Real-world effectiveness of abrocitinib treatment in patients with difficult-to-treat atopic dermatitis.

BACKGROUND: Abrocitinib is a JAK-1 selective inhibitor registered for the treatment of moderate-to-severe atopic dermatitis (AD). Although efficacy and safety have been shown in phase 3 clinical trials, data on real-world patients with a treatment history of advanced systemics are scarce. OBJECTIVES: The objective of the study was to evaluate the effectiveness and safety of abrocitinib treatment in patients with difficult-to-treat AD in daily practice. METHODS: In this prospective observational single-centre study, all AD patients who started abrocitinib treatment in the context of standard care between April 2021 and December 2022 were included. Effectiveness was assessed using clinician- and patient-reported outcome measures. Adverse events were evaluated. RESULTS: Forty-one patients were included. The majority (n = 30; 73.2%) had failed (ineffectiveness) on other targeted therapies, including JAK inhibitors (n = 14, 34%) and biologics (n = 16, 39%). Abrocitinib treatment resulted in a significant decrease in disease severity during a median follow-up period of 25 weeks (IQR 16-34). Median EASI score at baseline decreased from 14.7 (IQR 10.4-25.4) to 4.0 (IQR 1.6-11.4) at last review (p < 0.001). Median NRS itch decreased from 7.0 (IQR 5-8) to 3.0 (IQR 1-2) at last review (p < 0.001). The most frequently reported AEs included gastrointestinal symptoms (27.6%), acne (20.7%) and respiratory tract infections (17.2%). 16 (39%) patients discontinued abrocitinib treatment due to ineffectiveness, AEs or both (41.2%, 41.2% and 11.8%, respectively). CONCLUSION: Abrocitinib can be an effective treatment for patients with moderate-to-severe AD in daily practice, including non-responders to other targeted therapies.

[Peripheral arterial occlusive disease as predictor of high atherosclerotic burden]. / Periphere arterielle Verschlusskrankheit als Prädiktor einer hohen Atheroskleroselast.

Atherosclerosis is a disease which affects the whole arterial vascular tree. In particular patients with peripheral arterial occlusive disease (PAOD) often suffer from additional atherosclerotic manifestations in other vascular territories. This has a direct impact on cardiovascular prognosis. Atherosclerosis is an inflammatory disease. A high inflammatory burden is associated with polyvascular atherosclerosis and also with the occurrence of cardiovascular events. Control of cardiovascular risk factors is crucial for the treatment of patients with polyvascular atherosclerosis. In addition, anticoagulation treatment is very important in patients with atherosclerosis. Moreover, exercise training is an important treatment option in PAOD patients not only to improve walking distance but also for multiple additional positive effects. So far the role of anti-inflammatory treatment is not clear and must be further elaborated by future clinical research.

Association between microfibrillar-associated protein 4 (MFAP4) and micro- and macrovascular complications in long-term type 1 diabetes mellitus.

AIMS: To evaluate microfibrillar-associated protein 4 (MFAP4) as a marker of micro- and macrovascular complications in patients with type 1 diabetes. METHODS: This cross-sectional study included 203 persons with a long duration of type 1 diabetes from a population-based cohort ascertained in the former Funen County, Denmark. Detection of plasma-MFAP4 (pMFAP4) was performed by the AlphaLISA Technique. Diabetic retinopathy (DR) was graded in accordance with the Early Treatment Diabetic Retinopathy Study adaptation of the modified Airlie House classification. A monofilament test was used to test for neuropathy, and nephropathy was evaluated in a single spot urine sample. Data describing macrovascular disease were obtained from the Danish National Patient Register. RESULTS: Median age and duration of diabetes were 58.7 and 43 years, respectively, and 61% were males. High levels of pMFAP4 were found in participants of old age, in women and in non-smokers (p < 0.05). In a multiple logistic regression model, patients with high levels of pMFAP4 were more likely to have diabetic neuropathy (OR 2.47 for quartile 4 versus quartile 1, 95% CI 1.01-6.03). No association was found between pMFAP4 and proliferative diabetic retinopathy, nephropathy or macrovascular disease. CONCLUSIONS: No association between pMFAP4 and macrovascular vascular complications was found. However, high levels of pMFAP4 correlated independently with diabetic neuropathy. Further studies on the predictive value of increased circulating MFAP4 in diabetic neuropathy are warranted.

