Multiple drug intolerance syndrome and multiple drug allergy syndrome: Epidemiology and associations with anxiety and depression.

BACKGROUND: The epidemiology of multiple drug intolerance syndrome (MDIS) and multiple drug allergy syndrome (MDAS) is poorly characterized. We used electronic health record (EHR) data to describe prevalences of MDIS and MDAS and to examine associations with anxiety and depression. METHODS: Patients with ≥3 outpatient encounters at Partners HealthCare System from 2008 to 2015 were included. Patients with MDIS had intolerances to ≥3 drug classes, and patients with MDAS had hypersensitivities to ≥2 drug classes. Psychiatric conditions and comorbidities were defined from the EHR and used in multivariable logistic regression models to assess the relation between anxiety/depression and MDIS/MDAS. RESULTS: Of 746 888 patients, 47 634 (6.4%) had MDIS and 8615 (1.2%) had MDAS; 3171 (0.4%) had both. Anxiety (adjusted odds ratio [aOR] 1.72 [1.65, 1.80]), depression (aOR 1.46 [1.41, 1.52]), and both anxiety and depression (aOR 1.97 [1.86, 2.08]) were associated with increased odds of MDIS. Depression was associated with increased odds of MDAS (aOR 1.41 [1.28, 1.56]), but there were no clear associations with anxiety (aOR 1.13 [0.99, 1.30]) nor both depression and anxiety (aOR 1.13 [0.92, 1.38]). CONCLUSION: While 6% of patients had MDIS, only 1% had MDAS. MDIS was associated with both anxiety and depression; patients with both anxiety and depression had an almost twofold increased odds of MDIS. MDAS was associated with a 40% increased odds of depression, but there was no significant association with anxiety. Psychological assessments may be useful in the evaluation and treatment of patients with MDIS and MDAS; physiologic causes for MDAS warrant further investigation.

Drug allergies documented in electronic health records of a large healthcare system.

BACKGROUND: The prevalence of drug allergies documented in electronic health records (EHRs) of large patient populations is understudied. OBJECTIVE: We aimed to describe the prevalence of common drug allergies and patient characteristics documented in EHRs of a large healthcare network over the last two decades. METHODS: Drug allergy data were obtained from EHRs of patients who visited two large tertiary care hospitals in Boston from 1990 to 2013. The prevalence of each drug and drug class was calculated and compared by sex and race/ethnicity. The number of allergies per patient was calculated and the frequency of patients having 1, 2, 3…, or 10+ drug allergies was reported. We also conducted a trend analysis by comparing the proportion of each allergy to the total number of drug allergies over time. RESULTS: Among 1 766 328 patients, 35.5% of patients had at least one reported drug allergy with an average of 1.95 drug allergies per patient. The most commonly reported drug allergies in this population were to penicillins (12.8%), sulfonamide antibiotics (7.4%), opiates (6.8%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (3.5%). The relative proportion of allergies to angiotensin-converting enzyme (ACE) inhibitors and HMG CoA reductase inhibitors (statins) have more than doubled since early 2000s. Drug allergies were most prevalent among females and white patients except for NSAIDs, ACE inhibitors, and thiazide diuretics, which were more prevalent in black patients. CONCLUSION: Females and white patients may be more likely to experience a reaction from common medications. An increase in reported allergies to ACE inhibitors and statins is noteworthy.

Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America.

Drug hypersensitivity reactions (DHRs) affect an unknown proportion of the general population, and are an important public health problem due to their potential to cause life-threatening anaphylaxis and rare severe cutaneous allergic reactions. DHR evaluations are frequently needed in both ambulatory and hospital settings and have a complex diagnosis that requires a detailed clinical history and other tests that may include in vitro tests and in vivo procedures such as skin tests and drug provocation tests. Although over the years both European and U.S. experts have published statements on general procedures for evaluating DHRs, a substantial discordance in their daily management exists. In this review, we highlight both the differences and the similarities between the European and U.S. PERSPECTIVES: While a general consensus exists on the importance of skin tests for evaluating DHRs, concordance between Americans and Europeans exists solely regarding their use in immediate reactions and the fact that a confirmation of a presumptive diagnosis by drug provocation tests is often the only reliable way to establish a diagnosis. Finally, great heterogeneity exists in the application of in vitro tests, which require further study to be well validated.

