Serum levels of soluble intercellular adhesion molecule-1 and soluble endothelial leukocyte adhesion molecule-1 in Alzheimer's disease

Serum soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble E-selectin (s-ELAM-1) were evaluated in 25 patients with Alzheimer's disease (AD), 54 patients with noninflammatory neurological diseases (NIND), and 15 control subjects. Patients with AD had a higher s-ICAM-1 level compared with the NIND patients and the control subjects (P< .001 and P< .04, respectively). The presence of high s-ICAM-1 values may be related to immunological processes involved in pathogenetic mechanisms of AD. The not statistically significant values of (s-ELAM-1), a glycoprotein considered an exclusive marker of endothelial activation, compared with the NIND patients and healthy subjects (P< .47 and P< .17, respectively), seem to suggest the neural rather than the endothelial s-ICAM origin in patients with AD.     

Isolation of conjunctival mucin and differential interaction with Pseudomonas aeruginosa strains of varied pathogenic potential

The purpose of the study was to investigate the adhesion of Pseudomonas aeruginosa strains with varying pathogenic potential to purified ocular mucin. Bovine conjunctival mucin was purified by three sequential density gradient centrifugation steps. Immobilised mucin was probed with biotin-labelled bacteria isolated from different contact lens events and quantified by densitometry. Bacterial pili were identified by electron microscopy. The results indicate that purified ocular mucin consisted of a polydisperse high molecular weight population containing at least one species of goblet cell origin and was associated with a 97 kDa mucin-associated protein. Three pathogenic P. aeruginosa strains, Paer1 (57.5 +/- 10.8x10(6) CFU ml(-1); contact lens induced acute red eye (CLARE)), 6294 (127.0 +/- 4.7x10(6) CFU ml(-1); microbial keratitis) and Paer25 (60.5 +/- 11.3x10(6) CFU ml(-1); CLARE) exhibited a significantly higher level of adhesion to mucin than the negative control, E. coli (14.3 +/- 9.6x10(6) CFU ml(-1)) (p<0.005). The remaining P. aeruginosa isolates, Paer3 (asymptomatic patient), Paer12 (microbial keratitis) and ATCC 15442 (standard environmental strain) did not significantly differ in their mucin adhesion from the negative control. The majority of bacterial strains tested contained pili; thus differences in mucin adhesion observed could not be solely explained by pili status. In conclusion, P. aeruginosa isolates exhibit differential adhesion patterns to purified ocular mucin. It is proposed that more avid mucin-adhering strains are given the opportunity to adhere and subsequently penetrate the mucous layer of the tear film to initiate pathogenesis.     

Adhesion of Pseudomonas aeruginosa ocular isolates to mucin

The purpose of this study was to compare the adhesion of Pseudomonas aeruginosa ocular isolates to mucin. An adhesion assay was developed using biotin‐labelled P. aeruginosa strains (two corneal ulcer, two acute red eye, one asymptomatic and one standard strains) incubated with porcine gastric mucin immobilized on a nitrocellulose membrane. The adhesion was semiquantified using densitometry. The results showed that all P. aeruginosa strains tested were able to adhere to mucin to various extents with three strains (one corneal ulcer, one acute red eye, one asymptomatic) binding significantly greater than the negative control (P < 0.1). Results suggest that ocular strains of P. aeruginosa strains differ in their adhesion to mucin but this did not correlate with the pathogenic origin of the strain. It is concluded that the adhesion of P. aeruginosa strains to mucin alone may not be a principal determinant of pathogenesis but may be a contributing factor along with other bacterial virulence traits.     

Cyst formation in the PKD2 (1-703) transgenic rat precedes deregulation of proliferation-related pathways

Background

Polycystic Kidney Disease is characterized by the formation of large fluid-filled cysts that eventually destroy the renal parenchyma leading to end-stage renal failure. Although remarkable progress has been made in understanding the pathologic mechanism of the disease, the precise orchestration of the early events leading to cyst formation is still unclear. Abnormal cellular proliferation was traditionally considered to be one of the primary irregularities leading to cyst initiation and growth. Consequently, many therapeutic interventions have focused on targeting this abnormal proliferation, and some have even progressed to clinical trials. However, the role of proliferation in cyst development was primarily examined at stages where cysts are already visible in the kidneys and therefore at later stages of disease development.

Methods

In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters.

