Case 1: lipoid proteinosis (hyalinosis cutis et mucosae; Urbach-Wiethe disease).
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Adult↗
Biomedical subjects
V Ramesh
Publications and source records attributed to V Ramesh.
Cutaneous Rosai-Dorfman disease preceding inguinal lymphadenopathy.
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Adult↗
Mnemonics in dermatology; an appraisal.
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Dermatology↗
Nutrition beyond nutrition: plausibility of immunotrophic nutrition for space travel.
BACKGROUND AND AIMS: Microgravity has adverse effects on the immune system. We examined the effects of supplemental dietary nucleotides on immune function in ground-based in vivo anti-orthostatic tail-suspended (AOS) mice and in vitro (bioreactor-BIO) analogs of microgravity. METHODS: BALB/c mice were divided into the following three groups: group housed, single isolation, and AOS. Mice were fed either control chow or chow supplemented with RNA or uracil. Immune function was assessed by in vivo popliteal lymph node proliferation (PLN), in vitro PHA-stimulated proliferation of splenocytes and cytokine production. BIO splenocytes were cultured in vitro with/without PHA, a nucleoside-nucleotide mixture (NS/NT) or uridine. The cell proliferation and scanning electron microscopic examination for cells were carried out. RESULTS: PLN response was significantly suppressed in AOS mice (P<0.05) and was restored by RNA and uracil diets. Splenocytes from AOS mice had decreased phytohemagglutinin (PHA)-stimulated proliferation, decreased IL-2 and IFN-gamma cytokine levels (P<0.05). These responses were restored by RNA and uracil diets. In BIO cultures, PHA response was suppressed significantly, and uridine and NS/NT restored the proliferative responses. Scanning electron microscopic analysis of cells cultured in BIO revealed cells with pinched, distorted and eroded membranes. Nucleotide supplementation especially uridine restored normal activated cell surface appearance and ruffling. CONCLUSION: In the microgravity analog environment of AOS and BIO, supplemental nucleotides and especially uracil/uridine have up-regulating and immunoprotective effects with potential as a countermeasure to the observed immune dysfunction in true microgravity.
Animals↗
Evaluation of enzyme-linked immunosorbent assay for diagnosis of post-kala-azar dermal leishmaniasis with crude or recombinant k39 antigen.
The diagnosis of post-kala-azar dermal leishmaniasis (PKDL), a dermatosis that provides the only known reservoir for the parasite Leishmania donovani in India, remains a problem. Timely recognition and treatment of PKDL would contribute significantly to the control of kala-azar. We evaluated here the potential of the enzyme-linked immunosorbent assay (ELISA) as a diagnostic tool for PKDL. Antigen prepared from promastigotes and axenic amastigotes with parasite isolates that were derived from skin lesions of a PKDL patient gave sensitivities of 86.36 and 92%, respectively, in the 88 PKDL cases examined. The specificity of the ELISA test was examined by testing groups of patients with other skin disorders (leprosy and vitiligo) or coendemic infections (malaria and tuberculosis), as well as healthy controls from areas where this disease is endemic or is not endemic. A false-positive reaction was obtained in 14 of 144 (9.8%) of the controls with the promastigote antigen and in 14 of 145 (9.7%) of the controls with the amastigote antigen. Evaluation of the serodiagnostic potential of recombinant k39 by ELISA revealed a higher sensitivity (94.5%) and specificity (93.7%) compared to the other two antigens used. The data demonstrate that ELISA with crude or recombinant antigen k39 provides a relatively simple and less-invasive test for the reliable diagnosis of PKDL.
Animals↗
Effect of chronic administration of 7alpha-methyl-19-nortestosterone on serum testosterone, number of spermatozoa and fertility in adult male bonnet monkeys (Macaca radiata).
Hormonal approaches to male contraception that are based on the suppression of LH secretion require androgen replacement treatment to maintain sexual behaviour and secondary sexual characteristics. Androgen supplementation not only involves large and frequent doses of testosterone esters but also results in undesirable effects on the prostate gland. In an attempt to avoid such problems, a synthetic androgen, 7alpha-methyl-19-nortestosterone (MENT), which is much more potent than testosterone, has been developed. In the present study, MENT was administered at different doses (25, 50, 100, 300 and 1000 microg day(-1)) either alone or in combination with oestradiol via Silastic implants for a specified period to adult male bonnet monkeys (Macaca radiata). Blood and semen samples were collected at specific intervals and analysed for serum testosterone and seminal parameters, respectively. The results of the present study clearly indicate that administration of MENT at all doses tested results in suppression of the nocturnal surge of testosterone (by day 3), as well as a decrease in the number of spermatozoa (by day 45). Co-administration of oestradiol resulted in a reduction in the dose of MENT required to suppress the nocturnal surge. None of the male bonnet monkeys treated with MENT were able to impregnate females, clearly demonstrating the efficacy of MENT in blocking fertility in male bonnet monkeys.
