Effects of Tumor Necrosis Factor Alpha Blocker Adalimumab in Experimental Spinal Cord Injury

Objective

Tumor necrosis factor alpha (TNF-α) have proven effects in pathogenesis of neuroinflammation after spinal cord injury (SCI). Current study is designed to evaluate the effects of an anti-TNF-α agent, adalimumab, on spinal cord clip compression injury in rats.

Methods

Thirty two male adult Wistar rats were divided into four groups (sham, trauma, infliximab, and adalimumab groups) and SCI was introduced using an aneurysm clip. Animals in treatment groups received 5 mg/kg subcutaneous adalimumab and infliximab right after the trauma. Malondialdehyde (MDA) levels were studied in traumatized spinal cord tissues 72 hours after the injury as a marker of lipid peroxidation.

Results

Animals that received anti-TNF-α agents are found to have significantly decreased MDA levels. MDA levels were significantly different between the trauma and infliximab groups (p<0.01) and trauma and adalimumab groups (p=0.022). There was no significant difference in neurological evaluation of the rats using Tarlov scale.

Conclusion

These results suggest that, like infliximab, adalimumab has favorable effects on lipid peroxidation induced by spinal cord trauma in rats.     

Predicting the Peritoneal Absorption of Icodextrin in Rats and Humans Including the Effect of α-Amylase Activity in Dialysate

♦ Background:

Contrary to ultrafiltration, the three-pore model predictions of icodextrin absorption from the peritoneal cavity have not yet been reported likely, in part, due to difficulties in estimating the degradation of glucose-polymer chains by α-amylase activity in dialysate. We incorporated this degradation process in a modified three-pore model of peritoneal transport to predict ultrafiltration and icodextrin absorption simultaneously in rats and humans.

♦ Methods:

Separate three-pore models were constructed for humans and rats. The model for humans was adapted from PD Adequest 2.0 including a clearance term out of the peritoneal cavity to account for the absorption of large molecules to the peritoneal tissues, and considering patients who routinely used icodextrin by establishing steady-state plasma concentrations. The model for rats employed a standard three-pore model in which human kinetic parameters were scaled for a rat based on differences in body weight. Both models described the icodextrin molecular weight (MW) distribution as five distinct MW fractions. First order kinetics was applied using degradation rate constants obtained from previous in-vitro measurements using gel permeation chromatography. Ultrafiltration and absorption were predicted during a 4-hour exchange in rats, and 9 and 14-hour exchanges in humans with slow to fast transport characteristics with and without the effect of amylase activity.

♦ Results:

In rats, the icodextrin MW profile shifted towards the low MW fractions due to complete disappearance of the MW fractions greater than 27.5 kDa. Including the effect of amylase activity (60 U/L) resulted in 21.1% increase in ultrafiltration (UF) (7.6 mL vs 6.0 mL) and 7.1% increase in icodextrin absorption (CHO) (62.5% with vs 58.1%). In humans, the shift in MW profile was less pronounced. The fast transport (H) patient absorbed more icodextrin than the slow transport (L) patient during both 14-hour (H: 47.9% vs L: 40.2%) and 9-hour (H: 37.4% vs L: 31.7%) exchanges. While the UF was higher during the longer exchange, it varied modestly among the patient types (14-hour range: 460 – 509 mL vs 9-hour range: 382 – 389 mL). When averaged over all patients, the increases in UF and CHO during the 14-hour exchange due to amylase activity (7 U/L) were 15% and 1.5%, respectively.

♦ Conclusion:

The icodextrin absorption values predicted by the model agreed with those measured in rats and humans to accurately show the increased absorption in rats. Also, the model confirmed the previous suggestions by predicting an increase in UF specific to amylase activity in dialysate, likely due to the added osmolality by the small molecules generated as a result of the degradation process. As expected, this increase was more pronounced in rats than in humans because of higher dialysate concentrations of amylase in rats.     

Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC₅₀) of 177 nM. Similarly, we identified 10 additional analogues with IC₅₀s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri.     

Could hepatitis B vaccine act as an adjuvant to lower risk and relapses of cancer?

In this review article, we hypothesize that Hepatitis B Virus Vaccine (HBV‐V) and certain antigens of Hepatitis B Virus (HBV) could act as anticancer immunoadjuvants in addition to their role of preventing HBV‐associated liver cancer. Evidence suggests that in animal breast cancer and melanoma models, combining hepatitis B‐surface antigen (HBsAg) with other cancer antigens resulted in enhanced antitumour activity. HBsAg shares antigenic mimicry with healthy and malignant cells including squamous epithelia, thymic epithelia, bladder‐ and colon cancer cells. There exist anecdotal reports and small case series about spontaneous remission of leukaemias and neuroblastoma following acute HBV‐infection. Recent studies also exist showing HBV‐carrier state is a good prognostic factor for intrahepatic cholangiocarcinoma. Further epidemiological studies and animal experiments are necessary whether HBV‐Vs exert additional immunoadjuvant benefits besides lowering the risk of liver cancer.     

