Biomedical subjects
Publications and source records attributed to A K Shetty.
Henoch-Schönlein purpura is a common cause of vasculitis in children. This condition is unusual in infants and children younger than 2 years. We describe a 4-month-old infant with infantile Henoch-Schönlein purpura and review the clinical spectrum, differential diagnoses, and the histopathologic features of the disease. Its relations to Henoch-Schönlein purpura in older children are discussed.
We report on the effectiveness of intravenous ribavirin for severe adenoviral pneumonia in a 10-month-old male following orthotopic liver transplantation. On day 20 post-transplantation, he developed high fever, marked respiratory compromise, and hypoxemia. The chest radiograph showed bilateral pulmonary infiltrates. Samples of bronchoalveolar lavage fluid grew adenovirus, serotype 1. Marked clinical and radiological improvement was noted after intravenous ribavirin therapy. A prospective clinical trial is needed to determine the efficacy of ribavirin therapy for severe adenovirus disease.
We hypothesize that the degree of graft cell survival within the damaged CNS correlates with the specificity of donor cells to the region of grafting. We investigated graft cell survival following transplantation of fetal micrografts into the CA3 region of the adult rat hippocampus at a time-point of 4 days after an intracerebroventricular administration of kainic acid (KA). Grafts consisted of 5'-bromodeoxyuridine (BrdU) labeled embryonic day (E) 19 cells from hippocampal fields CA3 and CA1 and E15 and E19 cells from the striatum. Absolute cell survival in these grafts was quantitatively analyzed at 1 month postgrafting, using BrdU immunostaining of serial sections and three-dimensional reconstruction of grafts. Absolute graft cell survival in lesioned CA3 was dramatically greater for cells having hippocampal origin (CA3 cells, 69% cell survival; CA1 cells, 42% cell survival) than those having nonhippocampal origin, such as striatal cells (E15 cells, 12% cell survival; E19 cells, 4% cell survival). This difference is in sharp contrast to survival of these cells in culture, where E19 cells from both hippocampal and nonhippocampal origins exhibited similar survival. Comparison of survival among hippocampal cell types indicated significantly greater survival for cells that are specific to the lesioned area (i.e., CA3 cells) than for those that are nonspecific to the lesioned area (i.e., CA1 cells). Graft cell survival in the intact CA3 region (contralateral to KA administration), however, did not differ either between cells having hippocampal and nonhippocampal origins or between CA3 and CA1 cells (CA3 cells, 26% cell survival; CA1 cells, 33% cell survival; and E15 striatal cells, 20% cell survival). These results underscore the finding that enhanced survival of fetal cell grafts in the lesioned CNS is critically dependent upon the specificity of donor fetal cells to the region of transplantation. Thus, grafting of cells that are specific to the lesioned area is a prerequisite for achieving maximal graft cell survival and integration in the lesioned host CNS.
The study objective was to determine the clinical value of positive antinuclear antibody (ANA) and ANA profile tests in children with autoimmune disorders. A retrospective chart review was carried out of all patients under 18 years of age with a positive ANA test (HEp-2 cell substrate, titre > or =1:40) and ANA profile (ELISA) referred to the paediatric rheumatology service at the authors' institution between 1992 and 1996. Of 245 children with a positive ANA test, 134 (55%) had an autoimmune disease, including juvenile rheumatoid arthritis (n = 49), systemic lupus erythematosus (SLE) (n = 40) and others (n = 45). The remaining 111 patients did not have identifiable autoimmune diseases. Patients with autoimmune disorders had significantly higher ANA titres of > or = 1:160 (chi2 = 16, P<0.0001). In addition, of the 245 patients with a positive ANA test, 86 had an ANA profile performed; this was positive in 32 and negative in 54. All 32 patients with a positive ANA profile (100%) had an autoimmune disorder, compared to 22 (41%) of 54 with a negative ANA profile who had autoimmune disorders. Of 22 SLE patients with a positive ANA profile, 16 (73%) had positive anti-dsDNA and 15 (68%) had positive anti-Sm and positive anti-RNP. A positive ANA profile correlated strongly with an ANA titre > or = 1:640 (chi2 = 5.7 , P<0.02). The study demonstrated that only 55% of children with a positive ANA test had a definitive diagnosis of autoimmune disorder. These children tend to have higher ANA titres of > or =1:160. However, a positive ANA profile was strongly correlated with an ANA titre > or =1:640 and highly indicative of an autoimmune disorder (100%). We suggest that in order to reduce cost, an ANA profile should not be performed on all patients with positive ANA, but reserved for those with an ANA titre of > or =1:640 and/or those with a high clinical index of suspicion for autoimmune disorder, especially SLE.
