DNA vaccination using bacillus Calmette-Guerin-DNA as an adjuvant to enhance immune response to three kinds of swine diseases

In order to enhance the immune efficacy of DNA vaccination, experiments were conducted to investigate the regulating effects of Bacillus Calmette-Guerin （BCG）-DNA as an adjuvant on immune responses of mice against foot-and-mouth disease （FMD）, Aujeszky＇s disease （AID） and classical swine fever （CSF）. BCG-DNA was purified from BCG by ion-exchange chromatography. Three DNA vaccines （pVSG, pVgD and pVE2） against the respective infection were constructed, and BCGDNA was coimmunized to mice by muscle injection. The results showed that titres of specific immunoglobulin （Ig）G to the vaccines mounted remarkably in the sera of the adjuvant covaccinated mice （P〈0.01）. Antibody isotype IgG2a and IgG1 also increased, respectively, in mice coimmunized with BCG-DNA compared with those of the control groups （P〈0.01）. Cellular immune cytokine interferon-gamma and cytotoxic T lymphocytes were detected in coimmunized BCG-DNA groups （P〈0. 05）. Whereas interleukin-4, humoral immune cytokine, was not significant （P〉 0. 05）. These results suggest that codelivery of BCG-DNA with DNA vaccines against FMD, AjD and CSF can enhance the induction of antigen-specific, especially, cell-mediated immunity.     

Hutchinson-Gilford progeria syndrome: oral and craniofacial phenotypes

Objective:  Hutchinson-Gilford progeria syndrome (HGPS) is a rare early-onset accelerated senescence syndrome. In HGPS, a recently identified de novo dominant mutation of the lamin A gene ( LMNA ) produces abnormal lamin A, resulting in compromised nuclear membrane integrity. Clinical features include sclerotic skin, cardiovascular and bone abnormalities, and marked growth retardation. Craniofacial features include 'bird-like' facies, alopecia, craniofacial disproportion, and dental crowding. Our prospective study describes dental, oral soft tissue, and craniofacial bone features in HGPS.
Methods:  Fifteen patients with confirmed p.G608G LMNA mutation (1–17 years, seven males, eight females) received comprehensive oral evaluations. Anomalies of oral soft tissue, gnathic bones, and dentition were identified.
Results:  Radiographic findings included hypodontia ( n  = 7), dysmorphic teeth ( n  = 5), steep mandibular angles ( n  = 11), and thin basal bone ( n  = 11). Soft tissue findings included ogival palatal arch ( n  = 8), median sagittal palatal fissure ( n  = 7), and ankyloglossia ( n  = 7). Calculated dental ages (9 months to 11 years 2 months) were significantly lower than chronological ages (1 year 6 months to 17 years 8 months) ( P  = 0.002). Eleven children manifested a shorter mandibular body, anterior/posterior cranial base and ramus, but a larger gonial angle, compared to age/gender/race norms.
Conclusion:  Novel oral-craniofacial phenotypes and quantification of previously reported features are presented. Our findings expand the HGPS phenotype and provide additional insight into the complex pathogenesis of HGPS.     

The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate

BACKGROUND AND PURPOSE

BAF312 is a next-generation sphingosine 1-phosphate (S1P) receptor modulator, selective for S1P₁ and S1P₅ receptors. S1P₁ receptors are essential for lymphocyte egress from lymph nodes and a drug target in immune-mediated diseases. Here, we have characterized the immunomodulatory potential of BAF312 and the S1P receptor-mediated effects on heart rate using preclinical and human data.

EXPERIMENTAL APPROACH

BAF312 was tested in a rat experimental autoimmune encephalomyelitis (EAE) model. Electrophysiological recordings of G-protein-coupled inwardly rectifying potassium (GIRK) channels were carried out in human atrial myocytes. A Phase I multiple-dose trial studied the pharmacokinetics, pharmacodynamics and safety of BAF312 in 48 healthy subjects.

