Red meat allergic patients have a selective IgE response to the α-Gal glycan.

Galactose-α-1,3-galactose (α-Gal) is a mammalian carbohydrate with significance in a novel type of food allergy. Patients with IgE against α-Gal report severe allergic symptoms 3-6 h after consumption of red meat. We investigated whether IgE from red meat allergic patients recognizes other mammalian glycans than α-Gal or glycans from the plant kingdom and insects of importance in allergy. We found that none of the 24 red meat allergic patients investigated had an IgE antibody response against the other abundant mammalian glycan N-glycolylneuraminic acid or against cross-reactive carbohydrate determinants from plant or venom sources (nCup a 1, nArt v 1, and MUXF3). Deglycosylation of an α-Gal-containing protein, bovine thyroglobulin, significantly reduced the IgE response. In conclusion, we show that red meat allergic patients have a selective IgE response to the α-Gal glycan found in red meat. Other common glycans reactive in allergic disease are not targets of red meat allergic patients' IgE.

Immunoproteomics of processed beef proteins reveal novel galactose-α-1,3-galactose-containing allergens.

BACKGROUND: Red meat allergy presents a novel form of food allergy with severe delayed allergic reactions where IgE antibodies are directed against the carbohydrate α-Gal epitope. Food preparation and processing can influence the allergenicity of proteins. The aim of this study was to characterize the proteomic profile of different beef preparations and to investigate their α-Gal reactivity and potential allergenicity. METHODS: Extracts from raw, boiled, fried, and medium rare prepared beef were assessed by 2D PAGE for the comparison of protein profiles. IgE-binding proteins were identified using immunoblot-coupled proteomic analysis using sera from red meat-allergic patients. Presence of the α-Gal epitope was verified using anti-α-Gal antibody and IgE inhibition immunoblot with α-Gal. RESULTS: Multiple IgE-binding proteins were detected in the different beef preparations, many of which were also recognized by the anti-α-Gal antibody. Protein spots reacting with IgE in patient sera were analyzed by MS/MS, resulting in identification of 18 proteins with high identification scores. Seven of the 18 beef allergens identified using meat-allergic patient sera were also recognized by the anti-α-Gal monoclonal antibody, and four of them were stabile to thermal treatment. Furthermore, a dose-dependent inhibition of red meat-allergic patients' IgE to beef by α-Gal was demonstrated. CONCLUSIONS: We show that the α-Gal epitope is commonly present in IgE-reactive beef proteins recognized by meat-allergic patients. Seven novel α-Gal-containing IgE-binding proteins were identified, of which four were stable to heat treatment. Thus, the allergenicity of red meat proteins is preserved even upon different thermal cooking.

Identification of galactose-α-1,3-galactose in the gastrointestinal tract of the tick Ixodes ricinus; possible relationship with red meat allergy.

Patients with IgE antibodies against the carbohydrate epitope galactose-α-1,3-galactose (α-Gal) have reported severe allergic reactions after consumption of red meat. Investigations have revealed associations between IgE to α-Gal and tick bites. We provide the first direct evidence that α-Gal is present within ticks thus potentially explaining the relationship between tick exposure and sensitization to α-Gal, with development of red meat allergy as a secondary phenomena. Serum from Swedish patients with delayed severe reactions to red meat was included in the study. A dose-dependent inhibition of IgE responses to α-Gal by the tick Ixodes ricinus is demonstrated. Furthermore, using cryostat-cut sections of I. ricinus, we show that both a monoclonal and a polyclonal antibody against α-Gal stains the gastrointestinal tract of the tick. The same pattern is seen when staining with patient sera IgE positive to α-Gal. These results confirm that the α-Gal epitope is present in I. ricinus and imply host exposure to α-Gal during a tick bite. This provides further evidence that tick bites are associated with IgE responses to α-Gal and red meat allergy.

