Pathological correlates of cognitive decline in Alzheimer's disease

Although Alzheimer's disease (AD) has been investigated for more than 100 years, it was not until the 60s that quantitative measures of the disease progression and severity in relation to function and neuropathology were made by Blessed and his colleagues. With the increasing understanding of the pathological changes of AD that take place, there is growing interest in identifying which pathological marker most reliably predicts the dementia and the cognitive profile. Markers of pathology that have been investigated include senile plaques, neurofibrillary tangles, synaptic loss, and neurochemical changes. Many clinical measures have been evaluated as well including Clinical Dementia Rating, Mini Mental State Examination, and Functional Assessment Staging as ways of both predicting the presence of pathological changes of AD as well as correlating with the specific measures of pathology. Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress through AD. This review will summarize evidence of which neuropathological change correlates robustly with cognitive decline and which cognitive index predicts pathological changes in AD. In general, tangles and synaptic loss are better correlates of cognitive decline and correlate better.     

Telomere length assessment in blood leukocytes of patients with sarcoidosis

Background:Accelerated aging and telomere shortening have been studied in many chronic diseases such as interstitial pulmonary fibrosis and chronic obstructive pulmonary disease. Different studies have shown that patients with these diseases have shorter telomere lengths than controls; this can be a marker of the progression and outcome of the disease. So far, a few studies have been evaluated the telomere length in sarcoidosis. In this study we determine the telomere length in patients with sarcoidosis and compare it with control subjects.Objective:Our aim is to compare telomere length in patients with sarcoidosis and normal population. Methods: We select 58 patients with sarcoidosis who were visited in the sarcoidosis clinic of Masih Daneshvari Hospital. 58 sex and age-matched (with±2 years) healthy control subjects were selected. Telomere length was measured by quantitative real time PCR as described by Cawthon on peripheral blood sample. The telomere repeat copy number (T) to single-gene copy number(S) ratio was calculated using the comparative Ct method. Results: The mean and standard deviation of telomere length in the patient and control group was 0.65 ± 0.05 and 0.72 ± 0.07 respectively. There was a statistically significant difference between the two groups. (P = 0.031). Conclusion: Sarcoidosis is an inflammatory disease that can involve many organs. Like other chronic diseases, aging phenomenon occurs in that; which led to decrease cellular and tissue telomere length. This article demonstrates shorter telomere length in Iranian sarcoidosis patients compared to normal population.     

Characterization of a PSE-4 Mutant with Different Properties in Relation to Penicillanic Acid Sulfones: Importance of Residues 216 to 218 in Class A β-Lactamases

