Macrophage migration inhibitory factor: a therapeutic target across inflammatory diseases

Macrophage migration inhibitory factor (MIF), a cytokine originally reported in the 1960s as the prototypic T lymphokine, has emerged in recent years as a key factor regulating inflammatory responses. Both by directly activating immune cells, and by participating in activation entrained by other stimuli, MIF is important in innate and adaptive immune responses as well as tissue-specific mechanisms of damage. As a consequence of its involvement in multiple stages of the immune-inflammatory response, MIF has the potential to be involved in the pathogenesis of a range of immune-mediated inflammatory diseases affecting multiple organ systems. Diseases in which a role for MIF has been strongly validated include rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, asthma, inflammatory liver disease, and most recently systemic lupus erythematosus. Recent data have provided mechanisms of action for MIF which further support its suitability as a therapeutic target. Finally, MIF has a unique relationship with glucocorticoids, acting to counter-regulate their anti-inflammatory effects, such that MIF antagonist therapy may be a direct route to 'steroid-sparing'. Methods of targeting MIF therapeutically have also emerged in recent years, based on the unique protein structure of MIF which affords opportunities for direct antagonism by small molecules, as well as by protein therapeutics such as monoclonal antibodies. Clinical trials of MIF antagonist therapies are likely before the end of the current decade.     

Effect of pretreatment with insulin on the response of buffaloes with inactive ovaries to gonadotrophin-releasing hormone agonist treatment in summer

The aim of the present study was to evaluate the effect of a pretreatment with insulin on the response of buffalo cows with inactive ovaries to gonadotrophin-releasing hormone agonist (GnRHa) treatment during hot summer months (July and August). Thirty-six Egyptian buffalo cows with inactive ovaries were randomly allocated into three groups: (1) group treated with GnRHa (G1, n = 16) in which each buffalo received an intramuscular injection of 250 mg of GnRHa (Day 0; gonadorelin, Fertagyl); (2) group treated with insulin before the GnRHa injection (G2, n = 8) in which each buffalo received a subcutaneous injection of biphasic insulin at a dose of 0.25 IU kg(-1) bodyweight once daily starting at Day -3 for 3 consecutive days, followed by an intramuscular injection of 250 mg of GnRHa on Day 0; and (3) the control group (G3, n = 12) in which each buffalo cow received an intramuscular injection of 2.5 mL of sterile saline on Day 0. The ovaries of all animals were examined by trans-rectal ultrasonography (5 MHz) on Days -7, -3 and 0 and continued thereafter at 4-day intervals until oestrus or the end of the experiment. On the same days that ultrasound examinations were performed blood samples were collected to measure the progesterone concentrations. Administration of insulin for 3 days before GnRHa injection (G2) significantly (P < 0.05) increased the diameter of the largest follicle from 6.85 +/- 0.64 to 12.4 +/- 0.88 mm. There was a significant (P < 0.01) increase in the oestrous induction rate in G2 compared with both G1 and G3 during the first 12 days after the treatment interval. It is concluded that pretreatment with insulin for 3 days before GnRHa injection increases the diameter of the dominant follicle and therefore the oestrous induction rate of acyclic buffaloes.     

Gene polymorphisms of tumor necrosis factor alpha-308 and interleukin-10-1082 among asthmatic Egyptian children.

Tumor necrosis factor (TNF) alpha-308 and interleukin (IL)-10(-1082) have potent inflammatory responses in the process of airway inflammation in asthma. The purpose of this study was to check for association of polymorphisms related to cytokine genes with susceptibility and severity of bronchial asthma in Egyptian children. Blood samples of 69 asthmatic children receiving treatment and follow-up at the Allergy and Respiratory Medicine Unit, Mansoura University Children Hospital, Mansoura, Egypt, were subjected to DNA extraction and amplification using polymerase chain reaction with sequence-specific primers for detection of single nucleotide polymorphisms in the promoter regions of cytokine genes TNF-alpha(-308(G-->A)), IL-10(-1082(G-->A)). Compared with normal controls, Egyptian asthmatic children showed a significant higher frequency of IL-10(-1082) G/G homozygosity genotype (p < 0.001; odds ratio [OR] = 7) with lower frequency of G/A heterozygosity genotype among cases. This finding also was detected in cases with persistent asthma and eczema. These cases showed significant lower frequency of TNF-alpha-308 G/A heterozygosity (p < 0.05; OR = 0.44). Also, male cases, cases with positive family history, and those patients with persistent types of asthma showed a higher frequency of TNF-alpha-308 G/G homozygosity. IL-10(-1082(G-->A)) G/G and TNF-alpha-308(G-->A) G/G may be a contributing factor in susceptibility as well as severity of asthma among Egyptian children. Separate studies should be specified relating these cytokine genotypes to response to various modalities in asthma therapy. This study reports that IL-10(-1082(G-->A)) G/G and TNF-alpha-308(G-->A) G/G genotypes may be contributing factors in susceptibility as well as in severity of asthma among Egyptian children. Separate studies may be specified relating these cytokine genotypes to response to various modalities in asthma therapy.     