Fetal hippocampal grafts transplanted to the lesioned CA3 of adult hippocampus can extend axonal projections to many regions of the host brain. However, the identity of grafted cells that project to specific host regions is unknown. We hypothesize that the pattern of long-distance axonal projections from distinct fetal hippocampal cells grafted to lesioned CA3 is specified by the intrinsic nature of respective donor cells rather than characteristics of the host graft region. We grafted fetal hippocampal CA3 or CA1 cells into kainic acid lesioned CA3 of adult hippocampus at four days post-lesion. Neurons projecting to either the contralateral hippocampus or the ipsilateral septum were then measured in these grafts at four months post-grafting using Fluoro-Gold and DiI tract tracing. CA3 grafts located close to the degenerated CA3 cell layer showed a high propensity for establishing projections into the contralateral hippocampus (commissural projections) compared to similarly located CA1 grafts, which exhibited negligible commissural projections. Similar distinction was observed between the two graft types even when they were located only partially in the lesioned CA3. Among CA3 grafts, those placed near the degenerated CA3 cell layer established significantly greater commissural projections than those placed only partially in the CA3 region. Septal projections, in contrast, were robust from both CA3 and CA1 grafts. This differential projection pattern between CA3 and CA1 grafts resembles projections of CA3 and CA1 cells in intact hippocampus.These results demonstrate that the intrinsic character of grafted fetal cells determines the type of efferent projections from fetal grafts into different targets in the lesioned adult host brain. However, the extent of efferent projections from specific grafts is also influenced by the location of grafted cells within the host region. Thus, graft-mediated appropriate reconstruction of damaged circuitry in the lesioned brain may require grafting of homotopic donor cells. Further, the robust and specific projections observed from CA3 grafts is likely beneficial for functional recovery of hippocampus following CA3 injury and hence of significance towards developing a graft-mediated therapy for human temporal lobe epilepsy.
Nephrotoxicity, as evidenced by renal insufficiency is a well-known consequence of gentamicin therapy. We report two patients with gentamicin-induced syndrome of hypokalemic metabolic alkalosis and hypomagnesemia. Both had complete recovery of renal tubular function after cessation of antibiotic therapy. These cases emphasize the need to routinely monitor patients receiving gentamicin therapy for electrolyte abnormalities to avoid potential morbidity.
We report a 12-year-old girl with features of the syndrome of microcephaly, mesobrachydactyly, and tracheoesophageal fistula, who also developed distinctive features of Rett syndrome including regression of milestones with repetitive actions, autistic-like behavior, stereotypic hand movements, and seizures. This unique combination of clinical manifestations appears to constitute a "new syndrome." We speculate that this association may represent a contiguous gene syndrome.
Compared to other brain regions, the hippocampus shows considerable susceptibility to the aging process. Aging may impair the compensatory plastic response of hippocampal neurons following lesions, target loss, and/or deafferentation. We hypothesize that sprouting of dentate granule cell axons (mossy fibers) in response to target loss and partial deafferentation diminishes with age. We quantified mossy fiber sprouting into the dentate supragranular layer (DSGL) following intracerebroventricular kainic acid administration in young adult, middle-aged, and aged rats, using Timm's histochemical method. Mossy fiber ingrowth into the DSGL was assessed in the septal hippocampus at 2- and 4 months postlesion by measuring both the average width and the relative density of sprouted terminals. Kainic acid lesions produced degeneration of CA3 pyramids with sparing of CA1 and dentate granule cells in all age groups. Although young adults demonstrated robust DSGL mossy fiber sprouting, sprouting was significantly reduced in both middle-aged and aged rats. Compared to the case in young adults, the overall sprouting in middle-aged animals was reduced by 52% at 2 months and 50% at 4 months postlesion, whereas in aged rats the sprouting was reduced by 53% at 2 months and 64% at 4 months postlesion. Aged animals also showed an overall reduction of 28% compared to middle-aged animals at 4 months postlesion. Dramatically reduced sprouting in aged animals may represent a deficit in recognition of target loss and partial deafferentation by aged granule cells and/or an impaired up-regulation of factors that stimulate neurite outgrowth in the aged brain.
