Polymorphisms of IL-17 and ICAM-1 and their expression in Guillain-Barré syndrome.

PURPOSE: Guillain-Barré syndrome (GBS) is an acute inflammatory, autoimmune disorder of peripheral nervous system. Interleukin-17 (IL-17) and intercellular adhesion molecule-1 (ICAM-1) polymorphisms with higher expression levels have already been studied in many inflammatory and autoimmune diseases. However, the possible role of IL-17 and ICAM-1 polymorphisms in GBS remains unknown. Therefore, the current study investigated IL-17 (His161Arg and Glu126Gly) and ICAM-1 (Gly241Arg) polymorphisms. MATERIALS AND METHOD: In this study, total 80 GBS patients and 75 normal healthy controls were included. IL-17 (His161Arg and Glu126Gly) and ICAM-1 (Gly241Arg) polymorphisms were performed using polymerase chain reaction -restriction fragment length polymorphism analysis. Further, the expression of ICAM-1 and IL-17 was determined by reverse-transcriptase PCR and enzyme-linked immunosorbent assay. RESULTS: IL-17 (Glu126Gly) mutant and ICAM-1 (Gly241Arg) heterozygous genotypes were strongly associated with increased risk of GBS (p < 0.016; OR = 3.706, 95% CI = 1.28-10.67; p < 0.001; OR = 4.148, 95% CI = 2.119-8.119, respectively). IL-17 and ICAM-1 genes showed significantly higher expression in GBS when compared with healthy controls. CONCLUSION: IL-17 and ICAM-1 polymorphisms showed significant association with GBS and their enhanced expressions have possible role in GBS development. IL-17 and ICAM-1 polymorphisms could be genetic markers to GBS susceptibility.

Formation of 1D-nanowires and 2D nanophases in heteroepitaxy of Sb on high index Si(5 5 12) surface.

The surface topography of high index Si(5 5 12) presents a single-domain planar reconstruction that is composed of (225) and (337) regions with nanoscale widths and row like trenches and provides an unique template for the growth of nanostructures. In this study, Sb has been adsorbed on this Silicon surface to form various superstructural phases by steering the kinetic parameters and post growth annealing of the surface. Different pathways adopted have shown the formation of stabilized ordered superstructural phases corresponding to various coverages and substrate temperatures and are probed in-situ by complementary surface sensitive techniques such as Low Energy Electron Diffraction (LEED), Auger Electron Spectroscopy (AES), and Electron Energy Loss Spectroscopy (EELS). The growth of Sb at 300 degrees C substrate temperature and annealing the formed system to different temperatures upto 820 degrees C leads to the formation of low dimensional phases having anisotropicity along the (110) direction like atomic wires. The results also demonstrate the pathways in tailoring 1 D and 2D nanostructure formation, on this technologically and scientifically important interface.

Psychiatric comorbidity in new daily persistent headache: A cross-sectional study.

BACKGROUND: New daily persistent headache (NDPH) is a type of chronic daily headache. NDPH can have migrainous (NDPH-CM) or tension-type character (NDPH-CTTH). Recently, NDPH patients have shown to have associated anxiety and depression. We compared anxiety, depressive symptoms, somatization and pain catastrophization among NDPH, healthy controls and patients with chronic low-back pain and between NDPH-CM and NDPH-CTTH. METHODS: We assessed the study population for depressive symptoms by Patient Health Questionnaire-9, anxiety by Generalized Anxiety Disorder Scale - 7, somatoform disorder using DSM IV (TR) criteria and pain catastrophizing by using Pain Catastrophizing Scale. RESULTS: Fifty-five patients each with NDPH (mean age 28.24 ± 12.05 years, 45.5% females) and age/sex matched healthy individuals and patients with chronic low-back pain were enrolled. Among NDPH patients, somatoform disorder was seen in 32.7%, severe anxiety in 65.5%, severe depressive symptoms in 40%, significant pain catastrophization in 85.5%. NDPH patients had significantly higher frequency of all psychiatric co-morbidities as compared to healthy controls and patients with chronic low-back pain. NDPH-CM patients had significantly higher frequency of depression and pain catastrophizing behaviour as compared to NDPH-CTTH. CONCLUSION: Anxiety, depressive symptoms, somatization and pain catastrophizing were significantly more prevalent in NDPH when compared to healthy individuals and patients with chronic low back pain. Such effects should be sought for, as they might contribute to refractoriness to treatment. SIGNIFICANCE: Anxiety, depressive symptoms, somatization and pain catastrophizing were significantly more prevalent in new daily persistent headache when compared to healthy individuals and patients with chronic low back pain. Such effects should be sought for, as they might contribute to refractoriness to treatment.

