Novel peptides as potential treatment of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immunologic tolerance, production of auto-antibodies, and inflammatory damage in multiple organs. We have tested the effect of anti-inflammatory peptide, a H2A histone fragment, termed IIIM1, on MRL/lpr mice, animal model of SLE. Oral administration of IIIM1 at early stage of disease caused reduction in proteinuria and serum anti-dsDNA antibodies. Starting the treatment at advanced stage of disease resulted in prolonged animal survival, decreased lymphadenosis and reduced levels of pathogenic or abnormal double negative CD4(-)CD8(-) cells and B220(+) cells in lymph nodes and spleen. We discovered that IIIM1 induces the production of an additional peptide, a fragment of alpha-1-antitrypsin, termed UBE. A relatively low dose (1 µg/kg) of UBE reduced proteinuria and hematuria in MRL/lpr mice. The beneficial effect of the peptide was corroborated by histological examination. Furthermore a significant reduction in serum IL17, IL12 and anti dsDNA antibodies was observed in the UBE-treated mice. Isolated CD4 cells incubated with the peptide showed a similar cytokine profile. Decreased levels of double negative CD4(-)CD8(-) and B220(+) cells were determined in lymph organs of UBE-treated animals. The beneficial effects of both UBE and IIIM1 suggest these peptides as potential drugs for SLE.

Enhanced 'Reading the Mind in the Eyes' in borderline personality disorder compared to healthy controls.

BACKGROUND: Borderline personality disorder (BPD) is partly characterized by chronic instability in interpersonal relationships, which exacerbates other symptom dimensions of the disorder and can interfere with treatment engagement. Facial emotion recognition paradigms have been used to investigate the bases of interpersonal impairments in BPD, yielding mixed results. We sought to clarify and extend past findings by using the Reading the Mind in the Eyes Test (RMET), a measure of the capacity to discriminate the mental state of others from expressions in the eye region of the face. METHOD: Thirty individuals diagnosed with BPD were compared to 25 healthy controls (HCs) on RMET performance. Participants were also assessed for depression severity, emotional state at the time of assessment, history of childhood abuse, and other Axis I and personality disorders (PDs). RESULTS: The BPD group performed significantly better than the HC group on the RMET, particularly for the Total Score and Neutral emotional valences. Effect sizes were in the large range for the Total Score and for Neutral RMET performance. The results could not be accounted for by demographics, co-occurring Axis I or II conditions, medication status, abuse history, or emotional state. However, depression severity partially mediated the relationship between RMET and BPD status. CONCLUSIONS: Mental state discrimination based on the eye region of the face is enhanced in BPD. An enhanced sensitivity to the mental states of others may be a basis for the social impairments in BPD.

The relationship of childhood abuse to impulsivity and suicidal behavior in adults with major depression.

OBJECTIVE: This study investigated whether a higher frequency of reported childhood trauma would be found in depressed adults with higher levels of trait impulsivity, aggression, and suicidal behavior. METHOD: In 136 depressed adult inpatients, the authors assessed trait impulsivity, aggression history, and number of lifetime suicide attempts as well as the medical lethality and the intent to die associated with the most lethal attempt. These variables were then compared between those with and those without a reported history of childhood physical or sexual abuse. RESULTS: Subjects who reported an abuse history were more likely to have made a suicide attempt and had significantly higher impulsivity and aggression scores than those who did not report an abuse history. Impulsivity and aggression scores were significantly higher in subjects with a history of at least one suicide attempt. A logistic regression analysis revealed that abuse history remained significantly associated with suicide attempt status after adjustment for impulsivity, aggression history, and presence of borderline personality disorder. Among those who attempted suicide, there were no significant differences in severity of suicidal behavior between those with and without a childhood history of abuse. CONCLUSIONS: Abuse in childhood may constitute an environmental risk factor for the development of trait impulsivity and aggression as well as suicide attempts in depressed adults. Alternatively, impulsivity and aggression may be inherited traits underlying both childhood abuse and suicidal behavior in adulthood disorders. Additional research is needed to estimate the relative contributions of heredity and environmental experience to the development of impulsivity, aggression, and suicidal behavior.