Analysis of interactions between proteins and fatty acids or cholesterol using a fatty acid/cholesterol pull-down assay.

Specific interactions between the polar head groups of membrane lipids and proteins have been described previously. In contrast, the specificity of the interaction between lipid acyl chains with proteins is less understood. By combining a fatty acid or cholesterol pull-down assay with Western blot analysis or mass spectrometry, we identified transmembrane and cytosolic proteins that bound preferentially to short or long acyl chains or to cholesterol. Thus, this approach allows identification of specific fatty acid-protein or cholesterol-protein interactions.

Stenting of stenotic mesenteric arteries for symptomatic chronic mesenteric ischemia.

BACKGROUND: We report the results of our single center series of patients with chronic mesenteric ischemia (CMI) to determine the role of stenting in the management of patients. PATIENTS AND METHODS: We retrospectively reviewed all patients with CMI treated endovascularly with stent revascularisation from January 2008 to January 2011.CMI diagnosis was made according to clinical symptoms, including postprandial abdominal pain, food fear, and weight loss. Additionally, the diagnosis was confirmed by duplex ultrasonography and/or computed tomography angiography and/or contrast-enhanced magnetic resonance angiography. RESULTS: All 45 patients presented with typical CMI symptoms: 45/45 (100 %) had postprandial pain, 31/45 (68.8 %) had a weight loss of more than 10 kilograms, and 11/45 (24.4 %) suffered from ischemic colitis combined with lower gastrointestinal bleeding. In three patients occlusion could not be crossed, therefore considered as technical failure. A total of 55 arteries were stented in the remaining 42 patients. Nineteen patients underwent SMA stenting alone, eight underwent celiac stenting, alone and three patients underwent stenting of inferior mesenteric artery (IMA) alone. We performed combined stenting of the celiac artery and superior mesenteric artery in ten patients, and one patient underwent a combined stenting of the celiac artery and the IMA. All three mesenteric arteries were stented in only one patient. Primary technical success was achieved in 42/45 (94.8 %) patients. Clinical symptom relief was achieved in 39/45 (86.6 %) patients with abdominal pain. Increased body weight was observed in 28/31 (90.3 %) patients with an average weight gain of 8.8 kilograms (5 - 12 kilograms), and 10/11 (90.9 %) patients recovered from ischaemic colitis/lower gastrointestinal bleeding. CONCLUSIONS: Stent revascularisation can be considered as the first-line therapy for patients with chronic mesenteric ischemia.

Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: up to 2 years exposure in 24-week phase III trials followed by a 78-week open-label extension.

Aim: The aim of this study was to evaluate the long-term safety, tolerability and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin given either alone or in combination with other oral glucose-lowering agents in persons with type 2 diabetes. Methods: A 78-week open-label extension study evaluated subjects who participated in one of four preceding 24-week, randomised, double-blind, placebo-controlled parent trials and who received linagliptin, linagliptin + metformin, linagliptin + metformin + a sulphonylurea or linagliptin + pioglitazone (all with linagliptin administered orally once daily). Individuals receiving one of these treatments during a previous trial continued the same treatment (n = 1532) for up to a total of 102 weeks, whereas those previously receiving placebo were switched to linagliptin (n = 589). All 2121 participants received at least one dose of the trial medication and were included in the primary safety analysis. Results: In subjects previously receiving active treatment, the glycosylated haemoglobin A(1c) reduction achieved during the 24-week parent trials was sustained through the 78-week extension period (change from baseline to week 102: -0.8%). Drug-related adverse events were experienced by 14.3% of participants. Hypoglycaemia occurred in 13.9% of participants and was similar between those previously receiving treatment (13.6%) and those switching from placebo to linagliptin (14.6%). Hypoglycaemia occurred most frequently with the use of metformin + a sulphonylurea background therapy (11%). Overall, no clinically relevant changes in body weight were observed. Conclusion: Long-term treatment with linagliptin was well tolerated with no change in the safety profile observed during the extension study. Sustained long-term glycaemic control was maintained for up to 102 weeks with either linagliptin monotherapy or linagliptin in combination with other oral glucose-lowering agents.

Processing speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroimaging.