Association of NOD1 and NOD2 polymorphisms with Guillain-Barré syndrome in Northern Indian population.

BACKGROUND: Nucleotide oligomerization domain (NOD) proteins are cytosolic pattern recognition receptors that respond to bacterial substrate and induce NF-κB activation in host. Association of NOD polymorphisms have been studied in many autoimmune disorders, however its role in Guillain-Barré syndrome (GBS) remains unknown. We have investigated NOD1 Glu266Lys and NOD2 (Arg702Trp and Gly908Arg) gene polymorphisms among patients with GBS. MATERIALS AND METHOD: Polymorphisms in NOD-1 (Glu266Lys) and NOD-2 (Arg702Trp and Gly908Arg) genes were studied using polymerase chain reaction-restriction fragment length polymorphism in 105 patients with GBS and 100 healthy controls. RESULTS: Homozygous genotype (Lys/Lys) of NOD1 was significantly associated with GBS (p=0.013); and its subtypes viz. acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) (p=0.008 and p=0.024 respectively) than controls. In NOD2 (Arg702Trp and Gly908Arg) polymorphisms, only heterozygous genotype (Arg/Trp and Gly/Arg) showed significant association with GBS (p=0.001 and p=0.01 respectively); subtypes AMAN, acute motor-sensory axonal neuropathy (AMSAN) and AIDP showed association with heterozygote Arg702Trp (p=0.001; p=0.029 and p=0.001 respectively) whereas only AIDP was associated with heterozygote genotype Gly908Arg (p=0.003). CONCLUSION: NOD1 (Glu266Lys) and NOD2 (Arg702Trp and Gly908Arg) polymorphisms were associated with an increased susceptibility to GBS. These polymorphisms could be genetic marker to GBS susceptibility.

Subcellular distribution of zinc and the presence of a metallothionein-like protein in bovine retina.

The mammalian retinas contain the highest concentrations of Zn in any known living tissues. Metallothionein is a low-molecular-weight, cysteine-rich metal-binding protein which occurs ubiquitously in nature and which has been recently identified in mammalian brains with a high affinity to bind Zn. In order to study the metabolism of Zn further, we have measured its subcellular distribution in the bovine retina and have found the distribution to be nonuniform, with the outer rod segments and the pellet 1 fraction, known to be highly enriched in photoreceptor cell synaptosomes, containing the highest amounts of 0.230 +/- 0.040 and 0.119 +/- 0.04 ? Zn/mg protein, respectively. In addition, the bovine retina contains a low-molecular-weight metallothionein-like protein which exhibits an elution volume (V(c)/V(0)) of 1.9 on gel permeation chromatography and which produces only one isoform on reverse-phase high performance liquid chromatography with a retention time of 16.67 min. The precise function of this metallothioneinlike protein, which may be related to the transport and compartmentation of Zn in the retina, remains to be elucidated.

Regulation of zinc metallothionein II mRNA level in rat brain.