Binding of Cerebratulus cytolysin A-III to human erythrocyte membranes.

Binding of Cerebratulus lacteus cytolysin A-III to intact human erythrocytes and erythrocyte membranes has been investigated. Binding to ghosts is essentially complete within 2.5 min of mixing which is slightly faster than the rate of hemolysis measured with intact cells. Approximately 4 X 10(4) binding sites per cell, exhibiting a K 0.5 of 0.7 microM exist; this compares with 50% hematocrit of about 0.3 microM for A-III. Binding is absent in ghosts extracted with Nonidet P-40, but is unaffected by pretreatment of ghosts with either trypsin or elastase.

Structure and action of heteronemertine polypeptide toxins. Specific cross-linking of Cerebratulus lacteus toxin B-IV to lobster axon membrane vesicles.

The binding of the crustacean-selective protein neurotoxin, toxin B-IV, from the heteronemertine Cerebratulus lacteus, to lobster axonal and muscle membranes has been studied. Synthesis of a radioactive bifunctional cross-linking reagent, 125I-azidosalicylic acid (ASA) B-IV, has allowed these studies as well as experiments that show cross-linking of toxin B-IV to its receptor in axonal membranes. In the absence of photolysis 125I-ASA-B-IV binds to vesicles with an apparent Kd of 30 nM and maximal binding of 7.5 pmol per mg membrane protein. Photolysis of the toxin-receptor complex at 366 nm greatly diminishes the rate of dissociation of bound toxin B-IV. Photolysis also results in the specific cross-linking to axonal proteins of molecular masses 38 and 40 kDa. This cross-linking is not observed in the presence of micromolar unlabeled toxin, in the absence of photolysis or in the presence of 150 mM K+. There is no evidence of cross-linking to proteins of higher molecular weight. The radiolabeled toxin B-IV was also found to bind to lobster muscle membranes with a dissociation constant of 500 nM and a maximum binding of approx. 4.50 pmol per mg membrane protein.

Membrane damage by Cerebratulus lacteus cytolysin A-III. Effects of monovalent and divalent cations on A-III hemolytic activity.

The effects of monovalent and divalent cations on the hemolytic activity of Cerebratulus lacteus toxin A-III were studied. The activity of cytolysin A-III is remarkably increased in isotonic, low ionic strength buffer, the HC50 (the toxin concentration yielding 50% lysis of a 1% suspension of erythrocytes after 45 min at 37 degrees C) being shifted from 2 micrograms per ml in Tris or phosphate-buffered saline to 20-30 ng per ml in sucrose or mannitol buffered with Hepes, corresponding to a 50-100-fold increase in potency. On the contrary, hemolytic activity decreases progressively as the monovalent cation concentration in the medium increases for Na+, K+, or choline salts. The divalent cations Ca2+ and Zn2+ likewise inhibit the cytolysin A-III activity, but more strongly than do the monovalent cations specified above. Zn2+ at a concentration of 0.3 mM totally abolishes both toxin A-III-dependent hemolysis of human erythrocytes and toxin-induced leakage from liposomes. The observation of similar effects in both natural membranes and artificial bilayers suggests an effect of Zn2+ on the toxin A-III-induced membrane lesion, especially since Zn2+ does not alter binding of the cytolysin. The dose-response curve for toxin A-III exhibits positive cooperativity, with a Hill coefficient of 2 to 3. However, analysis of toxin molecular weight by analytical ultracentrifugation reveals no tendency to aggregate at protein concentrations up to 2 mg per ml. These data are consistent with a post-binding aggregational step which may be affected by the ionic strength of the medium.