We explored relationships between decline in cognitive processing speed (CPS) and change in frontal lobe MRI/MRS-based indices of cerebral integrity in 38 healthy adults (age 57-90 years). CPS was assessed using a battery of four timed neuropsychological tests: Grooved Pegboard, Coding, Symbol Digit Modalities Test and Category Fluency (Fruits and Furniture). The neuropsychological tests were factor analyzed to extract two components of CPS: psychomotor (PM) and psychophysical (PP). MRI-based indices of cerebral integrity included three cortical measurements per hemisphere (GM thickness, intergyral and sulcal spans) and two subcortical indices (fractional anisotropy (FA), measured using track-based spatial statistics (TBSS), and the volume of hyperintense WM (HWM)). MRS indices included levels of choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), and N-acetylaspartate (NAA), measured bilaterally in the frontal WM bundles. A substantial fraction of the variance in the PM-CPS (58%) was attributed to atrophic changes in frontal WM, observed as increases in sulcal span, declines in FA values and reductions in concentrations of NAA and choline-containing compounds. A smaller proportion (20%) of variance in the PP-CPS could be explained by bilateral increases in frontal sulcal span and increases in HWM volumes.

Microfibril-associated protein 4 binds to surfactant protein A (SP-A) and colocalizes with SP-A in the extracellular matrix of the lung.

Pulmonary surfactant protein A (SP-A) is an oligomeric collectin that recognizes lipid and carbohydrate moieties present on broad range of micro-organisms, and mediates microbial lysis and clearance. SP-A also modulates multiple immune-related functions including cytokine production and chemotaxis for phagocytes. Here we describe the molecular interaction between the extracellular matrix protein microfibril-associated protein 4 (MFAP4) and SP-A. MFAP4 is a collagen-binding molecule containing a C-terminal fibrinogen-like domain and a N-terminal located integrin-binding motif. We produced recombinant MFAP4 with a molecular mass of 36 and 66 kDa in the reduced and unreduced states respectively. Gel filtration chromatography and chemical crosslinking showed that MFAP4 forms oligomers of four dimers. We demonstrated calcium-dependent binding between MFAP4 and human SP-A1 and SP-A2. No binding was seen to recombinant SP-A composed of the neck region and carbohydrate recognition domain of SP-A indicating that the interaction between MFAP4 and SP-A is mediated via the collagen domain of SP-A. Monoclonal antibodies directed against MFAP4 and SP-A were used for immunohistochemical analysis, which demonstrates that the two molecules colocalize both on the elastic fibres in the interalveolar septum and in elastic lamina of pulmonary arteries of chronically inflamed lung tissue. We conclude, that MFAP4 interacts with SP-A via the collagen region in vitro, and that MFAP4 and SP-A colocates in different lung compartments indicating that the interaction may be operative in vivo.

Skin biopsy findings and results of neuropsychological testing in the first confirmed cases of CADASIL in Norway.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by mutations in the notch3 gene. The mutation can be demonstrated by a gene test. The first group of Norwegian patients with CADASIL confirmed by gene testing was recently described. The present study includes six of the original nine patients with demonstrated notch3 mutation plus one patient with symptoms, who had been unwilling to go through gene testing. These seven patients underwent skin biopsy for electron microscopy. One patient was cognitively too impaired, but six went through neuropsychological testing. By electron microscopy characteristic granular osmiophilic material (GOM) was detected in all skin biopsies. The material is seen as granular deposits in the basal lamina of the smooth muscle layer, often making impressions upon adjacent smooth muscle cells. It seems important that blood vessels over a certain size (diameter >20 microm) are examined. A varying extent of cognitive decline was noted amongst all by neuropsychological testing. In cases with multiple infarctions reduction of perceptual speed, visuospatial skills and working memory could be demonstrated. Four patients showed executive dysfunction.

The novel Streptomyces olivaceoviridis ABC transporter Ngc mediates uptake of N-acetylglucosamine and N,N'-diacetylchitobiose.