KEY RESULTS

BAF312 effectively suppressed EAE in rats by internalizing S1P₁ receptors, rendering them insensitive to the egress signal from lymph nodes. In healthy volunteers, BAF312 caused preferential decreases in CD4⁺ T cells, T_naïve, T_{central memory} and B cells within 4–6 h. Cell counts returned to normal ranges within a week after stopping treatment, in line with the elimination half-life of BAF312. Despite sparing S1P₃ receptors (associated with bradycardia in mice), BAF312 induced rapid, transient (day 1 only) bradycardia in humans. BAF312-mediated activation of GIRK channels in human atrial myocytes can fully explain the bradycardia.

CONCLUSION AND IMPLICATIONS

This study illustrates species-specific differences in S1P receptor specificity for first-dose cardiac effects. Based on its profound but rapidly reversible inhibition of lymphocyte trafficking, BAF312 may have potential as a treatment for immune-mediated diseases.     

Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera

Essential thrombocythemia (ET) and polycythemia vera (PV) frequently present with erythromelalgia and acrocyanotic complications, migraine-like microvascular cerebral and ocular transient ischemic attacks (MIAs) and/or acute coronary disease. The spectrum of MIAs in ET range from poorly localized symptoms of transient unsteadiness, dysarthria and scintillating scotoma to focal symptoms of transient monocular blindness, transient mono- or hemiparesis or both. The attacks all have a sudden onset, occur sequentially rather than simultaneously, last for a few seconds to several minutes and are usually associated with a dull, pulsatile or migraine-like headache. Increased hematocrit and blood viscosity in PV patients aggravate the microvascular ischemic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Phlebotomy to correct hematocrit to normal in PV significantly reduces major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated erythromelalgia and MIAs. Complete long-term relief of the erythromelalgic microvascular disturbances, MIAs and major thrombosis in ET and PV patients can be obtained with low dose aspirin and platelet reduction to normal, but not with anticoagulation. Skin punch biopsies from the erythromelalgic area show fibromuscular intimal proliferation of arterioles complicated by occlusive platelet-rich thrombi leading to acrocyanotic ischemia. Symptomatic ET patients with erythromelalgic microvascular disturbances have shortened platelet survival, increased platelet activation markers β-thromboglobulin (β-TG), platelet factor 4 (PF4) and thrombomoduline (TM), increased urinary thromboxane B2 (TXB2) excretion, and no activation of the coagulation markers thrombin fragments F1+2 and fibrin degradation products. Inhibition of platelet cyclooxygenase (COX1) by aspirin is followed by the disappearance and no recurrence of microvascular disturbances, increase in platelet number, correction of the shortened platelet survival times to normal, and reduction of increased plasma levels of β-TG, PF4, TM and urinary TXB2 excretion to normal. These results indicate that platelet-mediated fibromuscular intimal proliferation and platelet-rich thrombi in the peripheral, cerebral and coronary end-arterial microvasculature are responsible for the erythromelalgic ischemic complications, MIAs and splanchnic vein thrombosis. Baseline platelet P-selectin levels and arachidonic acid induced COX1 mediated platelet activation showed a highly significant increase of platelet P-selectin expression (not seen in ADP and collagen stimulated platelets), which was significantly higher in JAK2^V617F mutated compared to JAK2 wild type ET.     

Percutaneous angioplasty in clinical management of renovascular hypertension: initial and long-term results

Between January 1980 and July 1983, percutaneous transluminal angioplasty was attempted on 137 stenotic renal arteries in 100 patients. At termination of follow-up studies (3-39 months, mean of 16 months), 70% of those treated for hypertension had benefited from the procedure. Stenosis secondary to fibromuscular dysplasia responded better than stenosis from arteriosclerosis (85% and 65% of the patients, respectively). Benefit was minimal for those with stenosis of the renal artery ostium or renal insufficiency. Determining levels of renal vein renin before angioplasty is helpful in selecting patients; following angioplasty, this has considerable significance in predicting the success of the procedure.