The complete amino acid sequence of the alpha-subunit of pea lectin, Pisum sativum.

The complete primary structure of the alpha-subunit of the lectin from the pea (Pisum sativum) has been determined using a combination of tryptic and staphylococcal protease digestion, purification using Sephadex gel filtration and high-voltage electrophoresis followed by either manual or automated Edman degradation. The molecular weight of the alpha-subunit from sequence data and gel filtration in guanidine-HCl is close to 5800, which is lower than that determined by sedimentation equilibrium techniques. The sequence reveals considerable homology to concanavalin A and near identity to the alpha-subunit of the lentil lectin (Lens culenaris). As in the case of the lentil alpha-subunit, the alpha-methyl glucose binding site(s) are not present in this region, nor are the S1 and S2 metal ion binding sites as judged by homology consideration, though the residues for the S3 lanthanide binding (Glu 87 and Asp 136) are conserved from the available data on the alpha- and beta-subunits. Preliminary metal exchange experimens on the intact pea lectin indicate some differnces in the metal exchange properties of this lectin compared to concanavalin A, and therefore possible ligand variations in this region of the beta-subunit.

Renaturation of neurotoxin B-IV from the heteronemertine Cerebratulus lacteus.

The heteronemertine Cerebratulus lacteus synthesizes a family of four structurally homologous, crustacean-selective polypeptide toxins (B-toxins) which affect action potential generation in nervous issue. The most abundant homolog, toxin B-IV, is completely inactivated by reduction of its four disulfide bands. Reduction is also accompanied by loss of secondary structure. Reoxidation of the reduced protein may be catalyzed by the oxidized forms of glutathione or dithiothreitol. Secondary structure and toxicity are recovered in parallel; the terminally reoxidized protein regains approximately 75% of both the neurotoxicity and the secondary structure of native B-IV.

Identification of oleic acid binding sites in cytolysin A-III from the heteronemertine Cerebratulus lacteus.

We previously demonstrated that binding of oleic acid to Cerebratulus lacteus cytolysin A-III results in aggregation of this monomeric protein to a tetramer, concomitant with an increase in hemolytic activity. In the present study, incubation of cytolysin A-III with [14C]-oleic acid in the presence of a water-soluble carbodiimide results in covalent incorporation of a maximum of two molecules of the fatty acid into the protein. Labeling is restricted to two large tryptic peptides. Sequence analysis of peptide mixtures derived from the labeled protein reveals that the predominant sites of labeling are Lys-31 and Lys-71; the latter site is part of the C-terminal amphipathic helix previously shown to be important for hemolytic activity while the former lies in the other significant hydrophobic region of this largely hydrophilic protein.

Identification and characterization of novel sodium channel toxins from the sea anemone Anthopleura xanthogrammica.

Six new toxins from the sea anemone Anthopleura xanthogrammica were identified using a molecular biological approach. Five of these novel isoforms resemble the 47 residue type I long polypeptides native to Anthopleura elegantissima, Anthopleura fuscoviridis and Anemonia sulcata, while one appears to be chimera of the two previously identified 49 residue toxins native to A. xanthogrammica. Four of these toxins were expressed in bacteria, purified and characterized by ion flux assays in RT4-B and N1E-115 cell lines expressing the cardiac and neuronal Na channel isoforms, respectively. The novel 47 residue toxin isoforms form a new subclass within the A. xanthogrammica neurotoxin family, although they are related to previously described anemone toxins. One of the three 47 residue toxins characterized, PCR2-10, enhances veratridine-dependent sodium uptake, displaying a K0.5 of 329 nM and 1354 nM in RT4-B and N1E-115 cell lines, respectively. The novel 49 residue toxin, PCR3-7, interacts with the sodium channel with even higher affinity, enhancing sodium uptake with a K0.5 of 47 nM and 108 nM in RT4-B and N1E-115 cells, respectively.

Dynamic splinting after extensor tendon repair in zones V to VII.

