Identification of alpha-gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis.

IgE antibodies (Ab) specific to galactose-α-1,3-galactose (alpha-gal) are responsible for a delayed form of anaphylaxis that occurs 3-6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha-gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha-gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha-gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha-gal are delayed and thus may be overlooked.

Development and validation of the mastocytosis quality of life questionnaire: MC-QoL.

BACKGROUND: Mastocytosis is a heterogeneous disease characterized by a clonal expansion of mast cells in various organs. The vast majority of patients affected suffer from signs and symptoms caused by mediator release from mast cells. Although the disease burden is high, there is currently no specific instrument to measure health-related quality of life (HRQoL) impairment in patients with mastocytosis. OBJECTIVE: The aim of this study was to develop and validate a disease-specific tool to assess HRQoL impairment in patients with cutaneous and indolent systemic mastocytosis, the Mastocytosis Quality of Life Questionnaire (MC-QoL). METHODS: Sixty-two potential MC-QoL items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. Item selection was performed by impact analysis with 76 patients and a final review for face validity. The resulting MC-QoL was tested for validity, reliability and influence factors. In parallel, an US American-English version of the MC-QoL was developed. RESULTS: A total of 158 patients (41 CM, 41 MIS and 76 ISM) took part in the MC-QoL validation study. The final 27-item questionnaire was found to have a four-domain structure ('symptoms', 'emotions', 'social life/functioning' and 'skin'), a valid total score and an excellent test-retest reliability. Multiple regression analysis revealed disease duration, but not age, gender or skin involvement to be a significant determinant of HRQoL impairment in mastocytosis. CONCLUSIONS: The MC-QoL is the first disease-specific HRQoL questionnaire for adult patients with cutaneous and indolent systemic mastocytosis. This short, validated and reliable instrument will serve as a valuable tool in future clinical studies and in routine patient care.

Management of colorectal cancer in patients with inflammatory bowel disease.

BACKGROUND: This study evaluated the clinicopathological features and survival rates of patients with inflammatory bowel disease who developed colorectal cancer (CRC). METHODS: A retrospective review was performed on a prospectively maintained institutional database (1981-2011) to identify patients with inflammatory bowel disease who developed CRC. Clinicopathological parameters, management and outcomes were analysed. RESULTS: A total of 2,843 patients with inflammatory bowel disease were identified. One thousand six hundred and forty-two had ulcerative colitis (UC) and 1,201 had Crohn's disease (CD). Following exclusion criteria, there were 29 patients with biopsy-proven colorectal carcinoma, 22 of whom had UC and 7 had CD. Twenty-six patients had a preoperative diagnosis of malignancy/dysplasia; 16 of these were diagnosed at surveillance endoscopy. Nodal/distant metastasis was identified at presentation in 47 and 71 % of the UC and CD group, respectively. Operative morbidity for UC and CD was 33 and 17 %, respectively. Despite the less favourable operative outcomes following surgery management of UC-related CRC, overall 5-year survival was significantly better in the UC group compared to the CD group (41 vs. 29 %; p = 0.04) reflecting the difference in stage at presentation between the two groups. CONCLUSIONS: Patients who undergo surgery for UC-related CRC have less favourable short-term outcomes but present at a less advanced stage and have a more favourable long-term prognosis than similar patients with CRC and CD.

Simian virus 40 large-T antigen expresses a biological activity complementary to the p300-associated transforming function of the adenovirus E1A gene products.

In this report we present evidence that simian virus 40 T antigen encodes a biological activity that is functionally equivalent to the transforming activity lost by deletion of the E1A p300-binding region. T-antigen constructs from which the pRb-binding region has been deleted are virtually unable to induce foci of transformed cells in a ras cooperation assay in primary baby rat kidney cells. Nevertheless, such a construct can cooperate with an E1A N-terminal deletion mutant, itself devoid of transforming activity, to induce foci in this assay. The heterologous trans-cooperating activity observed between E1A and T-antigen deletion products is as efficient as trans cooperation between mutants expressing individual E1A domains. The cooperating function can be impaired by a deletion near the N terminus of T antigen. Such a deletion impairs neither the p53-binding function nor the activity of the pRb-binding region.

Transforming growth factor beta 1 (TGF beta 1) reduces cellular levels of p34cdc2, and this effect is abrogated by adenovirus independently of the E1A-associated pRB binding activity.

We have used E1A probes to study the roles of the p34cdc2 kinase and the retinoblastoma tumor susceptibility gene product (pRB) in transforming growth factor beta 1 (TGF beta 1)-mediated growth suppression in mink lung epithelial (Mv1Lu) cells. In agreement with previous reports, we see a decline in p34cdc2 kinase activity and a loss of pRB phosphorylation after TGF beta 1 treatment. We report here that TGF beta 1 induces not only a change in p34cdc2 kinase activity but a strong repression of p34cdc2 synthesis. Loss of p34cdc2 kinase activity is not seen until the steady-state level of p34cdc2 declines, suggesting that the intra-cellular signals induced by TGF beta 1 affect p34cdc2 at the level of expression, rather than by altering the posttranslational modifications of p34cdc2 that regulate its kinase activity. Infection with adenovirus expressing either wild-type E1A or a mutant E1A (pm928) defective for pRB binding alleviated TGF beta 1-mediated suppression of DNA synthesis, indicating that E1A does not need to bind pRB physically to keep cell growth-suppressing functions from being activated by TGF beta 1. The E1A.928 mutant virus is able to maintain p34cdc2 expression and kinase activity, as well as pRB phosphorylation in the presence of TGF beta 1, which may account for its ability to maintain cell cycle activity without directly sequestering pRB. Overall our results suggest that TGF beta 1 acts by signaling changes at the level of control of G1 gene expression, not at the level of posttranslational modification of p34cdc2 or its substrates.