Primary peritoneal low-grade serous carcinoma forming a mass in the colon mimicking a colonic primary carcinoma: a case report.

Primary carcinomas of Müllerian origin involving the colon is not an uncommon phenomenon, with most cases reportedly associated with endometriosis. On the other hand, a primary peritoneal low-grade serous carcinoma presenting as a dominant mass in the colon and causing clinical symptoms mimicking a primary colonic carcinoma has not been reported in the literature to the best of the authors' knowledge. A case of a 66-year-old female patient who presented clinically with rectal bleeding and a rectosigmoid mass is described. The final histologic examination revealed a peritoneal low-grade serous carcinoma forming a dominant mass in the rectosigmoid colon. Of particular interest was a microscopic spectrum of serous epithelial proliferation in the peritoneal cavity and lymph nodes with morphologic features reminiscent of non-invasive and invasive implants in ovarian borderline serous tumors, which most likely denoted the precursors of the tumor in the colon.

Investigating the magnetic and magnetocaloric behaviors of LiSm(PO3)4.

We report a detailed study on the magnetic behaviors and magnetocaloric (MC) effect of a single crystal of lithium samarium tetraphosphate, LiSm(PO3)4. The analyses of temperature-dependent magnetization data have revealed magnetic ordering established with decreasing temperature below T p, where T p is the minimum of a dM/dT vs. T curve and varies as a linear function of the applied field H. The Curie temperature has been extrapolated from T p(H) data, as H → 0, to be about 0.51 K. The establishment of magnetic-ordering causes a substantial change in the heat capacity C p. Above T p, the crystal exhibits paramagnetic behavior. Using the Curie-Weiss (CW) law and Arrott plots, we have found the crystal to have a CW temperature θ CW ≈ -36 K, and short-range magnetic order associated with a coexistence of antiferromagnetic and ferromagnetic interactions ascribed to the couplings of magnetic dipoles and octupoles at the Γ7 and Γ8 states. An assessment of the MC effect has shown increases in value of the absolute magnetic-entropy change (|ΔS m|) and adiabatic-temperature change (ΔT ad) when lowering the temperature to 2 K, and increasing the magnetic-field H magnitude. Around 2 K, the maximum value of |ΔS m| is about 3.6 J kg-1 K-1 for the field H = 50 kOe, and ΔT ad is about 5.8 K for H = 20 kOe, with the relative cooling power (RCP) of ∼82.5 J kg-1. In spite of a low MC effect in comparison to Li(Gd,Tb,Ho)(PO3)4, the absence of magnetic hysteresis reflects that LiSm(PO3)4 is also a candidate for low-temperature MC applications below 25 K.

Reasons for Encounters and Comorbidities in Adolescents with Intellectual Disability in General Practice: A Retrospective Analysis of Data from the Ask Study.

Adolescents with intellectual disability have substantial health needs. This retrospective analysis of data from the Ask Study describes reasons for primary care encounters and the prevalence and incidence of chronic physical and mental conditions among a cohort of community-dwelling adolescents with intellectual disability. Participants attended secondary schools in southern Queensland, Australia. Primary care data were extracted from primary care records. Demographic and health information was collected using carer-completed questionnaires. Reasons for primary care encounters, disease prevalence at age 16 years, and disease incidence through adolescence were reported. Data were obtained for 432 adolescents with intellectual disability (median follow-up: 4.1 years). Skin problems (29.4 per 100 encounters) were the most common reason patients presented for primary care, followed by psychological and behavioural problems (14.4 per 100 encounters) and musculoskeletal problems (13.8 per 100 encounters). Conditions with the highest prevalence were autism spectrum disorder (18.6%) and asthma (18.1%). The prevalence of epilepsy, visual impairment, and cerebral palsy were 14.7, 11.1, and 8.0%, respectively. Gastroesophageal reflux had the highest incidence (9.4 cases per 1000 person-years). Adolescents with intellectual disability have significant healthcare needs, which general practitioners need to be aware of and address. Study findings should inform the development of training programs for general practitioners.

Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes.

OBJECTIVE: Longer-term effects of prolonged selective interleukin-1ß blockade with canakinumab were evaluated in the largest cohort of cryopyrin-associated periodic syndrome (CAPS) patients studied to date. METHODS: Adult and paediatric CAPS patients (n=166, including canakinumab-naive and pretreated patients from previous studies) received canakinumab subcutaneously 150 mg or 2 mg/kg (≤40 kg) every 8 weeks for up to 2 years. Response and relapse was assessed using scores for disease activity, skin rash and C-reactive protein (CRP) and/or serum amyloid A (SAA) levels. RESULTS: Complete response was achieved in 85 of 109 canakinumab-naive patients (78%; 79/85 patients within 8 days, and five patients between days 10 and 21). Of 141 patients with an available relapse assessment, 90% did not relapse, their CRP/SAA levels normalised (<10 mg/l) by day 8, and remained in the normal range thereafter. Median treatment duration was 414 days (29-687 days). Upward adjustments of dose or frequency were needed in 24.1% patients; mostly children and those with severe CAPS. Predominant adverse events (AE) were infections (65.7%) of mostly mild-to-moderate severity. Serious AE reported in 18 patients (10.8%) were mainly infections and were responsive to standard treatment. The majority of patients (92%) reported having no injection-site reactions and only 8% patients reported mild-to-moderate reactions. Patients receiving vaccination (15%) showed normal immune response. CONCLUSIONS: Subcutaneous canakinumab 150 mg every 8 weeks was well tolerated and provided substantial disease control in children and adults across all CAPS phenotypes. Higher canakinumab doses in younger patients and more severe CAPS disease were efficacious in achieving complete responses without evidence of increased AE. TRIAL REGISTRATION NUMBER: NCT00685373 (clinicaltrials.gov).

Neurological involvement in paediatric Behçet's disease.

INTRODUCTION: Behçet disease (BD) is a systemic vasculitis which can affect the neurological system. Neuro-Behçet's disease (NBD) is not well described in children. OBJECTIVE: Our study aimed to analyse the clinical patterns of paediatric NBD and to describe their repercussions on children's schooling. METHODS: We performed a retrospective chart review of 12 NBD children and a phone interview of patients and their physicians to investigate their last physical and schooling status. RESULTS: In 40 BD patients reviewed, 12 (sex ratio 8M/4F) had neurological involvement. The mean age of onset was 11 years. In 4 cases, neurological symptoms were the initial presentation. In other cases, NBD occurred within a mean time of 10 months after BD was diagnosed. Cerebral venous thromboses were frequent (5/12) as compared to recurrent meningoencephalitis (2/12), rhombencephalitis (2/12), transverse myelitis (1/12), peripheral neuropathy (1/12) or psychiatric disturbances (1/12). 9 patients had sequelae and 8 had difficulties in learning. 6 stopped at middle school level. For the other patients, an arrangement of the teaching environment was needed due to visual, auditory and concentration disorders. CONCLUSION: Neurological involvement is frequent in BD children and its consequences could be severe. Timely accommodations are required to facilitate their ability to follow the normal curriculum.

α-Gal on the protein surface affects uptake and degradation in immature monocyte derived dendritic cells.