Metallothionein isoforms I and II (MTI and MTII) have been identified in the rat brain, monkey brain, bovine retina, pineal gland and hippocampus, and in the neuroblastoma IMR 32. Since intraperitoneally administered zinc passes across the blood-brain barrier slowly, the rat brain metallothionein can be induced in a time- and dose-dependent fashion only following intracerebroventricularly (i.c.v.) administered zinc sulfate at a rate of 0.20 ?mol/?l/h for 24 h using an Alzet minipump. The zinc-induced proteins, incorporate large quantities of [(35)S]cysteine, bind (65)Zn and produce two isoforms which contain 17 and 18 cysteine residues, respectively, but lack aromatic amino acids or histidine. In this communication, we report that i.c.v.-administered zinc in a bolus of 0.1 and 0.5 ?mol increased the synthesis of poly A(+) RNA from 6.6 to 8.0 and 9.6 ?g/g brain tissue, respectively. Furthermore, we probed the poly A(+) RNA with (32)P-labeled 180 base pair BamH1/PvuII restriction fragment containing the cDNA for human MTII from the phMT-II(3) plasmid. Slot blot analysis of poly A(+) RNA revealed a dose-dependent increase in brain MTII hybridizable mRNA. Northern blot analysis of poly A(+) RNA extracted from the rat liver and brain using (32)P-labeled cDNA exhibited a major band of hybridization at 700 bases in both tissues. These data provide evidence that the zinc-induced MT synthesis in the brain is associated with an accumulation of mRNA which is analogous to the zinc-induced synthesis of hepatic MT mRNA. However, other evidence indicates that the factors regulating the synthesis of the brain and the hepatic metallothioneins are not identical.

Isolation and characterization of a metallothionein-like protein from monkey brain.

A cadmium-binding protein from monkey brain has been isolated, purified and characterized. The absorption spectrum of this protein indicates the presence of Cu-Zn thionein in the normal monkey brain which has a strong affinity to bind cadmium. On cadmium exposure the protein sequestered most of the cadmium which entered the brain. The apparent molecular weight of this protein as determined on a gel filtration column calibrated with marker proteins has been found to be in the range of 11,500-12,000 Da. The ratio of absorbance at 254 nm/280 nm is more than 1 indicating the presence of cadmium-mercaptide bonds, which was further confirmed by the presence of 15 cysteine residues. Polyacrylamide gel electrophoresis of the protein shows 3 bands indicating the presence of 3 isometallothionein forms. Unlike hepatic or renal thioneins, the cadmium-binding protein in brain is not inducible following administration of cadmium. However, when antibodies raised against hepatic metallothionein were cross-reacted with brain Cd-binding protein, a line of identity was observed, indicating the 2 proteins are immunologically identical and share a high degree of structural similarity.

Induction of Cd-metallothionein in cadmium exposed monkeys under different nutritional stresses.

Induction of cadmium metallothionein (MT) in chronic cadmium exposure in Rhesus monkeys undergoing protein calorie malnutrition (PCM) and calcium deficiency has been studied. A positive correlation between cadmium content and levels of MT in kidney, liver, intestine, testis, heart and lung, has been observed. The accumulation of cadmium and synthesis of MT in these tissues was highest in monkeys subjected to cadmium exposure during calcium deficiency. Although more of cadmium is directed towards kidneys of calcium-deficient monkeys the MT-inducing ability of kidney is lower than that of liver. Monkeys on PCM diet also showed enhanced accumulation of cadmium and MT as compared to those on normal diet during cadmium exposure.

T1-weighted dynamic contrast-enhanced MR evaluation of different stages of neurocysticercosis and its relationship with serum MMP-9 expression.

BACKGROUND AND PURPOSE: Epileptogenesis in NCC is associated with perilesional inflammation and disruption in BBB. We quantified BBB in different stages of NCC by using DCE-MR imaging to look for the differences in perfusion indices and to correlate these indices with serum MMP-9 expression. MATERIALS AND METHODS: DCE-MR imaging along with conventional MR imaging was performed in 57 single cysticercous brain lesions to quantify the kep, K(trans), and ve around the lesions, which were in different stages of evolution. There were 6 lesions in the vesicular stage and 17 lesions each in the colloidal, granular-nodular, and calcified stages. Serum MMP-9 was quantified from all patients, whereas perfusion indices were quantified from all stages except for the vesicular stage. RESULTS: We observed significant differences among the 3 stages of NCC in serum MMP-9 expression as well as DCE-derived kep values. In addition, kep showed a strongly significant positive correlation with MMP-9 expression when modeled with the individual stage of the disease as well as with all stages when pooled together. Other DCE-derived hemodynamic and pharmacokinetic parameters showed inconsistent differences with each stage of the disease. The correlation of DCE-derived parameters with serum MMP-9 expression and edema volume also showed inconsistency with the stage of the disease. CONCLUSIONS: We conclude that kep correlates best with serum MMP-9 expression among the pharmacokinetic indices and most closely represents the degree of BBB breakdown, which is highest in the colloidal stage and lowest in the calcified stage. kep may be used as a noninvasive image biomarker of BBB breakdown in different stages of NCC.