During cultivation in the presence of N-acetylglucosamine or chitin, Streptomyces olivaceoviridis mycelium efficiently takes up [(14)C]-labelled N-acetylglucosamine. Uptake of the labelled compound can be completely inhibited by unlabelled N-acetylglucosamine and partially by chitobiose. After extraction of the membrane with Triton X-100, two forms of a protein that binds to N-acetylglucosamine and N, N'-diacetylchitobiose (chitobiose) were purified to homogeneity by two consecutive rounds of anionic exchange chromatography. The protein was named NgcE. Using surface plasmon resonance, its binding parameters were determined. It showed highest affinity for N-acetylglucosamine (K(D)=8.28 x 10(-9) M) and for chitobiose (K(D)=2.87 x 10(-8) M). Varying equilibrium dissociation constants in the micromolecular range were ascertained for chitotetraose (K(D)=4.5 x 10(-6) M), chitopentaose (K(D)=1.03 x 10(-6) M) and chitohexaose (K(D)=3.02 x 10(-6) M); the lowest value was measured for chitotriose (K(D)=19.4 x 10(-6) M). After having determined the sequences of several internal peptides from the binding protein by Edman degradation, the corresponding ngcE gene, which encodes a predicted lipid-anchored protein, was identified by reverse genetics. Using a genomic phage library of S. olivaceoviridis genes encoding two other membrane proteins (named NgcF and NgcG) were identified adjacent to ngcE. Each of these is predicted to have six membrane-spanning helices and a consensus motif for integral membrane proteins characteristic of ABC transporters. In addition, the gene for a predicted regulator protein (NgcR) was detected. The ngcEFG operon lacks a gene for an ATP-hydrolysing protein. NgcE is a new member of the CUT-1 family of ABC transporters for carbohydrates. Comparative studies of the wild-type and a mutant strain carrying an insertion within the ngc operon clearly demonstrate that the Ngc system mediates the uptake of N-acetylglucosamine and chitobiose in vivo.

Fluorescence-monitored conformational change on the 3'-end of tRNA upon aminoacylation.

Fluorescent tRNAs species with formycine in the 3'-terminal position (tRNA-CCF) were derived from Escherichia coli tRNA(Val). Thermus thermophilus tRNA(Aap) and Thermus thermophilus tRNA(Phe). The fluorescence of formycine was used to monitor the conformational changes at the 3'-terminus of tRNA caused by aminoacylation and hydrolysis of aminoacyl residue from aminoacyl-tRNAs. An increase of about 15% in the fluorescence intensity was observed after aminoacylation of the three tRNA-CCF. This change in fluorescence amplitude that is reversed by hydrolysis of the aminoacyl residue, does not depend on the structure of the amino acid or tRNA sequence. A local conformational change at the 3'-terminal formycine probably involving a partial destacking of the base moiety in the ACCF end takes place as a consequence of aminoacylation. A structural change at the 3'-terminus of tRNA induced by attachment and detachment of the acyl residue may be important in controlling the substrate/product relationship in reactions in which tRNA participates during protein biosynthesis.

Rapid tryptophan depletion plus a serotonin 1A agonist: competing effects on sleep in healthy men.

In the present study, we hypothesized that the REM-suppressing effects of 5-HT(1A) receptor stimulation would counteract the REM-disinhibiting effects of rapid tryptophan depletion (RTD), and vice versa. We administered RTD plus ipsapirone (10 mg, p.o.) or RTD plus placebo to 10 healthy men. In contrast to our previous findings but partially consistent with other studies, RTD in combination with placebo did not produce a significant enhancement of any REM sleep measure. The combination of RTD and ipsapirone produced a significant suppression of REM sleep that was remarkably similar to the effect of ipsapirone alone. These data appear to deepen the mystery of variable and inconsistent RTD-induced responses in healthy subjects. In the case of REM sleep measures, this differs markedly from the consistent RTD-induced REM-disinhibiting effect seen in medicated depressed patients.

Ultradian rhythms of alternating cerebral hemispheric EEG dominance are coupled to rapid eye movement and non-rapid eye movement stage 4 sleep in humans.