Red meat allergy is characterized by an IgE response against the carbohydrate galactose-α-1,3-galactose (α-Gal), which is abundantly expressed on glycoproteins from non-primate mammals. The mechanisms of how α-Gal is processed and presented to the immune system to initiate an allergic reaction are still unknown. The aim of this study was to reveal whether the presence of α-Gal epitopes on the protein surface influence antigen uptake and processing in immature monocyte-derived dendritic cells (iMDDCs). Immature MDDCs were prepared from healthy blood donors and red meat allergic patients. We found an increased internalization of α-Gal carrying proteins over time in iMDDCs by flow cytometric analysis, which was independent of the donor allergic status. The uptake of α-Gal carrying proteins was significantly higher than the uptake of non-α-Gal carrying proteins. Confocal microscopy revealed α-Gal carrying proteins scattered around the cytoplasm in most iMDDCs while detection of proteins not carrying α-Gal was negligible. Fluorescent detection of protein on SDS-PAGE showed that degradation of α-Gal carrying proteins was slower than degradation of non-α-Gal carrying proteins. Thus, the presence of α-Gal on the protein surface affects both uptake and degradation of the protein, and the results add new knowledge of α-Gal as a clinically relevant food allergen.

[Type 3 Gaucher disease, also an adult disease?] / Maladie de Gaucher de type 3, une maladie également de l'adulte ?

INTRODUCTION: Gaucher disease is a genetic lysosomal storage disorder due to a glucocerebrosidase deficiency. Type 3, including neurological impairment, may have a specific phenotype in the context of the D409H mutation. OBSERVATION: We report the case of a 22-year-old woman who presented with Gaucher disease. Enzyme replacement therapy by imiglucerase was followed by rapid clinical and biological improvement. However, communication difficulties, which were initially attributed to the language barrier, revealed neurological impairment. After complementary assessment, the diagnosis of type 3 Gaucher disease was suspected. Gene analysis of the glucocerebrosidase showed a homozygous D409H mutation. CONCLUSION: This mutation results in calcified heart valves, corneal opacities, alteration of oculomotricity and hydrocephalus. The mild manifestation at onset and the late neurological involvement in the medical history make the diagnosis more difficult. This particular clinical phenotype deserves to be known in adult medicine departments.

Effect of ultrasound-activated microbubbles on the cell electrophysiological properties.

New clinical applications of ultrasound contrast microbubbles extend beyond imaging and diagnosis toward therapeutic applications. Cell membrane permeability and the uptake of substances have been shown to be enhanced by microbubbles under ultrasound stimulation. However, the mechanisms of action of ultrasound-activated microbubbles are still unknown. The aim of our study was to examine how microbubbles and ultrasound interact with cells in an attempt to understand the sonoporation mechanism. The ruptured-patch-clamp whole-cell technique was used to measure membrane potential variations of a single cell. SonoVue microbubbles and mammary breast cancer cell line MDA-MB-231 were used. Ultrasound was applied using single-element transducers of 1 MHz. Microbubbles and cells were simultaneously video monitored during ultrasound exposure. Our results showed that, during sonoporation, a marked cell membrane hyperpolarization occurs (n = 6 cells) at negative pressures above 150 kPa, indicating the activation of specific ion channels while the cell and the microbubbles remain viable. The hyperpolarization was sustained for as long as the microbubbles are in a direct contact with the cell and the ultrasound waves are transmitted. Smaller acoustic amplitudes induced only mild hyperpolarization, whereas shutting off the ultrasound brings the cell membrane potential to its resting value. However, ultrasound alone did not affect the cell membrane potential. A similar hyperpolarization of the cell membrane was observed when a mechanical pressure was applied on the cell through a glass probe. In conclusion, the results demonstrate that microbubbles' oscillations under ultrasound activation entail modifications of the electrophysiologic cell activities by triggering the modulation of ionic transports through the plasmic cell membrane. However, only cells in direct contact with the microbubbles are impacted. The mechanisms involved are likely related to activation of specific channels sensitive to mechanical stresses (stretch-activated channels) and possibly nonspecific ion channels.

135La as an Auger-electron emitter for targeted internal radiotherapy.