Epidermal growth factor (EGF)-responsive stem cells from both developing and adult central nervous system (CNS) can be expanded and induced to differentiate into neurons and glia in vitro. Because of their self-renewal and multipotent properties, these cells can potentially provide an unlimited tissue source for neural grafting in neurodegenerative disorders. However, the capability of neurons derived from these stem cells to project axons to distant targets following grafting, thereby enabling the restoration of damaged CNS circuitry, remains unknown. We hypothesize that grafted EGF-responsive stem cells and their progeny are not competent to project axons into distant target sites unless exposed to specific neurotrophic factors. We compared neurite outgrowth between gestation day 14 primary mouse hippocampal cells and EGF-generated secondary neurospheres of postnatal mouse hippocampal stem cells, following grafting onto the CA3 region of organotypic hippocampal slice cultures prepared from postnatal rats. Neurite outgrowth from grafted cells was visualized using immunohistochemical staining for the mouse specific antigen M6. Fetal hippocampal cells showed extensive and specific neurite outgrowth into many regions of the slice, including the CA1 region and distant subiculum, by 7 days after grafting. In contrast, neurite outgrowth from neurosphere cells was nonspecific and restricted to the immediate surrounding region after either 7 or even 15 days following grafting. Application of brain-derived neurotrophic factor (BDNF) (5 ng in 0.5 microL) to slices on day 1 after grafting significantly enhanced neurite outgrowth from neurosphere cells, but overall neurite outgrowth from neurosphere cells remained decreased compared to that from fetal hippocampal cells. These results underscore that EGF-responsive stem cell-derived neurons possess limited intrinsic capability for long-distance neurite outgrowth compared to fetal neurons. However, neurite outgrowth from EGF-responsive stem cell-derived neurons can be enhanced by treating with specific neurotrophic factors such as BDNF.
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The hippocampal formation is highly vulnerable to the aging process, demonstrating functional alterations in circuitry with aging. Aging may also change the sensitivity of the hippocampal formation to excitotoxic lesions. In this study, using young adult, middle aged, and aged Fischer 344 rats, we evaluated morphometric changes in the dentate gyrus as a function of age and also in response to an administration of an excitotoxin (kainic acid) into the right lateral ventricle. The dentate gyrus was measured for changes in the area of dentate hilus and the dentate granule cell layer, alterations in the width of the dentate granule cell layer, and degree of dentate hilar cell loss. With aging, the hilar area increased in size while the area and width of the dentate granule cell layer remained constant. However, the most striking change with aging was a significant reduction in the number of dentate hilar neurons. Intracerebroventricular kainic acid produced consistent lesions in the entire ipsilateral CA3 region, and the size of CA3 lesion was identical in all three ages of animals. Following the lesion, areas of both the dentate hilus and the granule cell layer were significantly decreased in only young adult and middle aged animals whereas the width of the dentate granule cell layer was significantly increased only in the middle aged group. In contrast, dentate hilar neurons were significantly reduced in all ages of animals with the maximum reductions in neuron number observed in the aged group. Thus, aging in the dentate gyrus is characterized by a significantly decreased number of dentate hilar neurons and also a significantly increased susceptibility of dentate hilar neurons to excitotoxic damage.
Sarcoidosis is a chronic multisystemic granulomatous disease of unknown etiology. It is relatively rare in children. Renal involvement in sarcoidosis is described less commonly than other organ involvement such as pulmonary, eye, musculoskeletal, and skin. We report a 13-year-old girl with sarcoidosis and nephrotic syndrome. Renal biopsy showed findings of membranous nephropathy. She received intravenous pulse methylprednisolone and oral cyclophosphamide with resolution of the symptoms of fever and edema, and improvement of the proteinuria. Her condition is stable with no progression of her renal disease. To the best of our knowledge, this is the first report of membranous nephropathy associated with childhood sarcoidosis.
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This case report describes nephrotic syndrome in a 7-year-old boy coincident with Toxocara canis infection. This rare association was confirmed by elevated Toxocara-specific IgM titres. Treatment with corticosteroids resulted in remission of renal symptoms as well as abatement of the T. canis infection. The relationship between T. canis infection and glomerular disease is still unclear; nephrotic syndrome may be another manifestation of T. canis infection.