Biomedical subjects
Publications and source records attributed to V Ramesh.
Two girls with dissecting cellulitis of the scalp are described. In one Pseudomonas aeruginosa was isolated from the sinus discharge. Both patients were controlled with prolonged antibiotic therapy and periodic aspiration of the fluctuant lesions. Role of infection in perpetuating the condition is highlighted.
A case of healed tuberculoid leprosy (TT) with multiple superficial nerve abscesses involving the whole cutaneous network on the patch is reported. To the best of our knowledge multiple cutaneous nerve abscesses involving the entire subcutaneous plexus on a TT patch is a very uncommon observation.
Skin biopsy specimens from nine patients with lupus vulgaris were examined in situ by means of monoclonal antibodies directed against phenotypes of lymphocyte subsets, Langerhans cells, HLA-DR antigens, and interleukin 2 receptor. The epidermis showed prominent changes, including intense expression of HLA-DR on keratinocytes, increase in epidermal cell layers, moderate to high Langerhans cell hyperplasia, and infiltration by CD3+ pan-T cells as well as CD8+ (cytotoxic/suppressor) and CD4+ (helper/inducer) T cells. The predominant lymphocyte in the dermal granulomas was the activated CD3+ T cell, expressing major histocompatibility complex class II antigens and interleukin 2 receptor. CD4+ and CD8+ cells were randomly distributed among the epithelioid cells, which showed intense staining for major histocompatibility complex class II antigens. In all except two patients, the CD4+ population was greater than that of the CD8+ cells. CD1+ Langerhans cells were scattered in moderate numbers in the dermal granulomas. Acid-fast bacilli were conspicuously absent in the biopsy specimens. These features suggest that T-cell activation and Langerhans cell hyperplasia are prominent features of dermal tuberculosis.
Fifty children with culture proven acute meningococcaemia were studied during the winter outbreak of the disease in 1986-87. Purpuric lesions were seen in 60 per cent, erythematous papules in 32 per cent, faint pink macules in 28 per cent, conjunctival petechiae in 10 per cent and herpes labialis in 20 per cent. Histopathology of skin lesions showed that the primary damage was to the dermal vessels, the extent of damage depending on the type of skin involvement. Diplococci in Gram's stained sections were seen frequently in purpuric as compared to the other skin lesions. They were located in degenerating neutrophils, endothelial cells, fibrin clots or freely in the vascular lumen. Electron microscopic study showed vascular changes accompanied by a perivascular phagocytic response. Both light and electronmicroscopy indicated the involvement of the coagulative mechanism in the pathogenesis of meningococcaemia. However, clinical parameters of clotting were often within normal limits. In the case of a child (who died eventually), a low platelet count and prolonged coagulation indices were observed. Sera from some of the children were tested for the presence of antibodies against meningococci by indirect immunofluorescence. Antibodies were detected in the sera and they may have a role in regulating the severity and course of the illness. The significance of immunoglobulin deposits in the skin lesions is not clear.
Gyrate atrophy (GA), a recessive eye disease involving progressive vision loss due to chorioretinal degeneration, is associated with the deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT), with consequent hyperornithinemia. We and others have reported a number of missense mutations at the OAT locus which result in GA. Here we report a GA patient of Danish/Swedish ancestry in whom one OAT allele produces an mRNA that is missing a single 96-bp exon relative to the normal mRNA. Polymerase-chain-reaction amplification and sequencing revealed a 9-bp deletion covering the splice acceptor region of exon 5, resulting in the absence of exon 5 sequences from the mRNA with no disruption to the reading frame. This mutation, which was not present in 15 other independent GA patients, adds to the array of allelic heterogeneity observed in GA and represents the first example of a splicing mutation associated with this disorder.
A sixty-year-old woman with multiple proliferating trichilemmal cysts over the vulva is described. The appearance of the eruptions suggests a hamartomatous origin. The lesions in the later stages resembled basal cell carcinoma. The malignant potential of the cysts and their treatment are discussed.