The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.

The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.

Problems of mothers in management of children with diabetes.

This study was designed to determine which aspects of diabetic management were perceived by mothers of children with diabetes to be the most problematic. A secondary purpose was to explore how age and sex of the child, age at diagnosis, illness duration, marital status, and socioeconomic status of the mother were related to the mother's perception of problematic aspects of care. The 84 subjects in this study were asked to complete the Diabetic Management Concern Questionnaire, which measures concern about 11 dimensions of diabetes management, along with a personal-situational information sheet. Results indicated that the three dimensions classified by mothers as most problematic were future concerns, hypoglycemia, and diabetic control. The younger the child, the greater the maternal concern about hypoglycemic reactions and availability of help/support. The younger the child was at diagnosis, the more the mother was concerned with hypoglycemic reactions. A shorter duration of illness was related to concern about insulin injections. Subjects with lower socioeconomic status were concerned about finances, the availability of help/support, and the psychological stigma of diabetes. Single mothers were also concerned about financial aspects of management. There were no differences in concerns between mothers of boys and girls. Implications of the findings for clinical practice are presented.

Instability of succinyl ester linkages in O2'-monosuccinyl cyclic AMP-protein conjugates at neutral pH.

Chromatographic and immunological evidence is presented regarding the hydrolysis of the ester linkage of O2'-monosuccinyl cyclic AMP in neutral solutions. Such hydrolysis occurs whether the nucleotide derivative is present in free form in solution or conjugated through its succinyl carboxyl group via an amide bond to proteins. The latter process apparently occurs when succinyl cyclic AMP is conjugated to human serum albumin for use as an immunogen in the production of anti-cyclic AMP antibodies and when the derivative is coupled to the enzyme glucose-6-phosphate dehydrogenase (E.C. 1.1.1.49). The enzyme conjugate has been used in developing a homogeneous enzyme immunoassay for cyclic AMP. Inhibition of the catalytic activity of enzyme-cyclic AMP conjugates by anti-cyclic AMP antibody decreases with time, apparently due to the loss of cyclic AMP from enzyme-cyclic AMP conjugates stored in neutral solutions. In addition, the ability of free cyclic AMP to completely reverse the inhibition process decreases with time because of the presence of antibodies in the anti-cyclic AMP sera that apparently inhibit enzyme activity because of their binding specificity for the residual succinate-protein determinant sites of the enzyme conjugates. Lyophilization of the conjugates immediately after preparation helps to overcome the problem; however, in vivo hydrolysis of immunogens prepared with the succinyl cyclic AMP derivative may always occur. The consequence of this hydrolysis reaction and the subsequent formation of anti-succinyl-protein antibodies will be discussed with regard to existing RIAs for cyclic AMP and a new homogeneous enzyme immunoassay for the nucleotide.

Specific and nonspecific obstructive lung disease in childhood: causes of changes in the prevalence of asthma.

Reversible airway obstruction in childhood includes two major groups of patients: those with recurrent wheezing following bronchiolitis in early childhood, and those with allergic asthma, which represents an increasingly large proportion of cases through the school years. Over the last 40 years of the 20th century, allergic asthma has increased in many countries and in relation to several different allergens. Although this increase has differed in magnitude in different countries and also in the social groups most affected, it has had several features in common. The increase generally started between 1960 and 1970, has been progressive since then, and has continued into the 1990s without a defined peak. Among children 5-18 years of age, the increase has predominantly been among allergic individuals. Theories about the causes of the increase in asthma have focused on two scenarios: a) that changes in houses combined with increased time spent indoors have increased exposure to relevant allergens, or b) that changes in diet, antibiotic use, immunizations, and the pattern of infections in childhood have led to a change in immune responsiveness such that a larger section of the population makes T(H)2, rather than T(H)1 responses including IgE antibodies to inhalant allergens. There are, however, problems with each of these theories and, in particular, none of the proposed changes can explain the progressive nature of the increase over 40 years. The fact that the change in asthma has much in common with epidemic increase in diseases such as Type II diabetes or obesity suggests that similar factors could be involved. Several lines of evidence are reviewed that suggest that the decline in physical activity of children, particularly those living in poverty in the United States, could have contributed to the rise in asthma. The hypothesis would be that the progressive loss of a lung-specific protective effect against wheezing has allowed allergic children to develop symptomatic asthma. What is clear is that current theories do not provide either an adequate explanation of the increase or a practical approach to reversing the current trend.