Cardiac involvement in patients with systemic lupus erythematosus and correlation of valvular lesions with anti-Ro/SS-A and anti-La/SS-B antibody levels

The aim of this study was to evaluate the incidence of morphologic and functional cardiac abnormalities in patients with systemic lupus erythematosus (SLE) and to correlate the findings with levels of anti-Ro/SS-A, anti-La/SS-B, and anti-cardiolipin antibody (aCL). Sixty-two patients with SLE were enrolled in this study. All patients underwent complete history taking, clinical assessment, and standard two-dimensional and Doppler echocardiography. Anti-Ro/SS-A, anti-La/SS-B, and aCL levels were measured using a standardized ELISA test. The patients were subdivided into two subgroups based on the presence or absence of valvular involvement. The two subgroups were then compared. Valvular involvement was present in 19 patients (30.6%), pericardial effusion in 12 patients (19.4%), impaired left ventricular relaxation abnormalities in 2 patients (3.2%), and pulmonary hypertension in 3 patients (4.8%). More patients in the valvular involvement group had positive anti-Ro/SS-A antibodies than in the valvular noninvolvement group (7/19 vs. 4/43). The difference was significant, with P 0.01. Serum levels of anti-Ro/SS-A levels were significantly higher in the valvular involvement group (33.7 ± 36.0 vs. 13.7 ± 25.1; P 0.01), as were the serum anti-La/SS-B levels (21.9 ± 23.5 vs. 10.7 ± 17.8; P 0.05). The results suggest a causative correlation between anti-Ro/SS-A and anti-La/SS-B antibodies and the pathogenesis of the valvular lesions in SLE patients.     

Assessment of left internal mammary artery graft patency by transthoracic Doppler echocardiography

BACKGROUND: The successful application of noninvasive Doppler spectrum analysis has been reported for the hemodynamic assessment of LIMA graft after myocardial revascularization. HYPOTHESIS: The objective of this study was to assess the utility of transthoracic Doppler echocardiography (TTE) in providing information on LIMA flow in patients after coronary artery bypass graft surgery. METHODS: In all, 22 patients (aged 62 +/- 8 years) with LIMA graft to the left anterior descending (LAD) coronary artery who underwent coronary angiography were assessed using high-frequency (5 MHz) transthoracic Doppler echocardiography. They were compared with 25 patients with angina (control group A, aged 59 +/- 12 years), in whom an ungrafted LIMA was assessed, and with 17 patients (control group B, aged 59 +/- 9 years) with angiographically normal coronary arteries, in whom the LAD was assessed. RESULTS: A biphasic pattern (systolic and diastolic) was recorded in all cases. In 14 patients with a normal graft or < 70% stenosis (Group 1) and in control group B, blood flow was maximal during diastole. In eight patients with severe graft stenosis > 70% (Group 2) and control group B, blood flow was maximal during systole, with low diastolic flow. The diastolic fraction of the velocity time integrals was 0.81 +/- 0.11 for Group 1 and 0.25 +/-0.06 for Group 2 (p < 0.05). A diastolic velocity time integral fraction < 0.5 predicted > 70% stenosis with a sensitivity and specificity of 100%. The ratio of systolic/diastolic peak velocities was 0.61 +/- 0.31 for Group 1 and 3.21 +/- 0.49 for Group 2 (p < 0.05). A systolic/diastolic peak velocity > 1 predicted stenosis > 70% with a sensitivity and specificity of 100 and 90%, respectively. CONCLUSIONS: High-frequency TTE is a useful noninvasive method for detecting LIMA graft blood flow. Severe graft stenoses exhibited Doppler velocity patterns, which were different from those of patent grafts, or grafts with moderate stenoses.     

Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression

In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy.     

Comparative Study of Conventional Lateral Internal Sphincterotomy, V-Y Anoplasty, and Tailored Lateral Internal Sphincterotomy with V-Y Anoplasty in the Treatment of Chronic Anal Fissure

Background

Lateral internal sphincterotomy has been proven highly effective in curing anal fissure but with a high incidence of postoperative incontinence.