Understanding epileptogenesis in calcified neurocysticercosis with perfusion MRI.

OBJECTIVES: Calcified cysticercus larva with perilesional abnormality is thought to be responsible for seizures in patients with neurocysticercosis (NCC). However, it is not well understood why some calcified cysts are associated with seizures even without perilesional abnormality. METHODS: The study group consists of 30 subjects from an ongoing survey for disease burden estimation of a swine farming community who had a single calcified lesion without any perilesional abnormality with or without presentation of seizures. Each group consisted of 15 patients with calcified cysts and was labeled as asymptomatic and symptomatic. We performed dynamic contrast-enhanced (DCE) MRI on all these subjects and determined serum matrix metalloproteinase-9 (MMP-9) levels and MMP-9 gene polymorphisms. RESULTS: DCE-MRI-derived rate transfer constant (k(ep)) and serum MMP-9 levels showed significant differences between symptomatic and asymptomatic subjects. We observed an increase in the MMP-9 levels, k(ep), and the volume transfer coefficient (k(trans)) in these lesions. We also observed a significant increase in MMP-9 (R279Q) gene polymorphism in symptomatic subjects compared with asymptomatic and control subjects. CONCLUSIONS: Perilesional inflammation, which varies from symptomatic to asymptomatic subjects, can be quantified using DCE-MRI in calcified cysticercosis and may help distinguish these 2 groups with similar imaging findings. The observed increase in k(ep) with serum MMP-9 levels suggests that the former may serve as a biomarker of MMP-9 levels in these subjects. The significant MMP-9 (R279Q) gene polymorphism in symptomatic subjects might explain the differences in the observed DCE-MRI indices between symptomatic and asymptomatic subjects.

Neuromyotonia masquerading as tetanus.

Neuromyotonia, or Isaac's syndrome, is a rare neuromuscular disorder of peripheral nerve hyperexcitability characterized by muscle stiffness, muscle hypertrophy, pseudomyotonia, myokymia and electromyographic evidence of myokymic or neuromyotonic discharges. A young boy with neuromyotonia is presented who was diagnosed with tetanus for severe muscle spasms, trismus and ophisthotonos. We discuss differentiation of neuromyotonia from tetanus and other disorders with similar features on clinical and electrophysiological examination.

Diffusion tensor MR imaging in children with pantothenate kinase-associated neurodegeneration with brain iron accumulation and their siblings.

BACKGROUND AND PURPOSE: It has been reported that iron concentration influences DTI metrics in deep gray matter nuclei. We hypothesized that increased FA in the deep gray nuclei may indicate abnormal iron accumulation in patients with PKAN and their siblings. MATERIALS AND METHODS: Seven patients with the characteristic "eye-of-the-tiger sign," their 5 siblings, and 5 age-matched controls were prospectively studied. One-way ANOVA with Bonferroni post hoc multiple comparisons was used to compare DTI metrics (FA and MD) among subject groups in the putamen, CN, GP, SN, and ALIC. In addition, hypointense and hyperintense regions of the eye-of-the-tiger sign were segmented, and their DTI metrics were compared. In the patient group, the values of DTI metrics in hypointense regions were also compared with those of the ALIC. RESULTS: A significant increase in FA values of the GP and SN from controls to the patient group to siblings was observed. In the GP, MD values were significantly higher in patients compared with controls and siblings. The patients showed significantly increased FA with decreased MD in hypointense compared with hyperintense regions of the eye-of-the-tiger sign. No difference in FA values were observed between the ALIC and hypointense regions of the eye-of-the-tiger sign in patients. CONCLUSIONS: High FA values in siblings of patients with PKAN suggest the presence of abnormal iron in deep gray matter nuclei, even in the absence of its demonstration on T2*-weighted GRE.

Delayed diagnosis of brain tumor in a patient with flexor spasms and spastic foot drop.