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The resonances in the aromatic region of the 1H-NMR spectrum of the Escherichia coli trp aporepressor have been assigned to amino acid type by two-dimensional correlated spectroscopy (COSY), homonuclear Hartmann-Hahn (HOHAHA) spectroscopy and nuclear Overhauser enhancement spectroscopy (NOESY) techniques and studies of the pH dependence of the chemical shifts, in combination with selective deuteration of the protein. Complete sequence-specific assignments of the aromatic resonances have been made by comparing the observed inter-residue NOEs with those expected on the basis of the crystal structure of the protein [Zhang, R.-G., Joachimiak, A., Lawson, C.L., Shevitz, R.W., Otwinowski, Z. & Sigler, P.B. (1987) Nature 327, 591-597]. The latter experiments have also permitted the sequence-specific assignment of some of the high-field methyl resonances. The complete assignment of the aromatic region of the spectrum, in particular of resonances from residues at the dimer interface, opens the way to detailed studies of the conformational effects of corepressor and operator binding.
A detailed 1H NMR analysis of ligand binding to the human plasminogen kringle 4 domain has been carried out at 300 MHz. The ligands that were investigated are N alpha-acetyl-L-lysine, L-lysine methyl ester, N alpha-acetyl-L-lysine methyl ester, L-lysine hydroxamic acid, trans-(aminomethyl)cyclohexanecarboxylic acid (AMCHA), and 4-(aminomethyl)bicyclo[2.2.2]octane-1-carboxylic acid (AMBOC). Specific ligand-binding effects were detected via two-dimensional COSY experiments. The side chains that are the most perturbed by ligand presence are those from Trp62, Phe64, and Trp72. Ligand-kringle saturation transfer (Overhauser) experiments show that the aromatic rings from these three residues, especially Trp72, are in direct contact with the ligand. These results add support to a previously reported model of the kringle 4 lysine-binding site [Ramesh, V., Petros, A. M., Llinás, M., Tulinsky, A., & Park, C. H. (1987) J. Mol. Biol. 198, 481-498] by which these aromatic groups are assigned a key role in establishing hydrophobic interactions with the ligand molecule. Equilibrium association constants (Ka) and kinetic rate constants (kon, koff) were determined for the binding of the various linear and cyclic ligands to kringle 4. We find that those ligands whose carboxylate function is blocked bind significantly weaker (Ka approximately less than 2 mM-1) than the corresponding analogues where the anionic center is present (Ka approximately greater than 20 mM-1), which underscores the relevance of the polar group in stabilizing the interaction with the kringle 4 binding site.(ABSTRACT TRUNCATED AT 250 WORDS)
Skin biopsies were taken from an infant girl with Hypomelanosis of Ito (Incontinentia Pigmenti Achromians) for histopathological, histochemical and electron microscopic studies. Histological observations were similar to those reported previously. Electron microscopy revealed two groups of melanocytes, an effete group and another group with a highly dendritic appearance. The significance of these findings is discussed.
The clinical course, therapy and investigations in a man with lichenoid mycosis fungoides which resulted in fatal spread to the brain is described. Immunological studies revealed a significant reduction in T cell numbers. Brain lesions were confirmed by CT Scan and drill biopsy. The literature on the subject is discussed.
A three-year-old boy is reported who had congenital spastic paraparesis caused by severe segmental narrowing of the spinal cord. X-rays of the spine showed thoracolumbar scoliosis and anomalies of the thoracic vertebrae from T5 to T11. Myelography, with CT scanning, demonstrated severe narrowing of the T5 to T12 segments of the spinal cord, measuring only 1.5 mm at T10. This is believed to be the first report of this unusual anatomical finding in congenital spastic paraparesis. An early embryonic vascular insult is thought to be the most likely cause.