Results

Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Specifically, gene expression analysis demonstrated that at day 0 the RAS system is involved. This is altered at day 6, when Wnt signaling and focal adhesion pathways are affected. However, at and after 24 days, proliferation, apoptosis, altered ECM signaling and many other factors become involved.

Conclusions

Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation.     

Molecular dynamics in drug design: new generations of compstatin analogs

We report the computational and rational design of new generations of potential peptide-based inhibitors of the complement protein C3 from the compstatin family. The binding efficacy of the peptides is tested by extensive molecular dynamics-based structural and physicochemical analysis, using 32 atomic detail trajectories in explicit water for 22 peptides bound to human, rat or mouse target protein C3, with a total of 257 ns. The criteria for the new design are: (i) optimization for C3 affinity and for the balance between hydrophobicity and polarity to improve solubility compared to known compstatin analogs; and (ii) development of dual specificity, human-rat/mouse C3 inhibitors, which could be used in animal disease models. Three of the new analogs are analyzed in more detail as they possess strong and novel binding characteristics and are promising candidates for further optimization. This work paves the way for the development of an improved therapeutic for age-related macular degeneration, and other complement system-mediated diseases, compared to known compstatin variants.     

Clinical dimensions of auditory hallucinations in schizophrenic disorders

BACKGROUND: Auditory hallucinations occupy, along with delusional beliefs, the center stage of active or "positive" psychotic clinical psychopathology. During the last decade, several sets of auditory hallucinations' clinical features were subjected to multivariate statistical analyses to disclose major dimensions of psychotic patients' overall hallucinatory experience and behavior. However, these studies failed, to a large extent, to provide satisfactory external validations of the thereby extracted factors. METHODS: We investigated the major clinical dimensions of verbal auditory hallucinations in a sample of 100 inpatients with schizophrenic disorders. Patients (61 men and 39 women) were examined before the initiation of antipsychotic treatment and their assessment included 18 major clinical features of auditory hallucinations. Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, Global Assessment Scale, and Mini-Mental State Examination were used as external validators. RESULTS: Principal component analysis resulted in the extraction of 5 factors interpreted as the dimensions of severity of auditory hallucinations, emotional and behavioral impact, rate of their intrusion in self-consciousness, delusional elaboration, and similarity to ordinary auditory perception, respectively. The second and third factors extracted in our study correlated with short duration of illness, whereas the first, fourth, and fifth ones correlated with chronicity. Our second factor correlated with clinical severity of patients' current mental state, the fifth factor with severity of their cognitive impairment, and the first and fourth ones with lower clinical depression despite patients' chronicity. CONCLUSION: The findings of our study contribute to the further elucidation of the major clinical dimensions of auditory hallucinations and the testing of their external validity.     

Facial fear processing and psychotic symptoms in schizophrenia: functional magnetic resonance imaging study

BACKGROUND: The recognition of negative facial affect is impaired in people with schizophrenia. The neural underpinnings of this deficit and its relationship to the symptoms of psychosis are still unclear. AIMS: To examine the association between positive and negative psychotic symptoms and activation within the amygdala and extrastriate visual regions of patients with schizophrenia during fearful and neutral facial expression processing. METHOD: Functional magnetic resonance imaging was used to measure neural responses to neutral and fearful facial expressions in 11 patients with schizophrenia and 9 healthy volunteers during an implicit emotional task. RESULTS: No association between amygdala activation and positive symptoms was found; the activation within the left superior temporal gyrus was negatively associated with the negative symptoms of the patients. CONCLUSIONS: Our results indicate an association between impaired extrastriate visual processing of facial fear and negative symptoms, which may underlie the previously reported difficulties of patients with negative symptoms in the recognition of facial fear.     

Investigation of possible cytokine induction in peripheral blood mononuclear cells by heat-stable serotypes of Campylobacter jejuni

Several Campylobacter jejuni heat-stable (HS) serotypes have been associated with the autoimmune Guillain-Barre neurological syndrome (GBS). In order to examine the possible involvement of cytokines in this phenomenon, the levels of three pro-inflammatory cytokines (interleukin (IL)-2sRa, IL-6 and interferon (IFN)-gamma) and one anti-inflammatory cytokine (IL-10) were measured in peripheral blood mononuclear cells after induction by different C. jejuni serotypes. No differences were found for IL-6, IFN-gamma and IL-10, but the non-sialylated serotype HS:3 was associated with decreased production of IL-2sRa. The results raise the possibility that absence of sialylation might be associated with the inability to induce inflammatory factors such as cytokines.