This retrospective study evaluates a dynamic active motion protocol for extensor tendon repairs in zones V to VII. Fifty-eight patients with 87 extensor tendon injuries were examined. Using Geldmacher's and Kleinert and Verdan's evaluation systems, the results were graded as "excellent" and "good" in more than 94%, and as "satisfactory" in the remainder. The need for secondary tenolysis was low (6%), and no other surgical complication occurred.

[Washington regime after-care of flexor tendon injuries in zone 2]. / Die Nachbehandlung von Beugesehnenverletzungen in Zone 2 nach dem Washington-Regime.

The Washington-regimen for the rehabilitation of flexor tendon injuries (Chow et al., 1987) represents a combination of the established Kleinert-method and the controlled passive motion of Duran and Houser. This paper presents the results of a study which was carried out in 99 patients with 113 injured fingers treated in the Department of Burns, Plastic and Hand Surgery of the Accident Hospital Ludwigshafen. 55 patients with injuries of the fingers and 29 patients with injuries of the thumb were evaluated according to functional and subjective criteria and compared to a group of 15 patients treated by the Kleinert-method. The results showed that the Washington-regimen yielded an improvement of up to 27% of very good and good results in injured fingers compared to the Kleinert-method. The improvement of results in thumb injuries was 8%. The subjective estimation of the results by the patients corresponded generally with the functional outcome. In cases with additional laceration of digital nerves, the subjective evaluation of two thirds of the patients was significantly worse than the objective functional results.

Structure and action of heteronemertine polypeptide toxins. Membrane penetration by Cerebratulus lacteus toxin A-III.

The heteronemertine worm Cerebratulus lacteus produces a family of three structurally homologous proteins that function as direct lytic factors for a variety of cells [Kem, W. R., & Blumenthal, K. M. (1978) J. Biol. Chem. 253, 5752-5757]. It is demonstrated herein that the hemolytic activity of the most abundant variant, designated toxin A-III, is unaffected by either extensive iodination or complete blockage of carboxylate groups by tyramine or glycine ethyl ester. Iodination of A-III with lactoperoxidase produced a derivative that is preferentially labeled at His-67 and to a lesat the hemolytic activity of the most abundant variant, designated toxin A-III, is unaffected by either extensive iodination or complete blockage of carboxylate groups by tyramine or glycine ethyl ester. Iodination of A-III with lactoperoxidase produced a derivative that is preferentially labeled at His-67 and to a lesat the hemolytic activity of the most abundant variant, designated toxin A-III, is unaffected by either extensive iodination or complete blockage of carboxylate groups by tyramine or glycine ethyl ester. Iodination of A-III with lactoperoxidase produced a derivative that is preferentially labeled at His-67 and to a lesser extent at Tyr-6. The ratio of labeling at these two positions is approximately 3 to 1. Iodinated A-III is completely insoluble in 10% C13CCOOH. However, following treatment with trypsin-containing liposomes, 15% of the input counts are converted to a Cl3CCOOH-soluble form. Incubation with free trypsin in the presence of liposomes containing N alpha-tosyl-L-lysine chloromethyl ketone results in approximately 60% of the input counts becoming C13CCOOH soluble. Free trypsin renders toxin A-III 90% soluble in 10% C1CCOOH. Electrophoretic analysis of the labeled tryptic peptides generated in the presence of liposomes shows that internal trypsin hydrolyzed the Arg-13-Ser-14 bond, generating exclusively peptide T-1 (residues 1-13) while external trypsin produces peptide T-11 (residues 60-71) as the major radioactive product. These data are consistent with insertion of at least the amino-terminal 13 residues of A-III into the liposome and imply that membrane penetration by this protein may be important for its cytolytic activity.

Release of liposomal markers by Cerebratulus toxin A-III.