Animals↗
Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.
BACKGROUND: The genetic basis of most common forms of human paroxysmal disorders of the central nervous system, such as epilepsy, remains unidentified. Several animal models of absence epilepsy, commonly accompanied by ataxia, are caused by mutations in the brain P/Q-type voltage-gated calcium (Ca(2+)) channel. We aimed to determine whether the P/Q-type Ca(2+) channel is associated with both epilepsy and episodic ataxia type 2 in human beings. METHODS: We identified an 11-year-old boy with a complex phenotype comprising primary generalised epilepsy, episodic and progressive ataxia, and mild learning difficulties. We sequenced the entire coding region of the gene encoding the voltage-gated P/Q-type Ca(2+) channel (CACNA1A) on chromosome 19. We then introduced the newly identified heterozygous mutation into the full-length rabbit cDNA and did detailed electrophysiological expression studies of mutant and wild type Ca(2+) channels. FINDINGS: We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (R1820stop) resulting in complete loss of the C terminal region of the pore-forming subunit of this Ca(2+) channel. Expression studies provided direct evidence that this mutation impairs Ca(2+) channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect. INTERPRETATION: Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca(2+) channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.
Adult↗
Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions.
Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumor-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at loci of both TSC1 and TSC2. LOH has been documented in renal angiomyolipomas (AMLs), but loss of the wild-type allele in cortical tubers appears to be very uncommon. Analysis of second, somatic events in tumors for which the status of both TSC1 and TSC2 is known is essential for exploration of the pathogenesis of TSC-lesion development. We analyzed 24 hamartomas from 10 patients for second-hit mutations, by several methods, including LOH, scanning of all exons of both TSC1 and TSC2, promoter methylation of TSC2, and clonality analysis. Our results document loss of the wild-type allele in six of seven AMLs, without evidence of the inactivation of the second allele in many of the other lesions, including tumors that appear to be clonally derived. Laser-capture microdissection further demonstrated loss of the second allele in all three cellular components of an AML. This study thus provides evidence that, in both TSC1 and TSC2, somatic mutations resulting in the loss of wild-type alleles may not be necessary in some tumor types-and that other mechanisms may contribute to tumorigenesis in this setting.
Clone Cells↗
The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association.
The neurofibromatosis 2 protein product merlin, named for its relatedness to the ezrin, radixin and moesin (ERM) family of proteins, is a tumour suppressor whose absence results in the occurrence of multiple tumours of the nervous system, particularly schwannomas and meningiomas. Merlin's similarity to ERMs suggests that it might share functions, acting as a link between cytoskeletal components and the cell membrane. The N-terminus of merlin has strong sequence identity to the N-terminal actin-binding region of ezrin; here we describe in detail the merlin-actin interaction. Employing standard actin co-sedimentation assays, we have determined that merlin isoform 2 binds F-actin with an apparent binding constant of 3.6 microM and a stoichiometry of 1 mol of merlin per 11.5 mol of actin in filaments at saturation. Further, solid-phase binding assays reveal that merlin isoforms 1 and 2 bind actin filaments differentially, suggesting that the intramolecular interactions in isoform 1 might hinder its ability to bind actin. However, merlin does not bind G-actin. Studies of actin filament dynamics show that merlin slows filament disassembly with no influence on the assembly rate, indicating that merlin binds along actin filament lengths. This conclusion is supported by electron microscopy, which demonstrates that merlin binds periodically along cytoskeletal actin filaments. Comparison of these findings with those reported for ERM proteins reveal a distinct role for merlin in actin filament dynamics.
Actins↗
Structural alterations in cardiac calcium release units resulting from overexpression of junctin.