The crystal and molecular structure of a collagen-like peptide with a biologically relevant sequence.

A detailed description of the 2.0 A structure of the triple-helical peptide, (Pro-Hyp-Gly)(3)-Ile-Thr-Gly-Ala-Arg-Gly-Leu-Ala-Gly-Pro-Hyp-Gly-(Pro-Hyp-Gly)(3), denoted as T3-785, is presented. This peptide contains a biologically relevant sequence and was designed to model the imino acid-poor 785-796 region of human type III collagen just C-terminal to the matrix metalloproteinase cleavage site. The crystal structure of the T3-785 peptide demonstrates that sequence can influence local conformational changes in triple-helical structure, in terms of superhelical pitch, hydrogen bonding pattern, and hydration patterns. The novel packing arrangement displayed by the T3-785 structure, compared with those of collagen-like peptides with more imino acid-rich sequences indicates the sequence dependence of intermolecular assemblies in collagen as well. The observed synergy between the packing arrangements and the extended hydration network indicates that hydration of the triple helix is directly related to its association with other molecules.

Neuropsychological dysfunction in depressed suicide attempters.

OBJECTIVE: Neuropsychological deficits in the context of psychiatric disease may be associated with suicide risk. In this study, neuropsychological performance was compared among depressed patients with at least one prior suicide attempt of high lethality, depressed patients with low-lethality prior attempts, depressed patients with no prior suicide attempts, and nonpatients. METHOD: Fifty unmedicated patients in a major depressive episode (21 with no history of suicide attempts and 14 and 15 patients with previous attempts of low and high lethality, respectively) and 22 nonpatients were assessed. Groups were comparable in age, education, occupational level, and estimated premorbid intelligence. The neuropsychological battery produced scores within five composite domains: general intellectual functioning (current), motor functioning, attention, memory, and executive functioning. RESULTS: Patients whose prior suicide attempts were of high lethality performed significantly worse than all groups on tests of executive functioning and were the only group to perform significantly worse than nonpatients on tests of general intellectual functioning, attention, and memory. A discriminant function analysis revealed two prominent dimensions in the data: one that discriminated high-lethality suicide attempters from all other groups (primarily associated with performance on tests of executive functioning) and another that discriminated all depressed patient groups from nonpatients (associated with performance on measures of attention and memory). For the patients with high-lethality prior suicide attempts, deficits did not appear to reflect diffuse brain damage from past attempts, since the results of tests commonly affected by diffuse injury were not selectively impaired. CONCLUSIONS: Neuropsychological deficits in depressed patients with high-lethality prior suicide attempts suggest impairment of executive functioning beyond that typically found in major depression. This more extensive neuropsychological impairment in the context of depression may be a risk factor for severe suicide attempts.

Dioxin exposure and public health in Chapaevsk, Russia.