The case of an elderly man with tuberculous cavernositis of the penis leading to distortion and sinus tract formation is reported. The condition resembled carcinoma. Histopathology, a positive tuberculin test result, and a good response to treatment aided in making the diagnosis.
Prevalence of leprosy in the low endemic areas of India is described based on the observations of patients attending an Urban Leprosy Centre in the Union Territory of Delhi from the neighbouring states. The rising incidence in these so-called low to moderate endemic places is closely linked to factors related to urbanisation, movement of people in search of employment, etc., which necessitate fresh surveys in these areas. A significant number of leprosy patients attending the Centre were irregular (37.7%) in therapy and many absconded after the initial visit (35.3%), the reasons for which are discussed. These figures are compared to that from similar low endemic areas and known high endemic parts of the country. Suitable modifications to the control programme in these areas are suggested under the purview of the National Leprosy Eradication Programme.
In a study of 50 tumours of pilar origin, it was observed that tumours arise from each cell type depending upon the phase of the hair cycle. Thus nevoid lesions arise from the pluripotent cells of the early anagen phase; tumours from the hair matrix, outer root sheath and inner root sheath arise during the anagen phase, and the keratoacanthomas during the interphase between anagen and telogen. Basal cell epitheliomas can arise at any phase. It was observed that the tumours arising during the anagen phase from the fully differentiated follicles formed the bulk (88%) and the keratoacanthoma simulating the catagen/telogen phase was rare in consonance with the length of each phase. It is proposed that the inner root sheath tumours be named trichilemmomas and the outer root sheath tumours trichochlamydomas to distinguish them from one another.
A kringle 5 domain fragment from human plasminogen has been investigated by 1H-NMR spectroscopy at 300 MHz and 620 MHz. The study focuses on the kringle 5 aromatic spectrum as aromatic side chains appear to mediate the binding of benzamidine. Spin-echo experiments and acid/base-titration studies in conjunction with two-dimensional double-quantum and chemical-shift-correlated spectroscopies were used to identify individual spin systems. Sequence-specific assignments of aromatic resonances are derived from direct comparison of the kringle 5 spectrum with spectra of the homologous kringle 1 and kringle 4 domains of plasminogen. As previously observed for kringles 1 and 4, the pattern we detect for Tyr9 in kringle 5 reflects a slow conformational exchange between two states in equilibrium, one in which the Tyr9 ring is freely mobile and one in which its flip dynamics are constrained. Proton Overhauser experiments in 1H2O and in 2H2O have been used to probe aromatic ring interactions and to identify residues which are part of the hydrophobic core centered at the Leu46 side chain. Overall, the data indicate a strong structural homology among the three plasminogen kringles.
Gyrate atrophy (GA), a recessive eye disease involving progressive loss of vision due to chorioretinal degeneration, is associated with a deficiency of the mitochondrial enzyme ornithine aminotransferase (OATase; ornithine-oxo-acid aminotransferase; L-ornithine:2-oxo-acid aminotransferase, EC 2.6.1.13) with consequent hyperornithinemia. Genetic heterogeneity of GA has been suggested by the demonstration that administration of pyridoxine to increase the level of pyridoxal phosphate, a cofactor of OATase, reduces hyperornithinemia in a subset of patients. We have cloned and sequenced cDNAs for OATase from two GA patients, one responsive and one nonresponsive to pyridoxine treatment. The respective cDNAs contained different single missense mutations, which were sufficient to eliminate OATase activity when each cDNA was tested in a eukaryotic expression system. However, like the enzyme in fibroblasts from the pyridoxine-responsive patient, OATase encoded by the corresponding cDNA from this individual showed a significant increase in activity when assayed in the presence of an increased pyridoxal phosphate concentration. These data firmly establish that both pyridoxine responsive and nonresponsive forms of GA result from mutations in the OATase structural gene. Moreover, they provide a molecular characterization of the primary lesion in a pyridoxine-responsive genetic disorder.
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