Objective: To replicate the left minus right (L-R) hemisphere EEG power shifts coupled to rapid eye movement (REM) and non-rapid eye movement (NREM) sleep observed in 1972 by Goldstein (Physiol Behav (1972) 811), and to characterize the L-R EEG power spectra for total EEG, delta, theta, alpha and beta bands.Background: Ultradian alternating cerebral hemispheric dominance rhythms are observed using EEG during both waking and sleep, and with waking cognition. The question of whether this cerebral rhythm is coupled to the REM-NREM sleep cycle and the basic rest-activity cycle (BRAC) deserves attention.Methods: L-R EEG signals for ten young, normal adult males were converted to powers and the means were normalized, smoothed and subtracted. Sleep hypnograms were compared with L-R EEGs, and spectra were computed for C3, C4 and L-R EEG powers.Results: Significant peaks were found for all C3, C4 and L-R frequency bands at the 280-300, 75-125, 55-70 and 25-50 min bins, with power dominating in the 75-125 min bin. L-R EEG rhythms were observed for all bands. Greater right hemisphere EEG dominance was found during NREM stage 4 sleep, and greater left during REM for total EEG, delta and alpha bands (Chi-squares, P<0.001). Theta was similar, but not significant (P=0.163), and beta was equivocal.Conclusions: Earlier ultradian studies show that lateral EEG and L-R EEG power have a common pacemaker, or a mutually entrained pacemaker with the autonomic, cardiovascular, neuroendocrine and fuel-regulatory hormone systems. These results for L-R EEG coupling to sleep stages and multi-variate relations may present a new perspective for Kleitman's BRAC and for diagnosing variants of pathopsychophysiological states.

Peri-marketing surveillance of lamotrigine in The Netherlands: doctors' and patients' viewpoints.

PURPOSE: Evaluation of daily clinical practice in prescribing lamotrigine in refractory epilepsy patients. METHODS: A collaborative, retrospective, peri-marketing study was performed in in- and out-patients attending one of the three Dutch epilepsy centres. Analysis of both patients' and doctors' information was performed in 520 patients using questionnaires and medical files. RESULTS: After one year of treatment 76% of patients maintained LTG treatment, an intention-to-treat analysis showed > = 50% seizure reduction in 23% of patients; 20-50% seizure reduction in 23% of patients. Six percent of patients became at least three months seizure free. In about 20% of patients seizures became less severe and shorter of duration, while in 6% an increase was found. After three months a significant decrease in number of concomitant antiepileptic drugs was found (change from mean 1.8 to 1.5 AEDs) (p = < 0.01). After twelve months the mean number of AEDs was 1.4 per patient. Overall percentage of side effects appeared to be significantly higher if patients' questionnaire data were used. Epilepsy patients considered side effects as an important factor in the choice of medication and in withdrawal of medication. Future developments of new AEDs should take this into account. CONCLUSION: This perimarketing study gives insight information about long-term daily use of lamotrigine, with emphasis on effectiveness. Patients complained in the questionnaires much more about side-effects, than was known according to the medical file. Therefore, it seems necessary to perform perimarketing studies more systematically.

Synthesis of the Streptomyces lividans maltodextrin ABC transporter depends on the presence of the regulator MalR.

During growth with maltotriose or amylose, Streptomyces lividans and Streptomyces coelicolor A3(2) synthesize a maltodextrin uptake system with highest specificity for maltotriose. The transport activity is absent in mutants of S. coelicolor A3(2) lacking a functional MalE binding protein. Cloning and sequencing data suggest that the mal operon of S. coelicolor A3(2) corresponds to the one of S. lividans and that the deduced S. lividans Reg1 amino acid sequence is identical to that of MalR from S. coelicolor A3(2). It can be concluded that both strains have the same ABC transport system for maltodextrins. The S. lividans malR was cloned in Escherichia coli in frame with six histidine-encoding codons. The resulting, purified 6HisMalR(SI) was shown to bind to two motifs within the S. lividans malR-malE intergenic region and to dissociate in the presence of maltopentaose.

Analysis of protein phosphorylation by a combination of elastase digestion and neutral loss tandem mass spectrometry.

Loss of phosphoric acid is the most effective fragmentation reaction of pSer- and pThr-containing phosphopeptides of small size (up to 10-15 residues) in low-energy collision-induced dissociation. Therefore, tandem mass spectrometry with neutral loss scanning was evaluated for its utility to analyze protein phosphorylation using protein kinase A (PKA) catalytic subunit, which is phosphorylated at Thr197 and Ser338, as an example. Analysis of tryptic digests of phosphoproteins by tandem mass spectrometry with scanning for neutral loss of phosphoric acid resulted in spectra with poor signal-to-noise ratio, mainly because of the large size of the phosphopeptides formed (>2 kDa). This unfavorable size was caused by the distribution of tryptic cleavage sites in PKA and by interference of phosphorylation with tryptic cleavage. To generate a set of smaller peptide fragments, digestion was performed using the low-specificity protease elastase. Analysis of the total elastase digest with neutral loss scanning resulted in observation of a set of partially overlapping phosphopeptides with high abundance, providing a complete coverage of PKA phosphorylation sites. The peptide size generated by elastase (0.5-1.5 kDa) is ideally suited for this scan mode, which was found to provide the highest specificity for detection of singly charged phosphopeptides (neutral loss of 98). Identification of the PKA phosphorylation sites was performed by mass spectrometric sequencing of the elastase-derived phosphopeptides, which provided highly informative product ion spectra.