One of the largest environmental polluters in Chapaevsk (Samara Region, Russia) is the Middle Volga chemical plant. From 1967 to 1987, it produced hexachlorocyclohexane (lindane) and its derivatives. Currently, it produces crop protection chemicals (liquid chlorine acids, methyl chloroform, vinyl chloride, and some other chemicals). Dioxins were detected in air (0.116 pg/m3), in soil (8.9-298 ng/kg), in the town's drinking water (28.4-74.1 pg/liter), and in the cow's milk (the content of 2,3,7,8-TCDD was 17.32 pg TEQ/g fat). The mean content of dioxins in seven pooled samples of human milk (40 individual trials) was 42.26 pg TEQ/g fat, in four female workers' blood samples -412.4 pg TEQ/g fat, in six residents blood samples (those who lived 1-3 km from the chemical plant) -75.2 pg TEQ/g fat, in four residents' blood samples (5-8 km from the plant) -24.5 pg TEQ/g fat. To assess cancer risk and reproductive health status, official medical statistical information was used. In general, the male cancer mortality observed rate in Chapaevsk is higher than expected. The SMR is higher for lung cancer 3.1(C.I. 2.6-3.8), urinary organs 2.6(C.I. 1.7-3.6). Chapaevsk women have a higher risk overall due to breast cancer 2.1(C.I. 1.6-2.7) and cervix cancer 1.8(C.I. 1.0-3.1). The incidence rates were higher for lung cancer in males and for female breast cancer in all age groups compared to Russia and Samara Region in 1998. Significant disruptions in reproductive function were detected. The mean frequency of spontaneous abortions in the last seven years was statistically higher 24.4% in Chapaevsk (compared to other of the towns region). The average rate of premature labor was 45.7 per 1000 women in Chapaevsk that is significantly higher than in most Samara Region towns. The frequency of newborns with low birth weight was 7.4%. In Russia and in most of the Samara Region towns, this rate is lower (6.2-5.1%) but not statistically different. For the determination of congenital morphogenetic conditions (CMGC), 369 children born between 1990 and 1995 were examined. The average number of CMGC per child was significantly higher, 4.5 for boys and 4.4 for girls. The first results indicated serious disruptions associated with high dioxin levels in human milk and blood in Chapaevsk. We suggest that Chapaevsk is an incredibly interesting site for further environmental-epidemiological research to assess the impact of dioxins on human health.

Effects of iodine on inducible nitric oxide synthase and cyclooxygenase-2 expression in sulfur mustard-induced skin.

In a previous study we demonstrated the protective effect of topical iodine as postexposure treatment for sulfur mustard (SM) application. The iodine treatment results in significantly reduced inflammation and necrosis and increased epidermal hyperplasia. The expression and localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in paraffin-embedded skin samples from that study were evaluated in the present investigation. We compared the immunoreactivity of iNOS and COX-2 using five samples from each of the following four test sites: untreated control sites, SM-exposed sites, sites treated with iodine mixture 15 min after SM exposure, and sites treated with iodine 30 min after SM exposure. All animals were killed 2 days after irritant exposure. iNOS immunoreactivity was present only in skin sites exposed to SM without iodine treatment. The ulcerated skin was covered with a relatively thick band of exudate composed of iNOS-immunostained polymorphonuclear cells and macrophages. In untreated skin, COX-2 immunostaining was limited to the thin suprabasal epidermal layer. In SM-exposed skin, induction of COX-2 was noted in inflammatory cells located close to the site of epidermal injury. In skin sites treated with iodine 15 or 30 min after SM exposure, the regenerating hyperplastic epithelium showed moderate cytoplasmic staining localized to the epithelium overlying the basal layer. This pattern of staining was also present in the nearby dermal fibroblasts. Thus, in contrast to the skin samples exposed to SM without iodine treatment, the epidermal layer expressing immunohistochemical positivity for COX-2 was thicker and corresponded to the epidermal hyperplasia noted in samples treated with iodine. It is well documented that prostaglandins (PGs) promote epidermal proliferation, thereby contributing to the repair of injured skin. That the induction of the COX-2 shown in our study may also play a role in the healing process is indicated by the present evidence. The results suggest that nitric oxide radicals (NO*) are involved in mediating the damage induced by the SM and that iodine-related reduction in acute epidermal inflammation is associated with reduced iNOS expression.

Interaction of collagen-like peptide models of asymmetric acetylcholinesterase with glycosaminoglycans: spectroscopic studies of conformational changes and stability.

The effect of heparin on the conformation and stability of triple-helical peptide models of the collagen tail of asymmetric acetylcholinesterase expands our understanding of heparin interactions with proteins and presents an opportunity for clarifying the nature of binding of ligands to collagen triple-helix domains. Within the collagen tail of AChE, there are two consensus sequences for heparin binding of the form BBXB, surrounded by additional basic residues. Circular dichroism studies were used to determine the effect of the addition of increasing concentrations of heparin on triple-helical peptide models for the heparin binding domains, including peptides in which the basic residues within and surrounding the consensus sequence were replaced by alanine residues. The addition of heparin caused an increased triple-helix content with saturation properties for the peptide modeling the C-terminal site, while precipitation, with no increased helix content resulted from heparin addition to the peptide modeling the N-terminal site. The results suggest that the two binding sites with a similar triple-helical conformation have distinctive ways of interacting with heparin, which must relate to small differences in the consensus sequence (GRKGR vs GKRGK) and in the surrounding basic residues. Addition of heparin increased the thermal stability of all peptides containing the consensus sequence. Heparan sulfate produced conformational and stabilization effects similar to those of heparin, while chondroitin sulfate led to a cloudy solution, loss of circular dichroism signal, and a smaller increase in thermal stability. Thus, specificity in both the sequence of the triple helix and the type of glycosaminoglycan is required for this interaction.