Heme-protein vibrational couplings in cytochrome c provide a dynamic link that connects the heme-iron and the protein surface

The active site of cytochrome c (Cyt c) consists of a heme covalently linked to a pentapeptide segment (Cys-X-X-Cys-His), which provides a link between the heme and the protein surface, where the redox partners of Cyt c bind. To elucidate the vibrational properties of heme c, nuclear resonance vibrational spectroscopy (NRVS) measurements were performed on (57)Fe-labeled ferric Hydrogenobacter thermophilus cytochrome c(552), including (13)C(8)-heme-, (13)C(5)(15)N-Met-, and (13)C(15)N-polypeptide (pp)-labeled samples, revealing heme-based vibrational modes in the 200- to 450-cm(-1) spectral region. Simulations of the NRVS spectra of H. thermophilus cytochrome c(552) allowed for a complete assignment of the Fe vibrational spectrum of the protein-bound heme, as well as the quantitative determination of the amount of mixing between local heme vibrations and pp modes from the Cys-X-X-Cys-His motif. These results provide the basis to propose that heme-pp vibrational dynamic couplings play a role in electron transfer (ET) by coupling vibrations of the heme directly to vibrations of the pp at the protein-protein interface. This could allow for the direct transduction of the thermal (vibrational) energy from the protein surface to the heme that is released on protein/protein complex formation, or it could modulate the heme vibrations in the protein/protein complex to minimize reorganization energy. Both mechanisms lower energy barriers for ET. Notably, the conformation of the distal Met side chain is fine-tuned in the protein to localize heme-pp mixed vibrations within the 250- to 400-cm(-1) spectral region. These findings point to a particular orientation of the distal Met that maximizes ET.     

Assessment of the left atrial volume index and plasma NT-proANP level in patients with acute ST-elevation myocardial infarction

OBJECTIVES:

Acute ST-elevation myocardial infarction is associated with ventricular dysfunction due to ischemia-induced progressive myocardial damage. The decrease in ventricular compliance causes left atrial dilatation and stretching of the atrial myocardium, which are the main stimuli for the secretion of atrial natriuretic peptide. The aim of this study was to evaluate left atrial dimensions and atrial natriuretic peptide levels in patients early after their first acute ST-elevation myocardial infarction and assess the probable interaction between coronary lesions and these measurements.

METHODS:

A total of 110 patients with acute myocardial infarction and 50 controls were studied. Plasma atrial natriuretic peptide was measured at admission. Left ventricular function, diameter, and volume index were evaluated using transthoracic echocardiography. Gensini and vessel scores of the patients who underwent coronary angiography were calculated.

RESULTS:

Plasma atrial natriuretic peptide in the patients with myocardial infarction was increased compared with that in controls (3.90±3.75 vs. 1.35±0.72 nmol/L, p<0.001). Although the left atrial diameter was comparable in patients and controls, the left atrial volume index was increased in patients with acute myocardial infarction (26.5±7.1 vs. 21.3±4.9 mL/m², p<0.01). Multivariate regression analysis showed a strong independent correlation between the left atrial volume index and the plasma atrial natriuretic peptide level (β = 0.23, p = 0.03).

CONCLUSIONS:

The left atrial volume index and plasma atrial natriuretic peptide level were correlated in patients with acute myocardial infarction.     

The impact of body mass index and central obesity on the spino-pelvic parameters: a correlation study

Introduction

Obesity is an increasing problem of epidemic proportion, and it is associated with various musculoskeletal disorders, including impairment of the spine. However, the relationship between obesity and spino-pelvic parameters remains to date unsupported by an objective measurement of the mechanical behavior of the spino-pelvic parameters depending on body mass index (BMI) and the presence of central obesity. Such analysis may provide a deeper understanding of this relationship.

Purpose

To assess whether BMI and central obesity are associated with modifications on spino-pelvic parameters and determine if exists any correlation between BMI and obesity with the type of lumbar lordosis (LL).

Methods

A cross-sectional study with 200 participants was conducted. Parameters measured were LL, pelvic tilt, sacral slope, and pelvic incidence (PI), using lumbosacral radiographs in lateral view. Subjects were classified depending on BMI. In a secondary analysis, the subjects were categorized into two groups depending on the presence or not of elevated abdominal circumference. The categorical variables were compared using Chi-square test, and the mean values were compared using ANOVA and student t test. A Spearman correlation test was used to analyze the correlation between BMI categories and LL types.

Results

From the total of participants, there were 51 (25.5 %) normal weight subjects, 93 (46.5 %) overweight, and 56 (28 %) obese individuals. The spino-pelvic parameters among these groups are practically equal. The correlation between the different BMI categories and LL types is poor 0.06 (P = 0.34). In a secondary analysis, grouping the participants in obese and non-obese, the results showed that obesity is modestly positively associated with increasing of spino-pelvic parameters values, in particular with PI (P = 0.078). The comparison made between the presence or not of central obesity, interestingly did not show significant differences.

Conclusions

Despite the results did not reach statistically significant differences, the results indicate that the obese spine is slightly different from the non-obese spine. Therefore, this relationship deserves future attention.