Plant structure and the searching efficiency of coccinellid larvae.

| 1. To determine the effect of plant structure on the searching efficiency of Coccinella septempunctata L. larvae, their functional response on pea and bean plants was compared. 2. The attack coefficient a was lower on pea than on bean plants. 3. This was not due to a difference in the coincidence of prey distribution and predator searching effort, but was due to larvae falling off the smooth leaves of pea plants significantly more frequently than off bean plants. 4. It was concluded that plant structure is an important factor in determining the quality of a habitat for coccinellids.

Electromyographic study of human jaw-closing muscle endurance, fatigue and recovery at various isometric force levels.

The effect of a sustained isometric clenching, at various force levels or maximum voluntary bite-force levels, was evaluated on normal jaw-function subjects. Surface electromyographic (EMG) recordings of the masseter and temporalis were taken and bite force was measured using an intra-oral force transducer placed unilaterally in the 2nd premolar-1st molar region. Subjects sustained isometric force at the 25, 50, 75 and 100 per cent force level. Maximal bite force and EMG contraction levels were measured before, during and after these sustained isometric tasks. Subjects showed no change in their brief maximal contraction or force levels during or after various fatigue-inducing isometric tasks. The findings suggested a lack of contractile failure in the jaw-closing muscles. Pain intolerance rather than neuromuscular fatigue is the limiting factor of a sustained submaximal or even maximal clenching effort.

The survivors of childhood solid tumors.

With the improvement in cancer therapy in recent years, the number of cancer survivors is rapidly increasing. Potential late medical and psychosocial sequelae of cancer therapy are reviewed. A practical guide for the primary health care giver is provided.

Analysis of electromyographic signals in human jaw closing muscles at various isometric force levels.

The effect of sustained isometric contraction on surface electromyograph (EMG) and force signals derived from these muscles was examined. Premolar-molar region force was measured with a small unilaterally positioned force transducer. Subjects produced and sustained 25, 50, 75 and 100 per cent isometric force levels, and measurements were made at the beginning and end of these efforts. There was no significant change in the resulting EMG/force ratio at any of the force levels. The EMG signal did exhibit a significant shift in its frequency both as the force level increased and during the sustained effort. Neuromuscular fatigue, when defined as a change in the EMG/force ratio, was not demonstrated even though there was a consistent change in the frequency of the EMG signal.

The specification of digit and duration during motor programming: a new method of precueing.

This experiment manipulated digit uncertainty, duration uncertainty, and response duration (dit or dah) in a choice reaction time key press task. A new method of precueing was developed that effectively "precued" the digit and/or the duration of the key press task without confounding the number of stimulus response alternatives with the levels of uncertainty of digit and duration. When the duration of the response was certain, there were no RT differences between dit and dah responses, however, when duration was uncertain, RT to dah responses were longer than dit. In addition, level of duration uncertainty and digit uncertainty produced an overadditive interaction upon RT. These results are discussed in terms of generalized motor programs and a feature construction hypothesis. In addition, these results support the view that precueing of movement dimensions can be accomplished without confounding the number of stimulus response alternatives and the uncertainties of movement dimensions.

Separation of fetal and maternal ECG complexes from a mixed signal using an algorithm based on linear regression.

Fetal scalp ECG and Doppler ultrasound are the two methods universally used to derive the fetal heart rate (FHR) for cardiotocography. Other fetal signal sources have not been used successfully because of the complexity of the signal and the need for an additional maternal ECG input. In this paper, we present an algorithm for separating the fetal and maternal ECG signals obtained from intrauterine electrodes during labour. The algorithm detects all occurrences of ECG complexes and uses linear regression functions to compare each complex with a set templates. Sets of templates are identified as either maternal or fetal in origin and two signals are output for heart rate measurement. The outputs are also processed to eliminate artefacts that may occur when the maternal and fetal complexes are coincident. The algorithm processes 10 seconds of data at a time (in about 200 ms on a standard PC) while a further 10 s of data is being acquired. It has the advantage that no extra input is required, such as maternal ECG obtained from chest leads, and only assumes that two different populations of complexes of two different shapes are present in the input signal. The algorithm could also be used for the separation of fetal and maternal signals obtained from abdominal electrodes.

Genetic relatedness of North American populations of Tomicus piniperda (Coleoptera:Scolytidae).

We used DNA fingerprinting by random amplified polymorphic (RAPD) DNA and electrophoretic characterization of esterase isozymes to investigate the genetic relatedness of North American populations of the exotic bark beetle Tomicus piniperda (L.). Cluster analyses of genetic distances among populations identified the Illinois population as an outlier population with mean genetic distances to other populations averaging 0.895 (where complete dissimilarity = 2), compared with genetic distance averages of 0.595 among populations excluding Illinois. When genetic distance means and geographical distance between populations were compared, the results suggested that T. piniperda populations in the United States were established separately in Illinois near Lake Michigan and in Ohio along Lake Erie. Molecular markers indicated that insects derived from the 2 founder groups were interbreeding in contiguous regions in western Indiana.