Amino acid propensities for the collagen triple-helix.

Determination of the tendencies of amino acids to form alpha-helical and beta-sheet structures has been important in clarifying stabilizing interactions, protein design, and the protein folding problem. In this study, we have determined for the first time a complete scale of amino acid propensities for another important protein motif: the collagen triple-helix conformation with its Gly-X-Y repeating sequence. Guest triplets of the form Gly-X-Hyp and Gly-Pro-Y are used to quantitate the conformational propensities of all 20 amino acids for the X and Y positions in the context of a (Gly-Pro-Hyp)(8) host peptide. The rankings for both the X and Y positions show the highly stabilizing nature of imino acids and the destabilizing effects of Gly and aromatic residues. Many residues show differing propensities in the X versus Y position, related to the nonequivalence of these positions in terms of interchain interactions and solvent exposure. The propensity of amino acids to adopt a polyproline II-like conformation plays a role in their triple-helix rankings, as shown by a moderate correlation of triple-helix propensity with frequency of occurrence in polyproline II-like regions. The high propensity of ionizable residues in the X position suggests the importance of interchain hydrogen bonding directly or through water to backbone carbonyls or hydroxyprolines. The low propensity of side chains with branching at the C(delta) in the Y position supports models suggesting these groups block solvent access to backbone C=O groups. These data provide a first step in defining sequence-dependent variations in local triple-helix stability and binding, and are important for a general understanding of side chain interactions in all proteins.

Topical iodine preparation as therapy against sulfur mustard-induced skin lesions.

Sulfur mustard (SM) is a powerful vesicant employed as an agent of chemical warfare. This study demonstrates the therapeutic effect of a novel topical iodine preparation as a postexposure treatment against SM-induced lesions in the fur-covered guinea-pig skin model. Iodine treatment 15 min after SM exposure resulted in statistically significant reductions of 48, 50, and 55% in dermal acute inflammation, hemorrhage, and necrosis, respectively, whereas, the epidermal healing markers, hyperkerathosis and acanthosis, were significantly elevated by 72 and 67%, respectively, 2 days after treatment. At the interval of 30 min between SM exposure and iodine treatment, there was a significant degree of healing or recovery, albeit to a lesser extent than that observed in the shorter interval. Although the epidermal healing markers were not elevated, the parameters indicative of active tissue damage, such as subepidermal microblisters, epidermal ulceration, dermal acute inflammation, hemorrhage, and necrosis, were significantly reduced by 35, 67, 43, 39, and 45%, respectively. At the 45-min interval between exposure and treatment, there was also a certain degree of healing or recovery expressed as significant reductions in dermal subacute inflammation, subepidermal microblister formation, and epidermal ulceration, whereas, acanthosis was statistically elevated, indicating an increased healing potential. At the 60-min interval, iodine was less efficacious; nevertheless, a significant reduction in the incidence of subepidermal microblisters and an expansion of the acanthotic area were observed. Gross ulceration was significantly decreased at intervals of 15 and 30 min between exposure and treatment. The local anesthetic, lidocaine, did not alter the therapeutic effect of iodine. SM was not affected chemically by iodine as measured by gas chromatography-mass spectrometry (GC-MS) analysis. These findings suggest that the iodine preparation functions as an antidote against skin lesions induced by SM.

Anxiety in major depression: relationship to suicide attempts.

