Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia

In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte-macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly-diagnosed JCML patients were investigated to characterize the disease further. In co-cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU-E, CFU-GM, CFU-Meg and CFU-GEMM colonies. Monoclonal anti-tumour necrosis factor alpha neutralizing antibodies (anti-TNF-alpha Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth-promoting effect on autologous JCML cells cultured in clonogenic assays. Anti-TNF-alpha Ab and anti-granulocyte-macrophage colony-stimulating factor neutralizing antibodies (anti-GM-CSF Ab) both reversed the stimulating effect. Recombinant GM-CSF and recombinant TNF alpha produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-alpha effect. Expression studies of TNF-alpha and TNF-alpha receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-alpha activity was assayed in a wide variety of cell culture supernatants and in normal and patients' plasma, and only the JCML specimens showed increased TNF-alpha values. Recombinant interleukin-1 alpha (IL-1 alpha) also stimulated JCML colony growth, but polyclonal anti-IL-1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF-alpha or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-alpha and that the endogenously-produced TNF-alpha and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1 alpha also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-alpha or both.     

Production of Antibodies That Recognize the Heterogeneity of Immunoreactive Sites in Human Hemoglobin Chemically Modified by Acetaldehyde

Human hemoglobin (Hgb) was incubated with acetaldehyde under two different conditions: (a) in the presence of 250 mM acetaldehyde for 1 hr then reduced with 100 mM NaCNBH₃ for an additional 4 hr at room temperature; and (b) in the presence of 500 mM acetaldehyde for 10 days at room temperature and then reduced with 1 mM NaBH₄ for 1 hr. It was found that 44% and 27% of free amino groups in Hgb-acetaldehyde adduct (AA) remained unmodified when Hgb was treated under conditions (a) and (b), respectively. SDS-PAGE analysis revealed that the molecular weight of Hgb-AA(a) [Hgb modified under condition (a)] was slightly greater than that of unmodified Hgb and extensive protein cross-linking had occurred in Hgb-AA(b) [Hgb modified under condition (b)]. Electrophoresis on agarose gel showed the order of negative charge was Hgb-AA(b) > Hgb-AA(a) > unmodified Hgb. Polyclonal antibody raised in rabbits using keyhole limpet hemocyanin as the carrier protein modified by acetaldehyde under condition (a) [i.e., KLH-AA(a)] preferentially recognized Hgb-AA(a), whereas antibody raised using KLH-AA(b) as the immunogen recognized only Hgb-AA(b). In conclusion, antibodies raised with protein-AA antigens produced under different conditions recognize different epitopes.     

The ventricular system of the brain: a comprehensive review of its history, anatomy, histology, embryology, and surgical considerations

Introduction

The cerebral ventricles have been recognized since ancient medical history. Their true function started to be realized more than a thousand years later. Their anatomy and function are extremely important in the neurosurgical panorama.

Methods

The literature was searched for articles and textbooks of different topics related to the history, anatomy, physiology, histology, embryology and surgical considerations of the brain ventricles.

Conclusion

Herein, we summarize the literature about the cerebral ventricular system.     

HLA‐DRA is associated with Parkinson's disease in Iranian population

The rs3129882, a noncoding variant in HLA‐DR, was found to be associated with Parkinson's disease (PD) using several genome‐wide association studies. The aim of this replication study was to explore the relationship between this variant and PD in Iranian population. Genomic DNA was extracted from peripheral blood samples, and the rs3129882 SNP was genotyped using a PCR‐RFLP method in 520 PD patients and 520 healthy Iranian controls. Significant differences were found in allele frequencies between patients and controls (χ² = 4.64, P = 0.031). Under additive and dominant models, the association of the SNP with PD risk is significant, where the A allele was observed to be protective. The results suggest that rs3129882 polymorphism may be a risk factor for PD in Iranian. This is the first study reporting such an association in this population. More replication studies are needed to confirm this data.     