135La has favorable nuclear and chemical properties for Auger-based targeted internal radiotherapy. Here we present detailed investigations of the production, emissions, and dosimetry related to 135La therapy. 135La was produced by 16.5 MeV proton irradiation of metallic natBa on a medical cyclotron, and was isolated and purified by trap-and-release on weak cation-exchange resin. The average production rate was 407 ± 19 MBq µA-1 (saturation activity), and the radionuclidic purity was 98% at 20 h post irradiation. Chemical separation recovered > 98 % of the 135La with an effective molar activity of 70 ± 20 GBq µmol-1. To better assess cellular and organ dosimetry of this nuclide, we have calculated the x-ray and Auger emission spectra using a Monte Carlo model accounting for effects of multiple vacancies during the Auger cascade. The generated Auger spectrum was used to calculate cellular S-factors. 135La was produced with high specific activity, reactivity, radionuclidic purity, and yield. The emission spectrum and the dosimetry are favorable for internal radionuclide therapy.

Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2.

BACKGROUND: Prostate cancer ranks as the second most lethal malignancy in the Western world. Previous targeting of prostate-specific antigen and human kallikrein-related peptidase 2, two related enzymes abundantly expressed in prostatic malignancies, with radioimmunoconjugates intended for diagnostic purposes, have proven successful in rodent prostate cancer (PCa) models. In this study, we investigated the uptake and therapeutic efficacy of (177)Lu-m11B6, a human kallikrein-related peptidase 2 (hK2)-targeting radioimmunoconjugate in a pre-clinical setting. METHODS: The murine 11B6 antibody, m11B6, with high affinity for hK2, was labeled with (177)Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of (177)Lu-m11B6 were administered to groups of mice. Body weight and general conditions of the mice were followed over a period of 120 days. RESULTS: The tumor uptake in LNCaP xenografts was 30 ± 8.2 % injected activity per gram 1 week post-injection. In vivo targeting was hK2-specific as verified by a 2.5-fold decrease in tumor uptake in pre-dosed xenografts or by a fourfold lower tumor accumulation in hK2-negative DU 145 xenografts. Therapy showed a dose-dependent efficacy in LNCaP xenografts treated with (177)Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of (177)Lu-m11B6 was 88 days compared to that of 38 days in mice given labeled non-specific IgG. For the higher administrated activities, total tumor regression was seen with minimal normal organ toxicity. CONCLUSIONS: We have proven the possibility of radioimmunotherapy targeting hK2 in subcutaneous prostate cancer xenografts. (177)Lu-m11B6 exhibited high therapeutic efficacy, with low observed toxicity. Additionally, an evaluation of the concept of pre-therapy planning using a dosimetry model was included in this radioimmunotherapy study.

[Hypercalcemia revealing sarcoidosis in a child]. / Hypercalcémie révélant une sarcoïdose chez un enfant.

Sarcoidosis is a systemic granulomatosis disease with a classic triad of presentation: typical clinical and radiological signs, presence of tuberculoid granuloma without caseum in histopathology, and exclusion of other causes of granulomatosis, especially tuberculosis. Sarcoidosis is rare in the general population, and even more so in children. In the literature, few cases of sarcoidosis associated with hypercalcemia have been reported in children. We report here the case of a 14-year-old boy with bone marrow and lymph node sarcoidosis suspected, based on poor general condition with hypercalcemia. The patient was treated with hydration, diuretics, and bisphosphonates with good results. We also performed a literature review of published cases of hypercalcemia since 1990 with a diagnosis of sarcoidosis in children, comparing 23 cases (including ours) on clinical and epidemiological, biological, imaging, and histopathological diagnosis. When hypercalcemia is present in the initial clinical presentation, the diagnosis of sarcoidosis is usually made in younger children. Classical locations of the lesions, including lung, skin, and lymph nodes, were highly suggestive of sarcoidosis. Corticosteroids are commonly used to treat sarcoidosis lesions including hypercalcemia. In conclusion, sarcoidosis in children remains difficult to diagnose because the disease is rare and it is common to have nonspecific symptoms in the clinical picture (with diagnosis delayed between 3 months and several years). The classic triad is not always present. Sarcoidosis should be systematically considered and investigated in case of hypercalcemia of unknown cause in children.

Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases.

There is interest in developing potent, selective, and cell-permeable inhibitors of human ferrous iron and 2-oxoglutarate (2OG) oxygenases for use in functional and target validation studies. The 3-component Betti reaction enables efficient one-step C-7 functionalisation of modified 8-hydroxyquinolines (8HQs) to produce cell-active inhibitors of KDM4 histone demethylases and other 2OG oxygenases; the work exemplifies how a template-based metallo-enzyme inhibitor approach can be used to give biologically active compounds.

Lamotrigine clearance during pregnancy.

OBJECTIVE: To evaluate changes in lamotrigine (LTG) clearance before, during, and after pregnancy. METHODS: Twelve pregnancies that had complete steady-state data before, during, and after pregnancy were evaluated. Data included weight, LTG dose, and LTG blood levels at preconception, during pregnancy, and postpartum, and concomitant use of other antiepileptic drugs and their dosages. Apparent clearance (L/[kg.day]) of LTG was calculated by dose/level/weight for time points at preconception; during the first trimester, second trimester, and third trimester; and postpartum. Apparent clearance was compared between preconception and each of the three trimesters. Statistical analysis was performed using one-way analysis of variance, the Student-Newman-Keuls test, and the paired Student's t-test. RESULTS: An increase in apparent clearance (>65%) was observed between preconception and the second and third trimesters (p < 0.05). Eleven pregnancies required higher doses of LTG to maintain therapeutic levels during pregnancy. There was no significant change in apparent clearance between each trimester. A decrease in apparent clearance was observed between the last two trimesters and postpartum (p < 0.05). In the postpartum period, apparent clearances returned to the preconception baseline, and LTG doses needed to be reduced. CONCLUSION: Pregnancy increases LTG clearance by >50%. This effect occurs early in pregnancy and reverts quickly after delivery. LTG levels should be monitored before, during, and after pregnancy.

Pseudomyxoma ovariilike posttherapeutic alteration in prostatic adenocarcinoma: a distinctive pattern in patients receiving neoadjuvant androgen ablation therapy.

Neoadjuvant combination endocrine therapy that uses leuprolide and flutamide may result in various histologic changes in nontumoral and cancerous prostatic tissues. Posttreatment pseudomyxoma ovariilike change in prostatic adenocarcinoma is a distinctive alteration that may be the only evidence of regressed tumor and can be potentially confused with mucinous carcinoma. We studied 53 clinically localized prostatic adenocarcinomas after 3 to 5 months of treatment with leuprolide and flutamide. Alterations in prostatic adenocarcinoma in posttreatment radical prostatectomy specimens were assessed and compared with pretreatment needle biopsies. All radical prostatectomy specimens exhibited previously well-characterized therapy-associated changes in benign and malignant elements. Thirteen (20%) cases exhibited a distinctive alteration not seen in pretreatment needle biopsies that consisted of minute to large pools of extravasated secretions that resembled pseudomyxoma ovarii and that dissected through prostatic stroma with an infiltrative appearance when viewed at low power. Associated recognizable tumor was present in 10 of 13 (77%) of these cases. Secretions were basophilic in routine sections and contained occasional degenerated cells. Rare pancytokeratin positive cells were seen at the secretion/stroma interface with uniformly negative staining for the high molecular weight keratin 34 beta E-12. The secretions were periodic acid-Schiff positive after diastase digestion and were mucicarminophilic and reactive with Alcian blue at a pH of 2.5. These foci comprised < 5% of the tumor in 5 cases and 5-40% in 5 cases. In 3 cases, 1-2 foci < 1.0 mm exhibited the pseudomyxoma ovariilike changes and were the only evidence of treated tumor. There was no correlation between the presence of pseudomyxomalike change and dose/duration of neoadjuvant therapy, postprostatectomy clinical follow-up, original or final Gleason pattern/score, or pathologic stage. Pseudomyxoma ovariilike change consists of extravasated acid mucin, lacks prostatic basal cells, often occurs in intimate association with residual prostatic adenocarcinoma in posttreatment radical prostatectomy specimens, and probably represents tumor regression as a result of tumor cell attrition secondary to androgen ablation.