OBJECTIVE: This study was an examination of the relationship of lifetime panic disorder and anxiety symptoms at index hospitalization to a history of a suicide attempt in patients with a major depressive episode. METHOD: A total of 272 inpatients with at least one major depressive episode, with or without a history of a suicide attempt, were entered into the study. They were given structured diagnostic interviews for axis I and axis II disorders. Suicide attempt history, current psychopathology, and traits of aggression and impulsivity were also assessed. RESULTS: The rates of panic disorder did not differ in the suicide attempters and nonattempters. Agitation, psychic anxiety, and hypochondriasis were more severe in the nonattempter group. A multivariate analysis confirmed that this effect was independent of aggression and impulsivity. CONCLUSIONS: Comorbid panic disorder in patients with major depression does not seem to increase the risk for lifetime suicide attempt. The presence of greater anxiety in the nonattempters warrants further investigation.

Staggered molecular packing in crystals of a collagen-like peptide with a single charged pair.

The crystal structure of the triple-helical peptide, (Pro-Hyp-Gly)(4)-Glu-Lys-Gly-(Pro-Hyp-Gly)(5) has been determined to 1.75 A resolution. This peptide was designed to examine the effect of a pair of adjacent, oppositely charged residues on collagen triple-helical conformation and intermolecular interactions. The molecular conformation (a 7(5) triple helix) and hydrogen bonding schemes are similar to those previously reported for collagen triple helices and provides a second instance of water mediated N--H . . . O==C interchain hydrogen bonds for the amide group of the residue following Gly. Although stereochemically capable of forming intramolecular or intermolecular ion pairs, the lysine and glutamic acid side-chains instead display direct interactions with carbonyl groups and hydroxyproline hydroxyl groups or interactions mediated by water molecules. Solution studies on the EKG peptide indicate stabilization at neutral pH values, where both Glu and Lys are ionized, but suggest that this occurs because of the effects of ionization on the individual residues, rather than ion pair formation. The EKG structure suggests a molecular mechanism for such stabilization through indirect hydrogen bonding. The molecular packing in the crystal includes an axial stagger between molecules, reminiscent of that observed in D-periodic collagen fibrils. The presence of a Glu-Lys-Gly triplet in the middle of the sequence appears to mediate this staggered molecular packing through its indirect water-mediated interactions with backbone C==O groups and side chains.

Interaction of the collagen-like tail of asymmetric acetylcholinesterase with heparin depends on triple-helical conformation, sequence and stability.

The collagen-like tail of asymmetric acetylcholinesterase (AChE) contains two heparin-binding domains (HBDs) that interact with heparan sulphate proteoglycans, determining the anchoring of the enzyme at the basal lamina and its specific localization at the neuromuscular junction. Both HBDs are characterized by a cluster of basic residues containing a core with the BBXB consensus sequence (where B represents a basic residue and X a non-basic residue). To study the interaction of such HBDs with heparin we have used synthetic peptides to model the N-terminal and C-terminal sites. CD spectroscopy showed that all peptides are triple-helical at low temperatures, and undergo trimer-to-monomer transitions. Displacement assays of asymmetric AChE bound to heparin were performed using the peptides in both monomeric and triple-helical states. In the monomeric conformation, all the peptides were able to displace low levels of AChE depending on the basic charge content. In the triple-helical conformation, peptides containing the consensus sequence showed a large increase in the ability to displace bound AChE. Results suggest that the specific binding of the collagen-like-tail peptides to heparin depends both on the presence of the core sequence and on the triple-helical conformation. Moreover, BBXB-containing peptides that are less stable are more effective in displacing AChE, suggesting that the interaction region needs a significant amount of structural flexibility to better accommodate the ligand.

Suicidal behavior in bipolar mood disorder: clinical characteristics of attempters and nonattempters.