Marker release from liposomes induced by the cytolytic protein Cerebratulus lacteus toxin A-III was studied. No phospholipid specificity was apparent, but the sensitivity of liposomes to A-III varied with the membrane fluidity. With dioleylphosphatidylcholine liposomes, complete release occurred at 10-20 micrograms toxin per ml, depending on marker size. Kinetic experiments showed that release was rapid and exhibited no lag phase. The diameter of the A-III produced membrane lesion must exceed 90 A, as tetrameric Concanavalin A is quantitatively released from A-III treated liposomes.

Structure and action of heteronemertine polypeptide toxins. Disulfide bonds of Cerebratulus lacteus toxin A-III.

The positions of the disulfides bonds in Cerebratulus lacteus toxin A-III were investigated by hydrolysis of the unreduced protein with trypsin. The resulting peptides were purified by gel filtration, paper electrophoresis, and paper chromatography. Determination of the amino acid compositions of the purified peptides demonstrated the existence of disulfide bonds linking half-cystine residues 17 and 38, 23 and 34, and 48 and 61.

Effects of N-ethylmaleimide treatment on the action potential Na+-ionophore of cultured neuroblastoma cells.

Treatment of murine neuroblastoma N18 cells with N-ethylmaleimide under conditions that favor diminution of membrane potential leads to a 65% increase in the rate of veratridine-stimulated, tetrodotoxin-sensitive Na+ uptake and to a 50% decrease in the concentration of veratridine required for half-maximal stimulation. This modification does not appear to occur in N18 cells having a normal membrane potential of approx. -40 mV. The data are consistent with the involvement of a sulfhydryl group in the Na+ channel inactivation gate and in the conformational change in this gate which results in closing of the channel.

Primary structure of Stoichactis helianthus cytolysin III.

The primary structure of Stoichactis helianthus cytolysin III has been determined by automated Edman degradation of the intact protein and of peptides derived therefrom by hydrolysis with trypsin and staphylococcal protease and by chemical cleavage with cyanogen bromide and o-iodosobenzoic acid. As a result of these studies, the positions of all 153 amino acid residues of toxin III have been unambiguously determined. Most regions of sequence were determined two times in different types of digests of the protein. A number of highly hydrophobic regions of sequence, which may be functionally significant, have been identified, including a region rich in tyrosine and tryptophan (residues 86-98). The secondary structure of toxin III has been predicted by Chou-Fasman analysis (Chou, P.Y., and Fasman, G.D. (1978) Annu. Rev. Biochem. 47, 251-276) of the primary structure. The predicted secondary structure contains 16% alpha-helix and 31% beta-structure.

Structure and action of heteronemertine polypeptide toxins: importance of amphipathic helix for activity of Cerebratulus lacteus toxin A-III.

The marine heteronemertine Cerebratulus lacteus produces a family of protein cytolysins designated as A-toxins. Limited subtilisin digests of the most abundant homolog, toxin A-III, yield two major products which may be purified by high-performance liquid chromatography. One product is shown to represent residues 1-86 and the other contains the entire toxin sequence (1-95). Both polypeptides are shown to lack internal protease nicks. The 1-95 polypeptide retains full cytolytic activity in comparison to native toxin, whereas 1-86 has an activity that is approximately four times lower. Extensive treatment of A-III with carboxypeptidase Y yields a polypeptide containing residues 1-75 which is totally devoid of hemolytic activity. Residues 63-95 of native A-III have been predicted to form a relatively hydrophobic alpha-helix which is potentially important for activity. The circular dichroism spectrum of 1-95 is in excellent agreement with both experimental and Chou-Fasman-predicted secondary structures of native A-III, while the spectra of 1-86 and 1-75 indicate a loss of helicity quantitatively consistent with the removal of residues 87-95 and 76-95, respectively. Combined with our earlier data on bilayer penetration by N-terminal sequences (K. M. Blumenthal (1982) Biochemistry 21, 4229-4233], the current results indicate a direct involvement of both ends of A-III in lytic activity. The C-terminal region may function by contributing a membrane binding site in the form of an amphipathic helix.