Junctin is a 26 kDa membrane protein that binds to calsequestrin, triadin, and ryanodine receptors (RyRs) within the junctional sarcoplasmic reticulum of calcium release units. The sequence of junctin includes a short N-terminal cytoplasmic domain a single transmembrane domain, and a highly charged C-terminal domain located in the sarcoplasmic reticulum lumen. Dog and mouse junctins are highly conserved at the transmembrane domains, but the luminal domains are more divergent. To probe the contribution of junctin to the architecture of calcium release units in heart, we engineered transgenic mice overexpressing canine junctin and examined the left ventricular myocardium by electron microscopy. Overall architecture of calcium release units is similar in control myocardium and in myocardium overexpressing junctin by 5-10-fold. In both myocardia, junctional SR cisternae are closely associated with exterior membranes (plasmalemma and transverse tubules). The cisternae are flat; they contain a string of calsequestrin beads and are lined by a row of feet, or RyRs, on the side facing the exterior membranes. T tubule surface density, measured as the perimeter of T tubule profiles v area of section, is the same in transgenic and control myocardia (305 v 289 nm/nm(2)). Three changes affecting the junctional SR architecture are apparent in the myocardium overexpressing junctin. One is a more tightly zippered appearance of the junctional SR cisternae. The width of the junctional SR is narrower and less variable in overexpressing than in control myocardium and the calsequestrin content is more compact. A second change is the extension of zippered junctional SR domains to non-junctional regions, which we term "frustrated" junctional SR. A third change is an increase in the extent of association between SR and T tubules. In junctin overexpressing myocardium junctional SR cisternae cover approximately 45% of the surface of all T tubule profiles, while in control myocardium the coverage approximately 30%. Junctional associations between SR and T tubules are increased in size. We conclude that the increase in junctin expression affects the packing of calsequestrin in the junctional SR and facilitates the association of SR and T tubules.
Amino Acid Sequence↗
Developmental expression of the tuberous sclerosis proteins tuberin and hamartin.
Tuberous sclerosis complex is an autosomal dominant multisystem disorder, characterized by the development of hamartomas in multiple organs, primarily the skin, heart, kidney, and brain. The tuberous sclerosis genes, TSC1 and TSC2, encode hamartin and tuberin, respectively. Employing specific antibodies for hamartin and tuberin, we analyzed the expression of these two proteins by Western blot analyses in normal developing human and rat tissues. Both proteins are expressed ubiquitously in human fetal tissues and placenta, but are expressed at relatively low levels in human adult tissues, except brain. Similarly, high expression of these two proteins is observed in rat embryonic tissues, with a progressive decline after birth. To better characterize the developmental expression of tuberin and hamartin, we conducted a detailed study in rat tissues from embryonic day 13 to adult by Western blot analysis and immunohistochemistry. Immunohistochemical staining of rat tissues for tuberin and hamartin revealed tissue-specific expression patterns throughout development. Both tuberin and hamartin are expressed in epithelia, muscle (smooth, cardiac and skeletal muscle) and the nervous system (neurons, glia, choroid plexus and arachnoid). Except for the central nervous system, immunostaining intensity declines with age, confirming the protein blot analysis. These results indicate that tuberin and hamartin may play a critical role in development, and thus provide a framework for understanding the developmental and hamartomatous manifestations of tuberous sclerosis. These findings also suggest that tuberin and hamartin have additional functions in the adult brain, consistent with the marked neurological problems that afflict many patients with tuberous sclerosis.
Age Factors↗
A close association of torsinA and alpha-synuclein in Lewy bodies: a fluorescence resonance energy transfer study.
TorsinA, a novel protein in which a mutation causes dominant, early onset torsion dystonia, may serve as a chaperone for misfolded proteins that require refolding or degradation. It has been hypothesized that misfolded alpha-synuclein, a protein in which two mutations cause autosomal dominantly inherited Parkinson's disease, serves as a nidus for the development of a Lewy body. We hypothesized that torsinA plays a role in the cellular processing of alpha-synuclein. We demonstrate that anti-torsin antibodies stain Lewy bodies and Lewy neurites in the substantia nigra and cortex. Using sensitive fluorescent resonance energy transfer (FRET) techniques, we find evidence of a close association between torsinA and alpha-synuclein in Lewy bodies.
Carrier Proteins↗
NHE-RF, a merlin-interacting protein, is primarily expressed in luminal epithelia, proliferative endometrium, and estrogen receptor-positive breast carcinomas.
NHE-RF, a regulatory cofactor for NHE (Na(+)-H(+) exchanger) type 3, interacts with ion transporters and receptors through its PDZ domains and with the MERM proteins (merlin, ezrin, radixin and moesin) via its carboxyl terminus. Thus, NHE-RF may act as a multifunctional adaptor protein and play a role in the assembly of signal transduction complexes, linking ion channels and receptors to the actin cytoskeleton. NHE-RF expression is up-regulated in response to estrogen in estrogen receptor-positive breast carcinoma cell lines, suggesting that it may be involved in estrogen signaling. To further understand NHE-RF function and its possible role in estrogen signaling, we analyzed NHE-RF expression in normal human tissues, including cycling endometrium, and in breast carcinomas, tissues in which estrogen plays an important role in regulating cell growth and proliferation. NHE-RF is expressed in many epithelia, especially in cells specialized in ion transport or absorption, and is often localized to apical (luminal) membranes. NHE-RF expression varies markedly in proliferative versus secretory endometrium, with high expression in proliferative (estrogen-stimulated) endometrium. Furthermore, estrogen receptor status and NHE-RF expression correlate closely in breast carcinoma specimens. These findings support a role for NHE-RF in estrogen signaling.