OBJECTIVE: Bipolar Disorder is associated with a higher frequency of attempted suicide than most other psychiatric disorders. The reasons are unknown. This study compared bipolar subjects with a history of a suicide attempt to those without such a history, assessing suicidal behavior qualitatively and quantitatively, and examining possible demographic, psychopathologic and familial risk factors. METHODS: Patients (ages 18 to 75) with a DSM III-R Bipolar Disorder (n = 44) diagnosis determined by a structured interview for Axis I disorders were enrolled. Acute psychopathology, hopelessness, protective factors, and traits of aggression and impulsivity were measured. The number, method and degree of medical damage was assessed for suicide attempts, life-time. RESULTS: Bipolar suicide attempters had more life-time episodes of major depression, and twice as many were in a current depressive or mixed episode, compared to bipolar nonattempters. Attempters reported more suicidal ideation immediately prior to admission, and fewer reasons for living even when the most recent suicide attempt preceded the index hospitalization by more than six months. Attempters had more lifetime aggression and were more likely to be male. However, attempters did not differ from nonattempters on lifetime impulsivity. LIMITATIONS: The generalizability of the results is limited because this is a study of inpatients with a history of suicide attempts. Patients with Bipolar I and NOS Disorders were pooled and a larger sample is needed to look at differences. We could not assess psychopathology immediately prior to the suicide attempt because, only half of the suicide attempters had made attempts in the six months prior to admission. Patients with current comorbid substance abuse were excluded. No suicide completers were studied. CONCLUSIONS: Bipolar subjects with a history of suicide attempt experience more episodes of depression, and react to them by having severe suicidal ideation. Their diathesis for acting on feelings of anger or suicidal ideation is suggested by a higher level of lifetime aggression and a pattern of repeated suicide attempts.

Site-specific NMR monitoring of cis-trans isomerization in the folding of the proline-rich collagen triple helix.

Understanding the folding of the proline-rich collagen triple helix requires consideration of the effects of proline cis-trans isomerization and may shed light on the misfolding of collagen in connective tissue diseases. Folding was monitored in real time by heteronuclear 2D NMR spectroscopy for the (15)N labeled positions in the triple-helical peptide T1-892 [GPAGPAGPVGPAGARGPAGPOGPOGPOGPOGV]. In the equilibrium unfolded monomer form, each labeled residue showed multiple peaks with interconversion rates consistent with cis-trans isomerization of Gly-Pro and Pro-Hyp bonds. Real-time NMR studies on the folding of T1-892 showed slow decay of monomer peaks and a concomitant increase in trimer peaks. Gly25 in the C-terminal rich (Gly-Pro-Hyp)(4) domain folds first, consistent with its being a nucleation domain. Analysis of the kinetics indicates that the folding of Gly25 is biphasic and the slower step represents cis-trans isomerization of imino acids. This illustrates that nucleation is limited by cis-trans isomerization. Monitoring Gly6, Gly10, Ala12, and Gly13 monomer and trimer peaks captures the C- to N-terminal propagation of the triple helix, which is also limited by Gly-Pro cis-trans isomerization events. The zipper-like nature of the propagation process is confirmed by the slower rate of folding of Ala6 compared to Gly13, reflecting the larger number of isomerization events encountered by the more N-terminal Ala6. The cis-trans isomerization events at multiple proline residues is a complex statistical process which can be visualized by these NMR studies.

Destabilization of osteogenesis imperfecta collagen-like model peptides correlates with the identity of the residue replacing glycine.

Mutations resulting in replacement of one obligate Gly residue within the repeating (Gly-Xaa-Yaa)(n) triplet pattern of the collagen type I triple helix are the major cause of osteogenesis imperfecta (OI). Phenotypes of OI involve fragile bones and range from mild to perinatal lethal. In this study, host-guest triple-helical peptides of the form acetyl-(Gly-Pro-Hyp)(3)-Zaa-Pro-Hyp-(Gly-Pro-Hyp)(4)-Gly-Gly-amide are used to isolate the influence of the residue replacing Gly on triple-helix stability, with Zaa = Gly, Ala, Arg, Asp, Glu, Cys, Ser, or Val. Any substitution for Zaa = Gly (melting temperature, T(m) = 45 degrees C) results in a dramatic destabilization of the triple helix. For Ala and Ser, T(m) decreases to approximately 10 degrees C, and for the Arg-, Val-, Glu-, and Asp-containing peptides, T(m) < 0 degrees C. A Gly --> Cys replacement results in T(m) < 0 degrees C under reducing conditions but shows a broad transition (T(m) approximately 19 degrees C) in an oxidizing environment. Addition of trimethylamine N-oxide increases T(m) by approximately 5 degrees C per 1 M trimethylamine N-oxide, resulting in stable triple-helix formation for all peptides and allowing comparison of relative stabilities. The order of disruption of different Gly replacements in these peptides can be represented as Ala

Collagen model peptides: Sequence dependence of triple-helix stability.