Class A β-lactamases are inactivated by the suicide inactivators sulbactam, clavulanic acid, and tazobactam. An examination of multiple alignments indicated that amino acids 216 to 218 differed among class A enzymes. By random replacement mutagenesis of codons 216 to 218 in PSE-4, a complete library consisting of 40,864 mutants was created. The library of mutants with mutations at positions 216 to 218 in PSE-4 was screened on carbenicillin and ampicillin with the inactivator sulbactam; a collection of 14 mutants was selected, and their bla genes were completely sequenced. Purified wild-type and mutant PSE-4 β-lactamases were used to measure kinetic parameters. One enzyme, V216S:T217A:G218R, was examined for its peculiar pattern of inhibition. There was an increase in the K_m from 68 μM for the wild type to 271 μM for the mutant for carbenicillin and 33 to 216 μM for ampicillin. Relative to the wild-type PSE-4 enzyme, 37- and 30-fold increases in K_i values were observed for the mutant enzyme for sulbactam and tazobactam, respectively. The results that were obtained suggested that positions 216 to 218 are important for interactions with penicillanic acid sulfone inhibitors. In contrast, V216 and A217 in the TEM-1 class A β-lactamase do not tolerate amino acid residue substitutions. However, for the PSE-4 β-lactamase, 11 of 14 mutants from the library of mutants with mutations at positions 216 to 218 whose sequences were determined had substitutions at position 216 (G, R, A, S) and position 217 (A, S). The data showed the importance of residues 216 to 218 in their atomic interactions with inactivators in the PSE-4 β-lactamase structure.The production of β-lactamases is one of several means by which bacteria can become resistant to β-lactam antibiotics. These enzymes hydrolyze the amide bond in the β-lactam ring of antibiotics, leading to a product that has lost its antibacterial properties (22). A way to counter this resistance is to use compounds that incapacitate the β-lactamase and that act in synergy with an antibiotic (19). These agents are known as suicide inactivators and include clavulanic acid and the penicillanic acid sulfones tazobactam and sulbactam (7).Clavulanic acid inactivates group 2a, 2b, and 2be β-lactamases, rendering the combination of clavulanic acid and ticarcillin effective in vitro and in animal models of infections (2, 6, 11). Tazobactam has been shown to be an inactivator of many group 2 β-lactamases (6). This suicide inactivator acts irreversibly against both serine-based β-lactamases and metallo-β-lactamases (7). Studies have demonstrated that the combination of tazobactam and piperacillin has a wide spectrum of activity that includes gram-positive organisms such as staphylococci, as well as many gram-negative aerobic and anaerobic bacteria (9).Wise et al. (32) have shown that the sulfone sulbactam enhances the activities of penicillin G, ampicillin, and carbenicillin against certain β-lactamase-producing bacteria like Bacteroides fragilis, Staphylococcus aureus, and Escherichia coli in vitro.All three inactivators are used clinically in combination with antibiotics to treat intra-abdominal infections, skin and soft tissue infections, and upper and lower respiratory tract infections (9, 12, 20). Different combinations of antibiotics and inactivators are used: ticarcillin with clavulanate, amoxicillin with clavulanate, piperacillin with tazobactam, and ampicillin with sulbactam. These combinations are used to treat infections caused by bacteria producing enzymes in group 2, including Pseudomonas aeruginosa, Serratia marcescens, E. coli, and others (5, 6, 10, 12, 20, 30).The model enzyme used in the study described here is PSE-4, a plasmid-derived β-lactamase from gram-negative bacteria. It was first found in P. aeruginosa (25). It is a class A β-lactamase of 271 amino acids, with the mature protein having a molecular mass of 29,810 Da. The PSE-4 β-lactamase has a very high rate of hydrolysis of carbenicillin and is genetically related to the PSE-1, CARB-3, and CARB-4 carbenicillinases (3). Analysis of the PSE-4 flanking DNA region revealed an integration site common to antibiotic resistance genes inserted into transposons of the Tn21 family (3).In this report we describe the structural and functional features of a mutant PSE-4 β-lactamase, V216S:T217A:G218R, with different properties related to inhibition by penicillanic acid sulfones such as sulbactam and tazobactam as they relate to amino acids 216 to 218 (by the standard numbering system for class A enzymes of Ambler et al. [1]) in the PSE-4 enzyme. We suggest that residues 216 to 218 could be crucial amino acids that have atomic interactions with suicide inactivators. This was established by computer-assisted modeling and structural comparisons from a three-dimensional structure model of PSE-4 constructed for TEM-1 (18), S. aureus PC1 (13, 14), and Bacillus licheniformis 749/C (23) enzymes.     

Experience of morning reports in the emergency department

Morning report in the emergency medicine departments is an emerging teaching modality in the medicine curriculum. Our institution, Hotel‐Dieu de France hospital, a multidisciplinary tertiary care university hospital affiliated to the Saint Joseph University of Medical Sciences, is the only hospital in Middle East to hold morning reports in the emergency department (ED). We evaluate the usefulness of the morning report as a pedagogic tool as it assesses the content, quality of the discussions, professionalism, leadership, participation and duration of the morning report. The particularity of this paper is that it takes into consideration the interns' input often under‐recognised in the studies. An anonymous questionnaire was diffused to the residents and interns that rotated in the ED during the previous year. It consisted of seven multiple‐choice questions to evaluate the quality of the presentations, targeted discussions, ethics and professionalism, evidence‐based medicine, clinical reasoning, relation of cases to discussions and implication of the ED physician. Overall, of the 63 patients who answered the survey, 65.1% were satisfied by the content. The majority considered the quality of the discussions acceptable and the leadership and participation satisfactory, professionalism was judged poor. Both residents and interns were satisfied of the teaching point of the morning reports. The only fail back observed was professionalism and pathophysiological discussions that require to be added to the sessions, whereas clinical management, teaching points, leadership and time management were completely satisfactory.     

A proteomic analysis on human sperm tail: comparison between normozoospermia and asthenozoospermia

Purpose

Asthenozoospermia is a common cause of human male infertility characterized by reduced sperm motility. The molecular mechanism that impairs sperm motility is not fully understood. This study proposed to identify novel biomarkers by focusing on sperm tail proteomic analysis of asthenozoospermic patients.