Adult↗
Adenosine, prolonged wakefulness, and A1-activated NF-kappaB DNA binding in the basal forebrain of the rat.
There is considerable evidence to suggest that adenosine is a modulator of behavioral state. Our previous reports showed that perfusion of adenosine into the basal forebrain decreased wakefulness. Furthermore, prolonged wakefulness resulted in increased levels of extracellular adenosine in the basal forebrain of cats and rats. However, the longer-term consequences of prolonged wakefulness and increased adenosine are largely unknown. We report here an increase in the DNA binding activity of the transcription factor, nuclear factor-kappa B (NF-kappaB) following 3 h of sustained wakefulness in the rat basal forebrain. Moreover, this treatment led to the appearance of the p65 subunit of NF-kappaB in the nucleus, as determined by western blot analysis of nuclear proteins. This contrasted with undetectable levels in the sleeping controls. A concomitant disappearance of I-kappaB in cytoplasm suggested the degradation of this inhibitor of NF-kappaB. In the acute in vitro basal forebrain slice preparation, perfusion of adenosine increased NF-kappaB DNA binding while pretreatment of the slices with the A1 adenosine receptor antagonist, cyclopentyl-1-3-dimethylxanthine, significantly reduced NF-kappaB DNA binding. These results are compatible with the hypothesis that increases in the levels of adenosine in the basal forebrain, that occur during prolonged wakefulness, act through an A1 adenosine receptor and a second messenger system to increase the activity of the transcription factor NF-kappaB. We further hypothesize that some of the long duration effects of prolonged wakefulness/sleep deprivation on performance and physiology, often termed 'sleep debt', might be mediated through adenosine and its activation of NF-kappaB, which is known to alter the expression of several behavioral state regulatory factors.
Adenosine↗
Tethering of the vertebral artery in the congenital arcuate foramen of the atlas vertebra: a possible cause of vertebral artery dissection in children.
Twelve children with vertebrobasilar artery stroke are reported (seven males, five females; aged 6 months to 15 years). Patient 1 showed an arcuate foramen in the posterior arch of the atlas, an anatomical variant occurring in 3 to 15% of the population. It was hypothesized that the presence of the arcuate foramen might cause tethering of the vertebral artery and lead to its dissection by repetitive trauma. Lateral plain films of the cervical spine in cases of posterior circulation stroke were taken. Eight of 11 patients showed aberrant arcuate foramina. Of the remaining three patients, one had normal cervical spine X-rays, one had an absent right posterior arch of the atlas following previous surgery for a cervical meningocele, and one patient had incomplete ossification of the vertebrae. Seven of the nine patients with arcuate foramina had vertebral angiograms. In all cases this showed the vertebral artery passing through the arcuate foramen before entering the brain and an appearance consistent with arterial dissection and occlusion at the same site below the foramen. Most documented cases of posterior circulation stroke in children follow trauma, which may be minimal or repetitive, with thrombotic occlusion of the artery at C1-C2 level. The association with an arcuate foramen and its possible causative role in the genesis of posterior circulation stroke in children has not been previously recognized. There may be a causal association between the presence of an arcuate foramen, tethering of the vertebral artery in the foramen, and dissection from repetitive trauma with movement of the neck.
Adolescent↗
A simple and sensitive test for field diagnosis of post kala-azar dermal leishmaniasis.
BACKGROUND: Current methods for diagnosis of post kala-azar dermal leishmaniasis (PKDL) do not offer adequate sensitivity and specificity. OBJECTIVES: To develop a simple and sensitive test for field diagnosis of PKDL. METHODS: Immunochromatographic nitrocellulose strips precoated with recombinant k39 antigen were evaluated for the detection of circulating antibodies to leishmanial k39 in PKDL sera. A drop of serum applied to the strip followed by buffer led to the development of two visible bands indicating the presence of anti-k39 IgG. RESULTS: The strip test was able to detect cases of PKDL with 91% sensitivity. The specificity of the test was evaluated using controls with other skin diseases, other common infections and healthy persons from endemic and non-endemic regions. Of 125 controls examined, all were negative on the strip test, indicating 100% specificity of the test. CONCLUSIONS: The immunochromatographic nitrocellulose strips provide a non-invasive, rapid and accurate method for diagnosing PKDL.
Adolescent↗
Case 4. Diagnosis: Tufted angioma (angioblastoma).
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Female↗