Design, Pharmacological Characterization, and Molecular Docking of Minimalist Peptidomimetic Antagonists of α4ß1 Integrin.

Integrin receptors mediate cell-cell interactions via the recognition of cell-adhesion glycoproteins, as well as via the interactions of cells with proteins of the extracellular matrix, and upon activation they transduce signals bi-directionally across the cell membrane. In the case of injury, infection, or inflammation, integrins of ß2 and α4 families participate in the recruitment of leukocytes, a multi-step process initiated by the capturing of rolling leukocytes and terminated by their extravasation. In particular, α4ß1 integrin is deeply involved in leukocyte firm adhesion preceding extravasation. Besides its well-known role in inflammatory diseases, α4ß1 integrin is also involved in cancer, being expressed in various tumors and showing an important role in cancer formation and spreading. Hence, targeting this integrin represents an opportunity for the treatment of inflammatory disorders, some autoimmune diseases, and cancer. In this context, taking inspiration from the recognition motives of α4ß1 integrin with its natural ligands FN and VCAM-1, we designed minimalist α/ß hybrid peptide ligands, with our approach being associated with a retro strategy. These modifications are expected to improve the compounds' stability and bioavailability. As it turned out, some of the ligands were found to be antagonists, being able to inhibit the adhesion of integrin-expressing cells to plates coated with the natural ligands without inducing any conformational switch and any activation of intracellular signaling pathways. An original model structure of the receptor was generated using protein-protein docking to evaluate the bioactive conformations of the antagonists via molecular docking. Since the experimental structure of α4ß1 integrin is still unknown, the simulations might also shed light on the interactions between the receptor and its native protein ligands.

Influence of food emulsifiers on cellular function and inflammation, a preliminary study.

Emulsifiers are extensively used as food additives and their consumption is increasing in Western countries. However, so far only few studies examined their potential effects on intestinal cellular functions and gut inflammation. The aim of this preliminary analysis was to study the emulsifiers and their concentrations capable of causing cellular damage compared to extra virgin olive oil (EVOO). We tested two commonly used emulsifiers (EMI, EMII) and EVOO on Caco-2 cells, derived from a colon carcinoma and widely used as a model of the intestinal inflammation. The diphenyltetrazolium bromide test MTT and clonogenic assay were used to study the effect of emulsifiers on cell viability. Cell migration was determined by the wound-healing assay. The inflammation was studied by measuring the levels of interleukin 6 (IL-6) and monocyte chemoattractant protein-1/C-C motif chemokine ligand 2 (CCL2), multifunctional cytokines with a major role in the acute-phase response. Furthermore, we analyzed the effect of conditioned media of Caco-2 cells treated with EMs on macrophages activation. In conclusion, our preliminary data provide evidence that EMs increase the proliferation and migration rate of Caco-2 cells. Moreover, Caco-2 cells treated with EMs enhance the IL-6 and CCL2 release and activated macrophages, supporting their role as proinflammatory molecules.

A survey of New Yorkers after the Sept. 11, 2001, terrorist attacks.

OBJECTIVE: This study examined the prevalence of psychiatric symptoms among residents/workers in Manhattan 3-6 months after the Sept. 11, 2001, terrorist attacks. METHOD: A total of 1,009 adults (516 men and 493 women) were interviewed in person throughout Manhattan. All answered questions about themselves before and after September 11 that included their emotional status. RESULTS: A total of 56.3% had at least one severe or two or more mild to moderate symptoms. Women reported significantly more symptoms than men. Loss of employment, residence, or family/friends correlated with greater and more severe symptoms. The most distressing experiences appeared to be painful memories and reminders; dissociation was rare. Only 26.7% of individuals with severe symptoms were obtaining treatment. CONCLUSIONS: Over half of the individuals had some emotional sequelae 3-6 months after September 11, but the percent was decreasing. Only a small portion of those with severe responses was seeking treatment.

Hospitalized psychiatric patients view the World Trade Center disaster.