Paraffin section immunophenotype of cutaneous and extracutaneous mast cell disease: comparison to other hematopoietic neoplasms.

Mast cell disease (MCD) is a rare proliferation that may be easily confused with other hematopoietic tumors. Several paraffin section antibodies immunoreact with mast cells but most are not specific. Tryptase, a specific marker of mast cells, may not be cost-effective to maintain in a laboratory because of the rarity of these lesions. This study was undertaken to assess the immunoreactivity of MCD and attempt to select a limited antibody panel for diagnosing MCD among hematopoietic tumors that morphologically mimic MCD. Immunophenotyping of cutaneous ( 10 cases) and extracutaneous (18 cases) MCD, as well as 94 other hematopoietic neoplasms, was performed on paraffin sections. All cases of MCD showed strong and diffuse positivity for CD68 and tryptase. In the vast majority of the cases, the mast cells were also positive for CD117 (27 of 28) and CD43 (25 of 27). Four cases (40%) of cutaneous MCD demonstrated a subpopulation of mast cells expressing myeloperoxidase (MPX), whereas all extracutaneous MCD were negative for MPX. Two (40%) extramedullary myeloid tumors (EMT) expressed CD43, CD68, CD 117, and MPX, but none expressed tryptase. CD43, CD68, CD117, and tryptase were expressed by 25%, 1%, 15%, and 1%, respectively, of all B-cell lymphoid neoplasms, and none expressed more than one of these four antigens. We conclude that (1) cutaneous MCDs may demonstrate a subpopulation of MPX antigen expressing tumor cells and may be confused with cutaneous involvement by myeloid leukemia if other antibodies are not used; (2) tryptase is the most specific mast cell marker among the antibodies studied; and, (3) the detection of tryptase, together with CD68, CD117, and usually CD43, is unique to MCD among hematopoietic tumors.

Conformational analyses of somatostatin-related cyclic hexapeptides containing peptoid residues.

We report the conformational analysis by 1H NMR in DMSO and computer simulations involving distance geometry and molecular dynamics simulations of a series of peptoid analogues of the cyclic hexapeptide c[Phe11-Pro6-Phe7-d-Trp8-Lys9-Thr10] (1). The proline residue in compound 1 is replaced with the peptoid residues N-benzylglycine (Nphe) (compound 2), N-(S)-alpha-methylbenzylglycine [(S)-beta-MeNphe] (compound 3), and N-(R)-alpha-methylbenzylglycine [(R)-beta-MeNphe] (compound 4). The peptoid analogues 2 and 4 exhibit potent binding activities to the hsst2 receptor, while the binding affinities to the hsst5 and to the hsst3 receptors are reduced compared to that of the parent compound 1. Compound 3 shows reduced binding activities to the hsst2, hsst3, and hsst5 receptors compared to compound 1. The results of in vivo assays indicate that these compounds inhibit the growth hormone release but do not affect the insulin release. These peptoid-containing analogues show two sets of NMR signals corresponding to cis and trans conformations of the peptide bond between Phe11 and Nxaa6. We demonstrate that the backbone conformation and the orientation of the relevant side chains of compound 1 are maintained in the cis isomers of the peptoid analogues which adopt a type VI beta-turn centered around residues 11 and 6 and a type II' beta-turn with d-Trp in the i+1 position. The enhanced selectivity of the peptoid-containing analogues compared to compound 1 and the results of the conformational analysis suggest that the presence of a conformationally constrained hydrophobic group in position 6 in complementary topology to the Phe11 side chain enhances selective binding to the hsst2 receptor.