Lack of association between carotid artery volume blood flow and cardiac output.

OBJECTIVE: The correlation of cardiac output and cerebral perfusion is unclear. We tested this potential association by correlating cardiac output data obtained by echocardiography and cerebral blood flow data as determined by color M-mode measurements of carotid artery blood flow. METHODS: We studied 43 patients with a broad spectrum of cardiac performance by means of transthoracic echocardiography. In these patients, different cardiac indices such as stroke volume, ejection fraction, and heart minute volume were determined. The data were correlated with volumetric flow measurements (color M-mode duplex system) of the common carotid arteries bilaterally. RESULTS: Heart minute volume ranged from 1.632 to 9.836 mL/min (mean +/- SD, 4.652 +/- 1.621 mL/min); ejection fraction ranged from 18% to 76% (mean, 48% +/- 16%). The relative fraction of carotid volume flow compared with heart minute volume was 15% +/- 6%. There was no correlation between ejection fraction, stroke volume, or heart minute volume and absolute volume flow in the carotid arteries when being adjusted for age. There was a highly significant inverse correlation (r = -0.8; P < .0001) of the relative fraction of the carotid volume flow (carotid volume flow/heart minute volume [percent]) and the heart minute volume. CONCLUSION: Our data support the concept that cerebral blood flow is independent of cardiac output.

Binding characteristics of CebR, the regulator of the ceb operon required for cellobiose/cellotriose uptake in Streptomyces reticuli.

The Streptomyces reticuli Avicelase (cellulase, Cell) hydrolyzes crystalline cellulose to cellooligomers, cellobiose and cellotriose which are taken up by mycelia via an ABC transport system (Ceb) induced during growth with cellobiose or cellulose. The cebR gene located upstream of the cebEFG operon was cloned in Escherichia coli in frame with six histidine-encoding codons. The resulting purified fusion protein was shown to bind to a motif of 23 bp, including a perfect 18-bp palindrome situated upstream of the cebEFG. Cytoplasmic extracts of induced, but not of uninduced S. reticuli protected the same DNA motif. Release of the CebR regulator from its operator occurs upon addition of cellopentaose which can be assumed to act as inducer within the mycelia.

MsiK-dependent trehalose uptake in Streptomyces reticuli.

During cultivation in the presence of trehalose Streptomyces reticuli expresses an inducible, highly specific trehalose uptake system that is absent in Streptomyces lividans. A palmitated trehalose-binding protein was identified in the cytoplasmic membrane of mycelia, extracted with the detergent Triton X-100 and purified using a trehalose affinity matrix. Immunological studies showed that within S. reticuli the synthesis of the ATP-binding protein MsiK is induced by trehalose. The data suggest that MsiK assists the trehalose ABC transporter, like the previously described ABC transport systems for maltose and cellobiose/cellotriose, respectively.

Five-membered ring formation in unimolecular reactions of peptides: a key structural element controlling low-energy collision-induced dissociation of peptides.

Unimolecular fragmentation reactions of peptides in low-energy collision-induced dissociation are reviewed in the mechanistic context of five-membered ring formation. This structure of intermediates or of fragment ions is recognized as a key element that governs unimolecular peptide fragmentation within the structural framework determined by the peptide backbone and its side-chains. A collection of collision-induced dissociation reactions is presented covering (i) b-ion formation, (ii) the fragmentation of N-terminally acylated peptides, (iii) neutral loss of the C-terminal amino acid in alkali or silver cationized peptides, (iv) the fragmentation of isoAsp-containing peptides and (v) the fragmentation of negatively charged Asp- or Glu-containing peptides. It appears that for all possible nucleophile-electrophile interactions leading to a five-membered ring structure an associated unimolecular peptide fragmentation reaction can be observed.