There is conflicting literature describing how psychiatric patients, particularly those with schizophrenia, respond to overwhelming environmental disasters, with some reports describing marked improvement in their symptoms. This view is contrary to the notion that those individuals who are most vulnerable (i.e. people with serious psychiatric illness) are at high risk for further increase in psychiatric symptoms subsequent to stressful events. Since the terrorist attack of September 11, 2001, was such a catastrophic event, the following project was undertaken to examine its consequences on a population of hospitalized and thus severely ill psychiatric patients. Medical records for 156 New York City psychiatric inpatients were examined to evaluate their psychiatric condition during the time prior to and subsequent to the September 11, 2001, terrorist attacks on the World Trade Center in New York City. We failed to find any difference between the patients who had the opportunity to directly view the disaster through windows and those who did not. However, significantly more patients with a schizophrenia spectrum diagnosis showed evidence of worsening in their symptoms than those with affective disorder or other diagnoses in response to the events of September 11.

Cerebral ventricular change over the first 10 years after the onset of schizophrenia.

Whether the brain structural abnormalities seen in schizophrenia are progressive is controversial. We previously reported on a longitudinal study of 50 first-episode patients with schizophrenia and 20 controls who had serial MRI scans during the first 5 years of illness. Greater enlargement of lateral ventricles and reduction of hemispheric volume was observed over time in the patients compared with controls. The present study obtained MRI scans from 26 of these patients and 10 controls at a follow-up 10 years subsequent to their first evaluations. The initial, 4-5th and 10th year scans were examined for the degree of change in ventricular and hemispheric volume. Significantly greater ventricular enlargement during the second 5 years was detected in the patient cohort compared with controls (P<0.05) with nine of the patients having ventricular enlargement (as measured by percent change) occurring at a rate exceeding that of any of the controls from years 1 through 10. The rate of ventricular change during the first 5 years was significantly correlated with age at first hospitalization, and ventricular enlargement in years 5-10 was correlated with the amount of time spent in hospital. Paradoxically, greater change in ventricles over time was correlated with better, not worse, outcome at the 10th year of follow-up with regard to the presence of symptoms. These data suggest heterogeneity in the course of brain change whereby some patients may exhibit active structural brain change only early in their illness or not at all after their first episode, while others continue to exhibit ventricular change spanning the decade subsequent to their first episode. Despite these differences among patients, the present study fails to detect any relationship of ventricular enlargement to poorer outcome as has been reported by other investigators.

The medical student experience with disasters and disaster response.

Medical students from New York City were integrally involved in the response by health professionals to aid the families of victims of the September 11, 2001, attacks on the World Trade Center. The present study was performed to investigate the emotional impact of this involvement on medical students from the Mount Sinai School of Medicine in New York City. One hundred fifty-seven students responded to a mail survey that explored their personal and professional involvement in the disaster as well as their psychiatric symptoms in the week after the event and at the time of the survey (3.5 months after the event). Findings suggested a differential emotional impact on female students and on students involved in less supervised and more emotionally intense activities. However, involvement in the relief effort, per se, did not contribute to psychiatric symptomatology. It may have been associated with enhanced professional self-esteem among the students. These findings have implications for future planning of psychiatric response to disasters.

Familial cognitive deficits in schizophrenia.

Susceptibility to schizophrenia is considered familial, but the mechanism for transmission has not been found. Since widespread cognitive deficits have been found in patients with schizophrenia, several of these have been proposed as candidate familial endophenotypes that may or may not be predictive of who develops the illness. The current study examines these candidates in individuals from 32 families with at least 2 members having the diagnosis of chronic schizophrenia and normal comparison subjects using an extensive neuropsychological battery. Consistent with previous literature, family members with schizophrenia were significantly impaired on all measures compared with controls. Well relatives demonstrated significantly worse performance on a measure of verbal learning, delayed visual recall, perceptual-motor, and pure motor speed. Expressive and receptive language, but not other functions, were highly correlated within both concordant for schizophrenia and discordant sibling pairs, suggesting that they are familial vulnerability endophenotypes, but not predictive of whom becomes ill. On the other hand, some measures of perceptual-motor, pure motor speed, and frontal/executive functioning were significantly correlated in concordant, but not discordant pairs. These latter correlations suggest that some cognitive measures may be genetically related to the illness.

Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders.

Males with an extra-X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyrus (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra-X chromosomes would be prime candidates.