Objective

We compared conventional lateral internal sphincterotomy, V-Y advancement flap, and combined tailored lateral internal sphincterotomy with V-Y advancement flap in treating anal fissure.

Patients

Consecutive patients treated for anal fissure at our colorectal unit were evaluated for inclusion. Participants were randomly allocated to receive conventional sphincterotomy (GI), V-Y advancement flap (GII), or combined tailored lateral sphincterotomy with V-Y advancement l flap (GIII).

Main Outcome Measures

The primary outcome measure was the incontinence rate; secondary outcomes included healing rate, operative time, anal manometery, and recurrence rate.

Results

One hundred fifty patients with chronic anal fissure were randomized. Healing rate after 1?year was 84?% in GI, 48?% in GII, and 94?% in GIII, respectively (P?=?0.001). The recurrence rate was 4?% in G1, 22?% in GII, and 2?% in GIII (P?=?0.01). Incontinence rate was 14?% in GI, 0?% in GII, and 2?% in GIII (P?=?0.03).

Conclusion

Although all three procedures are simple and easy to perform, tailored lateral internal sphincterotomy with V-YF appears to produce the greatest healing rate, with the fewest complications and less rate of recurrence.     

Effects of intravesical onabotulinumtoxinA on bladder dysfunction and autonomic dysreflexia after spinal cord injury: role of nerve growth factor

Study Type – Aetiology (case control) Level of Evidence 3c What's known on the subject? and What does the study add? Neurogenic detrusor overactivity (NDO) and autonomic dysreflexia (AD) are common outcomes following spinal cord injury (SCI). In this study, we showed that onabotulinumtoxinA controlled NDO and AD in rats with T4‐SCI, and also provided a mechanism for the control of AS.

OBJECTIVE

• ? To assess the significance of onabotulinumtoxinA (onabotA) intravesical administration in blocking autonomic dysreflexia (AD) response induced by cystometrogram (CMG) after T4 spinal cord transection (SCT).

MATERIALS AND METHODS

• ? Female rats were stratified into three groups: a sham group; a SCT‐only group; and a SCT with onabotA treatment group. Each group was further subdivided into two subgroups: AD assessment, or nerve growth factor (NGF) assessment via enzyme‐linked immunosorbent assay (ELISA).
• ? Three weeks after T4‐SCT, all groups were assessed. Arterial pressure and heart rate were measured during and after CMG.
• ? NGF was also extracted from the bladder and the dorsal root ganglia (DRG) of the T4 root and quantified by ELISA. In the onabotA‐treated group, 48 h before assessment, onabotA (1 mL, 20 U/mL in saline) was given using a urethral tube and was left indwelling for 30 min.
• ? Univariate anova was used to analyse the data and statistical significance was set at P < 0.05.

RESULTS

• ? The maximum voiding pressure and the number of uninhibited contractions were significantly lower in the group treated with intravesical onabotA than in the SCT‐only group.
• ? Intravesical onabotA significantly blocked the dysreflexia response (high arterial pressure with bradycardia) induced by CMG after SCT.
• ? Intravesical onabotA also significantly lowered NGF concentrations in the bladder and the T4 DRG segment.

CONCLUSIONS

• ? The results of the present study showed that intravesical onabotA controls neurogenic detrusor overactivity and AD after SCT.
• ? The findings shed light on the potential benefits of intravesical onabotA treatment in patients with spinal cord injury, and also provide a novel mechanism for the control of AD via a minimally invasive treatment modality.

     

Health effects associated with passenger vehicles: monetary values of air pollution

Air pollution is regarded as one of the highest priorities in environmental protection in both developed and developing countries. High levels of air pollution have adverse effects on human health that might cause premature death. This study presents the monetary value estimates for the adverse human health effects resulted from ambient air pollution. It aids decision makers to set priorities in the public health relevance of pollution abatement. The main driver of policymaker is the need to reduce the avoidable cardiopulmonary morbidity and mortality from pollutant exposures. The monetary valuation involves 2 steps: (i) relate levels of pollutants to mortality and morbidity (concentration-response relationships) and (ii) apply unit economic values. Cost of air pollution associated with passenger vehicles running over a major traffic bridge (6th of October Elevated Highway) is presented as a case study to demonstrate the use of monetary value of air pollution. The study proves that the cost of air pollution is extremely high and should not be overlooked.