed for the prosecution of GH abuse by horseracing authorities. This study describes such an HPLC electrospray mass spectrometry (LC/ESI-MS) method that was developed and then assessed for the specific analysis of IGF-1 at the low levels encountered in serum. The structural identity of IGF-1 was confirmed by endoproteinase Asp-N digestion followed by LC/MS and LC/MS/MS characterisation. This was followed by quantification of IGF-1 as the intact molecule against an internal standard.

The relationship between transport kinetics and glucose uptake by Saccharomyces cerevisiae in aerobic chemostat cultures.

The steady-state residual glucose concentrations in aerobic chemostat cultures of Saccharomyces cerevisiae ATCC 4126, grown in a complex medium, increased sharply in the respiro-fermentative region, suggesting a large increase in the apparent kS value. By contrast, strain CBS 8066 exhibited much lower steady-state residual glucose concentrations in this region. Glucose transport assays were conducted with these strains to determine the relationship between transport kinetics and sugar assimilation. With strain CBS 8066, a high-affinity glucose uptake system was evident up to a dilution rate of 0.41 h(-1), with a low-affinity uptake system and high residual glucose levels only evident at the higher dilution rates. With strain ATCC 4126, the high-affinity uptake system was present up to a dilution rate of about 0.38 h(-1), but a low-affinity uptake system was discerned already from a dilution rate of 0.27 h(-1), which coincided with the sharp increase in the residual glucose concentration. Neither of the above yeast strains had an absolute vitamin requirement for aerobic growth. Nevertheless, in the same medium supplemented with vitamins, no low-affinity uptake system was evident in cells of strain ATCC 4126 even at high dilution rates and the steady-state residual glucose concentration was much lower. The shift in the relative proportions of the high and low-affinity uptake systems of strain ATCC 4126, which might have been mediated by an inositol deficiency through its effect on the cell membrane, may offer an explanation for the unusually high steady-state residual glucose concentrations observed at dilution rates above 52% of the wash-out dilution rate.

The effect of vitamins and amino acids on glucose uptake in aerobic chemostat cultures of three Saccharomyces cerevisiae strains.

In the respiro-fermentative region of aerobic chemostat cultures at steady state, Saccharomyces cerevisiae CBS 8066 produced high concentrations of ethanol with concomitant low levels of residual glucose which followed Monod kinetics. By contrast, very high residual glucose concentrations were observed in cultures of S. cerevisiae strains ATCC 4126 and NRRL Y132 at dilution rates above 60% of the washout dilution rate, resulting in much lower ethanol concentrations, even though clearly glucose-limited at lower dilution rates in the respiratory region. The addition of a vitamin mixture resulted in decreased residual glucose concentrations in respiro-fermentative cultures of all three strains, but the effect was much more pronounced with strains ATCC 4126 and NRRL Y132. Meso-inositol was mainly responsible for this effect, although with strain ATCC 4126 other vitamins as well as an amino acid mixture were also required to minimise the steady-state residual glucose levels. The residual glucose concentration in continuous culture was, therefore, greatly dependent on the growth factor requirements of the particular yeast strain, which apparently increased on increasing the dilution rate into the respiro-fermentative region. The strain differences with respect to growth factor requirements at high dilution rates, which were not evident at low dilution rates, had a profound effect on the kinetics of glucose assimilation in aerobic chemostat culture.

Observations on cercarial chaetotaxy as a means for the identification of European species of Trichobilharzia Skrjabin & Zakharow, 1920 (Digenea: Schistosomatidae).

In order to evaluate the importance of cercarial chaetotaxy in the identification of European avian schistosomatids of the genus Trichobilharzia Skrjabin & Zakharow, 1920, papillary patterns of T. franki Müller & Kimmig, 1994 and T. ocellata (La Valette, 1855) Brumpt, 1931 were examined and compared. Scanning electron microscopy (SEM) was also employed to confirm the number and distribution of the sensory papillae. The chaetotaxy of T. franki and T. ocellata were identical, which suggests a close kinship between the two species. Some sensory papillae stained insufficiently with silver nitrate or were difficult to examine using light microscopy. Thus, the use of SEM in future examinations of Trichobilharzia chaetotaxy will ensure the collection of data that are comparable between studies, even though some argentophilic structures are not visible using SEM.

[Incidence and predisposing factors of persistent backache after lumbar catheter epidural anesthesia in a non-obstetrical settingø]. / Inzidenz und prädisponierende Faktoren persistierender Rückenschmerzen nach lumbaler Katheterperiduralanästhesie im nichtgeburtshilflichen Bereich.