Methods

Sperm were isolated from normozoospermic and asthenozoospermic semen samples. Tail fractions were obtained by sonication followed by Percoll gradient. The proteins were extracted by solubilization and subjected to two-dimensional gel electrophoresis (2-DE); then, the spots were analyzed using Image Master 2D Platinum software. The significantly increased/decreased amounts of proteins in the two groups were exploited by matrix-assisted laser desorption-ionization time-of-flight/time-of-flight (MALDI-TOF-TOF) mass spectrometry.

Results

Three hundred ninety protein spots were detected in both groups. Twenty-one protein spots that had significantly altered amounts (p < 0.05) were excised and exploited using MALDI-TOF-TOF mass spectrometry. They led to the identification of the following 14 unique proteins: Tubulin beta 2B; glutathione S-transferase Mu 3; keratin, type II cytoskeletal 1; outer dense fiber protein 2; voltage-dependent anion-selective channel protein 2; A-kinase anchor protein 4; cytochrome c oxidase subunit 6B; sperm protein associated with the nucleus on the X chromosome B; phospholipid hydroperoxide glutathione peroxidase-mitochondrial; isoaspartyl peptidase/L-asparaginase; heat shock-related 70 kDa protein 2; stress-70 protein, mitochondrial; glyceraldehyde-3-phosphate dehydrogenase, testis-specific and clusterin.

Conclusion

Fourteen proteins present in different amounts in asthenozoospermic sperm tail samples were identified, four of which are reported here for the first time. These proteins might be used as markers for the better diagnosis of sperm dysfunctions, targets for male contraceptive development, and to predict embryo quality.     

Thyroid-hypophyso-hypothalamic axis of the genetically hypoprolactinemic rats (IPL nude rats)

In order to evaluate thyrotropin function in the genetically hypoprolactinemic rat, (IPL nude), we measured by radioimmunoassay TRH hypothalamic content, pituitary TSH content and serum TSH, T3, T4, both in IPL nude and control rats at various times over the 24-hour period. Compared to normal rats, the hypothalamic TRH content in the IPL nude rat showed similar variations during the day, whereas a slight increase was observed during the night characterized by a significant difference at 20.00 h. Pituitary weight and TSH content were doubled in IPL nude rats; however, when expressed as micrograms TSH/micrograms protein or DNA, a significant increase was found only at 17.00 and 20.00 h. Serum TSH and total serum T3, T4 depicted similar variations although they were minute but nonetheless significant modifications, i.e. an increase of TSH at 17.00 and 23.00 h and a decrease of T4 at 11.00 h. However, only FT4 concentrations (and not-FT3) were slightly but significantly decreased in IPL rats over the experimental times. In conclusion, the slight increase in hypothalamic TRH and pituitary TSH contents and the absence of main associated variations of serum TSH, T3 and T4 do not lend support to the hypothesis that TRH could be the cause of the hypoprolactinemia of these rats. On the contrary, the observed thyrotropin axis variations might be rather interpreted as the consequence of it.     

Cigarette smoking and risk of Behcet’s disease: a propensity score matching analysis

Abstract

Objective: Behcet’s disease (BD) is an inflammatory disease and smoking may have a role in its triggering. This case-control study was conducted to investigate the association between smoking and the risk of BD.

Methods: We included 192 patients with BD and 822 healthy siblings of patient with BD and 373 healthy unrelated persons as control groups. Demographic data and smoking history of patients and their siblings were obtained by direct and in some cases by telephone interview with the participants. Demographic data and smoking history of healthy controls were obtained by direct interview. Propensity score matching (PSM) analyses for reducing the heterogeneity between studied groups and calculating the actual effect of smoking in BD was performed. Matching was performed based on demographic characteristics (age, gender, educational status and marital status). After PSM, we carried out multivariate analyses with BD as the main outcome variable and smoking history as the main predictor variable to calculate odds ratios with 95% confidence intervals.

Results: Ever smoking was not significantly associated with an increased risk of BD compared with never smoking. In comparison with healthy siblings and healthy unrelated persons, the relative risk of developing BD was 0.8–2.6. No significant differences were observed in the clinical manifestations of BD patients in ever smokers and never smokers. However, disease activity in ever smokers at disease presentation was significantly more than never smokers.

Conclusion: Smoking is not a significant risk factor for BD.