Flexor spasms are involuntary muscle contractions comprising dorsiflexion at the ankle and flexion at the knee and the hip, occurring as a result of nociceptive spinal release reflex. The presence of flexor spasms generally suggests a lesion in the spinal cord. Foot drop is usually seen with lesions of lumbosacral roots, peripheral nerves or muscles. We hereby present a patient with a rare combination of spastic foot drop and flexor spasms due to a brain tumor. The possible underlying pathophysiological mechanisms resulting in flexor spasms due to a cerebral lesion are briefly discussed.

Biochemical properties of metallothionein isoforms from bovine hippocampus.

The mammalian hippocampi not only contain high concentrations of zinc, but also exhibit regional variation in this essential element, with concentrations being highest in the hilar region and lowest in the fimbria. For example, the concentration of zinc in the mossy fiber axons has been estimated to approach 300-350 microM. Since "free" zinc is an extremely neurotoxic substance with an inherent ability to inhibit an extensive number of sulfhydryl-containing enzymes and receptor sites, we hypothesized that low-molecular weight zinc binding protein may exist in the hippocampus in order to regulate the steady-state concentration of zinc. In an attempt to investigate this hypothesis and the dynamic metabolism of zinc, we have searched for and have identified a metallothionein-like protein in bovine hippocampus which exhibits an elution volume (Ve/Vo) of 2.0 on gel filtration chromatography and which produces two isoforms, which on a reverse phase high performance liquid chromatography, show retention times of 15.70 min and of 16.37 min, respectively. The hippocampal metallothionein isoform II contains a cysteine to zinc ratio of 2.8 to 1.0, has an apparent molecular weight of 9,500 daltons and, as judged by studies involving UV spectral analysis, lacks aromatic amino acids, but possesses metallomercaptide bonds. The results of these studies suggest that the metallothionein may play an essential role in regulating the transport and/or accumulation of zinc in the hippocampus.

Role of metallothionein in metal detoxification and metal tolerance in protein calorie malnutrition and calcium deficient monkeys (Macaca mulatta).

A monkey model has been set up for protein calorie malnutrition and calcium deficiency. Oral exposure of 5ppm Cd/kg body wt./day for 24 weeks led to increased excretion of Cd, metallothionein (MT) and zinc. Rehabilitation of PCM monkeys for one year resulted in gradual reduction and finally complete disappearance of urinary metallothionein. During Cd exposure, the accumulation of Cd and induction of MT was significantly higher in liver, kidney and intestine. MT was also induced in heart, lung and testis of Cd exposed PCM and calcium deficient monkeys. Metallothionein from liver has been resolved into three isoforms, viz MTa, MTb and MTc on DEAE-Sephadex A 25 ion exchange column. MTc is the major isoform in Cd-treated, normal and protein calorie malnourished monkeys whereas MTb is the major isoprotein in the cadmium treated calcium deficient monkeys. The iso-metallothioneins varied in their metal composition in the nutritional stress conditions and showed different capacities to reactivate apo-enzymes viz. alkaline phosphatase, ceruloplasmin, superoxide dismutase and glutathione peroxidase. Thus, metallothionein plays a key role in metal metabolism during cadmium toxicity under nutritional stress conditions.

Effect of protein calorie malnutrition and calcium deficiency on hepatic iso-metallothioneins in Cd-exposed monkeys.

Oral administration of cadmium results in the induction of metallothionein in liver of rhesus monkeys subjected to protein calorie malnutrition and calcium deficiency. Metallothionein was resolved into three iso-proteins viz. MTa, MTb & MTc which varied in their quantities and metal composition in these nutritional stress conditions. 'MTc' was the major iso-protein in protein calorie malnourished monkeys, while 'MTb' predominated in the calcium deficient group.

Molecular aspects, physiological function, and clinical significance of metallothioneins.

Metallothioneins (MTs) are well-characterized low molecular weight, heat-stable cytosolic proteins with exceptional high content of cysteinyl sulfur and are known to bind heavy metals like cadmium (Cd), zinc (Zn), and copper (Cu). Since these proteins are induced on exposure to heavy metals, it is now accepted that they have a detoxifying role during heavy metal toxicity. It has also been suggested that the primary function of Mt is in the homeostasis of the essential metals Zn and Cu. Recently, a role MT in selenium metabolism in primates has been established. Further, MT has gained considerable importance in the clinical disorders related to trace metal metabolism.