OBJECTIVE: To determine the incidence of long term backache after lumbar epidural anesthesia with catheter (EPA) in the non-obstetrical setting. DESIGN: Prospective 1-year follow-up study. PATIENTS: All patients scheduled for elective arthroscopical surgery of the knee performed under EPA (n = 195). INTERVENTIONS: A first questionnaire was sent to each patient three months after the operation. To chose patients reporting persistent backache after three months, a second questionnaire was sent one year after the operation. MEASUREMENTS: Back pain before, within 5 days and at the time of the inquiry, i.e., three months and one year after EPA as well as patient satisfaction with the regional anesthetic. Statistic: contingency tables with Fisher's exact test (for categorical variables) and an unpaired t-Test (for continuous variables), p < 0.01 after adjustment for multiple testing (Bonferroni's method). MAIN RESULTS: Response rate was 67%. Before EPA 23 patients (17.5%) complained of back pain. The short term incidence of back pain (i.e, within 5 days after EPA) was 24 out of 131 patients (18.3%) and not associated with pre-epidural back pain (p = 0.036, n.s.). 15 out of 131 patients (11.5%) reported persistent back pain after three months, 13 of them had complained of back pain before EPA (p < 0.0001). Thus, the incidence of new back pain 3 months after EPA was only 1.5%. 7 of the 15 patients returned the second questionnaire: 6 reported still persistent back pain, and all had complained of back pain before EPA. Age, height, weight, sex, duration of anesthesia and operation were not associated with long term back pain. Despite persistent back pain after three months 10 out of 15 patients would opt again for EPA. CONCLUSION: The incidence of long term backache after EPA in the non-obstetrical setting is 11.5% and almost exclusively associated with pre-existing back pain. Biometrical factors seem to play no role. In patients with pre-existing back pain satisfaction with the anesthetic procedure might be improved by improving informed consent.

Mechanism for the stabilization in vivo of the aziridine precursor --(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride by serum proteins.

Oral and intraperitoneal administration of 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (Compound A), an analogue of phenyl aziridine precursors that occur in the shrub Salsola tuberculatiformis Botsch, had a contraceptive effect on female Wistar rats with a concomitant decrease in total body, uterus, and every mass and an increase in abronal mass. Compound A elicited a Type II difference spectrum and inhibited the Type I deoxycorticosterone (DOC) induced difference spectrum of sheep adrenal cytochrome P450c11 in a manner similar to that of S2, a biologically active fraction isolated from S. tuberculatiformis. The effects of Compound A on the spectral properties of P450c11 were diminished with time in PBS. Electrospray mass spectrometry (ES-MS) indicated that the rate of cyclization of Compound A to the corresponding aziridine followed a time course similar to the attenuation of cytochrome P450c11 inhibition. It was concluded that the aziridine precursor. Compound A, rather than aziridine itself, was the inhibiting agent of sheep adrenal P450c11. Addition of sheep and rat plasma prevented the attenuation of the effect of Compound A on the spectral properties of cytochrome P450c11. Subsequent ES-MS analysis indicated that Compound A was stabilized in plasma by sex hormone binding globulin and corticosteroid binding globulin. These results suggest a mechanism whereby natural plant products, which are highly reactive and unstable in vitro, can be stabilized by binding to plasma proteins, and so remain biologically active in vivo.

Control of B cell lymphoma recognition via natural killer inhibitory receptors implies a role for human Vgamma9/Vdelta2 T cells in tumor immunity.

The Vgamma9/Vdelta2 T cell receptor (TCR) is expressed by most human gammadelta T cells. We show here that cytotoxic T lymphocytes of the Vgamma9/Vdelta2 subset, but not of the Vdelta1 subset of human gammadelta T cells, express natural killer inhibitory receptors (KIR) with specificity for different HLA class I alleles that down-regulate TCR-mediated signaling in response to HLA class I-expressing B cell lymphomas. Vgamma9/Vdelta2 T cell clones with a T helper cell phenotype lack KIR and produce lymphokines in response to most human B cell lymphomas, just as they do upon recognition of the HLA class I-deficient human Burkitt's lymphoma Daudi. Thus, human Vgamma9/Vdelta2 T cells have an innate specificity for nonpolymorphic cell surface structures expressed by many lymphoma cells and their cytotoxic activity is controlled by KIR. These results imply a general role of human Vgamma9/Vdelta2 T cells in the defense against hematopoietic tumors that is distinct from NK cells.