Extraaxial primitive neuroectodermal tumor mimicking a vestibular schwannoma: diagnostic and therapeutic difficulties. Report of two cases

Extraaxial cerebellopontine angle (CPA) medulloblastomas and other primitive neuroectodermal tumors (PNETs) are rare tumors. The authors report on two patients with PNETs who presented with progressive audiovestibular symptoms. In each case magnetic resonance (MR) imaging revealed an extraaxial lesion that filled the internal auditory meatus and exhibited the neuroimaging features of a vestibular schwannoma (VS). No high signal intensity was apparent in either the brainstem or adjacent cerebellum on T2-weighted MR images. Surgery with maximum resection (total in one case and subtotal in the other) was performed, followed by craniospinal radiotherapy. One year postoperatively, both patients were free from tumor. A CPA PNET mimicking a VS is a rare entity, the diagnosis of which is important because its treatment differs dramatically from that of VS, including prescribed surgery followed by conventional craniospinal radiotherapy.     

Measurement of Hemoglobin-Acetaldehyde Adduct in Alcoholic Patients

A sensitive and specific test for chronic alcohol abuse is useful in the diagnosis and management of alcoholic patients. Herein, we report the measurement of hemoglobin-acetaldehyde adducts (Hb-AA) in alcoholic patients by a sandwich ELISA using different antibodies. Keyhole limpet hemocyanin (KLH), a peptide consists of eight amino acid residues (8-pep, V1 to K8) at the N-terminus of βchain-of human sickle-cell Hb and a segment of HbA β-chain consists of 11 amino acids rich in lysine or K (11-pep, G56-K66) were incubated with acetaldehyde and NaCNBH₃ to form protein-AAs. 8-Pep-AA and 11-pep-AA were individually conjugated to unmodified KLH as the carrier. Anti-protein-AA lgGs were raised in rabbits using these three protein-AA immunogens. When anti-KLH-AA IgG was-used in ELISA, optical densities for alcoholic patients and controls were 0.311 ± 0.124 and 0.147 ± 0.042 (means ± SD, n = 40/group, p < 0.001), respectively. Using mean value ± 2 SD of controls as the cut-off, sensitivities to detect alcoholic patients were 78, 75, and 43%, respectively, when anti-KLH-AA, anti-11-pep-AA, and anti-8- pep-AA were used. Correlation among optical densities obtained from the first two lgGs was excellent ( R² = 0.905). We conclude that:(1) Hb-AA has the potential of being a good marker for alcohol abuse, and (2) the site of Hb that is modified by acetaldehyde in vivo is- primarily located in a surface-accessible domain near the center of the βchain of HbA where several lysine residues are clustered.     

Omega-3 (n-3) fatty acids in health and disease: Part 1--cardiovascular disease and cancer

The omega-3 (n-3) polyunsaturated fatty acids have a wide range of beneficial effects in several human health conditions. Animal and in vitro studies have indicated that omega-3 fatty acids affect blood lipid profiles, cardiovascular health, membrane lipid composition, eicosanoid biosynthesis, cell signaling cascades, and gene expression. Findings from epidemiological studies suggest that intake of omega-3 fatty acids from natural sources or supplements may influence the onset and progression of several disease states, including cardiovascular disease and cancer. This review highlights some recent research findings that help advance our understanding of how omega-3 fatty acids influence cardiovascular disease and cancer.     

Spasticity in a child with myelomeningocele treated with continuous intrathecal baclofen

Patients with myelomeningocele may often suffer from severe spasticity. Surgical treatment of the underlying pathology such as hydromyelia and tethered cord may be successful, but failures are not uncommon. Those cases may offer a surgical challenge since further therapeutic options are limited. We present the case of a 7-year-old boy with myelomeningocele and related conditions suffering from severe spasticity and pain in his lower limbs. Surgical efforts with untethering and posterior fossa decompression failed to improve the symptoms. A test with 25 microg intrathecally delivered baclofen showed a total relief of spasticity and pain so that a pump for continuous baclofen delivery was implanted. During 32 months of follow-up, his spasticity has been under excellent control on 55-157 microg baclofen per day. Continuous delivery of intrathecal baclofen may be a surgical option to consider in patients with myelomeningocele and severe spasticity.