The triple helix is a specialized protein motif, found in all collagens as well as in noncollagenous proteins involved in host defense. Peptides will adopt a triple-helical conformation if the sequence contains its characteristic features of Gly as every third residue and a high content of Pro and Hyp residues. Such model peptides have proved amenable to structural studies by x-ray crystallography and NMR spectroscopy, suitable for thermodynamic and kinetic analysis, and a valuable tool in characterizing the binding activities of the collagen triple helix. A systematic approach to understanding the amino acid sequence dependence of the collagen triple helix has been initiated, based on a set of host-guest peptides of the form, (Gly-Pro-Hyp)(3)-Gly-X-Y-(Gly-Pro-Hyp)(4). Comparison of their thermal stabilities has led to a propensity scale for the X and Y positions, and the additivity of contributions of individual residues is now under investigation. The local and global stability of the collagen triple helix is normally modulated by the residues in the X and Y positions, with every third position occupied by Gly in fibril-forming collagens. However, in collagen diseases, such as osteogenesis imperfecta, a single Gly may be substituted by another residue. Host-guest studies where the Gly is replaced by various amino acids suggest that the identity of the residue in the Gly position affects the degree of destabilization and the clinical severity of the disease.

Protective effect of povidone iodine ointment against skin lesions induced by chemical and thermal stimuli.

Mustard gas (sulfur mustard, HD) is a powerful vesicant employed as a chemical weapon. The present study demonstrates the effect of povidone iodine (PI) ointment against skin toxicity caused by HD. Gross and histopathological examinations showed that application of PI 20 min or less following exposure to the vesicant resulted in marked skin protection. The shorter, interval between exposure and treatment, the better was the protection achieved. Povidone iodine was also effective against other mustards, such as carboxybutylchloroethyl sulfide (CBCS) and mechlorethamine. The fact that PI protected the skin against agents that cannot be oxidized, such as iodoacetic acid, divinylsulfone and cantharidine, indicated that the antidotal effect of PI was unrelated to oxidation of the nitrogen and sulfur atoms of the mustards. Furthermore, NMR spectroscopy of CBCS treated with iodine did not show oxidation of the sulfur atom. Clinical experience with patients after accidential heat burns (mostly of grade I) has shown that topical application of PI ointment immediately after the stimulus significantly reduced, and often prevented, skin lesions. Apart from being a safe and widely used disinfectant, PI ointment is recommended as an efficient protective agent against skin toxicity caused by hazardous chemicals and by heat stimuli.

A nonparametric method for the segmentation of the EEG.

A new method for segmentation of the EEG, based on a nonparametric statistical analysis, is proposed. A nonparametric approach was chosen because it minimises the need for a priori information about a signal. The method provides detection of change-points (quasi-stationary segments' boundaries) in almost any EEG characteristic for a given level of false alarm probability. The method was applied to 8-channels spontaneous EEG recordings obtained from 12 subjects in eyes closed and eyes open conditions to detect rapid fluctuations of the alpha rhythm power. After preliminary adjustment of false alarm probability values all the recordings were analysed in unsupervised regime with the same parameters. From 15 to 119 change-points were found per minute and EEG channel. Automatically detected change-points were in good correspondence with visual estimation of the instants of change in alpha activity.

Sequence dependent conformational variations of collagen triple-helical structure.

The 2 A crystal structure reported here of the collagen-like model peptide, T3-785, provides the first visualization of how the sequence of collagen defines distinctive local conformational variations in triple-helical structure.