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Biomedical subjects

K Bhatia

Publications and source records attributed to K Bhatia.

At least 55 records · Page 3Linked to original sources
PubMed1998

Epstein-Barr virus in nasal lymphomas contains multiple ongoing mutations in the EBNA-1 gene.

We have described 5 major subtypes of Epstein-Barr virus (EBV) based on variations in EBNA-1 sequences. These include P-ala (identical to the prototype B95.8 virus), P-thr, V-pro, V-leu, and V-val. Normal individuals often carry multiple EBV subtypes, the most common being P-ala, whereas EBV-associated tumors examined to date always contain a single subtype, which only on rare occasion is P-ala. The primary hypotheses that these observations generate are as follows: (1) Each of these EBV subtypes are naturally occurring, and in normal individuals the multiplicity of subtypes results from multiple infections. (2) EBV subtypes in normal individuals are generated in vivo from a single infecting virus subtype by mutations in EBNA-1. The second hypothesis essentially excludes the possibilities that the nonrandom association of certain subtypes with lymphomas is secondary to the geographic distribution of EBV subtypes and, if proven correct, could provide strong support for a direct role of EBV in tumorigenesis. In this report, we provide evidence for the latter hypothesis. We show that the P-ala EBV subtype present in most nasal lymphomas undergoes and accumulates multiple mutations consistent with the generation of variant species of EBNA-1 in vivo. This phenomenon is similar to the generation of quasispecies in RNA viruses and is the first description of in vivo generation of subtypes in DNA viruses. In RNA-based viruses, including human immunodeficiency virus and hepatitis C virus, the emergence of quasispecies is linked to replication infidelity and significantly influences disease processes through its effect on viral tropism, the emergence of viruses resistant to the host defenses or to therapy, and pathogenicity. The present data thus raise important questions relating to the mechanisms whereby these mutations are generated in EBV and their relevance to the pathogenicity of EBV-associated lymphomas.

Genes, Viral↗
PubMed1998

A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma.

The role of Epstein-Barr virus (EBV) in the pathogenesis of severe, chronic active EBV infection and its complications is unclear. We investigated two Japanese patients diagnosed with severe, chronic active EBV infection who subsequently developed EBV-positive T-cell lymphoma. The patients displayed abnormally high antibody titers to EBV antigens, and had evidence of peripheral blood CD4(+) T-cell infection with EBV, 19 months and 3 months, respectively, before the diagnosis of EBV-positive T-cell lymphoma. The lymphomas were infected with monoclonal EBV and expressed the EBV latency genes EBNA-1, LMP-1, and LMP-2. Genetic studies showed that the virus detected in the T-cell lymphoma was indistinguishable, with respect to type and previously defined LMP-1 and EBNA-1 gene variations, from virus detected in the peripheral blood T cells 19 months earlier. These studies support an important pathogenetic role of T-cell infection with EBV in chronic active EBV infection and in the EBV-positive T-cell lymphoma that followed.

Antibodies, Viral↗
PubMed1998

Slater revisited: 6 year follow up study of patients with medically unexplained motor symptoms.

OBJECTIVE: To investigate psychiatric and neurological morbidity, diagnostic stability, and indicators of prognosis in patients previously identified as having medically unexplained motor symptoms. DESIGN: Follow up study. SETTING: National Hospital for Neurology and Neurosurgery, London--a secondary and tertiary referral hospital for neurological disorders. SUBJECTS: 73 patients with medically unexplained motor symptoms admitted consecutively in 1989-91. 35 (48%) patients had absence of motor function (for example, hemiplegia) and 38 (52%) had abnormal motor activity (for example, tremor, dystonia, or ataxia). MAIN OUTCOME MEASURES: Neurological clinical diagnosis at face to face reassessment by a neurologist and a psychiatric diagnosis after a standardised assessment interview--the schedule for affective disorders and schizophrenia--conducted by a psychiatrist. RESULTS: Good follow up data were available for 64 subjects (88%). Only three subjects had new organic neurological disorders at follow up that fully or partly explained their previous symptoms. 44/59 (75%) subjects had had psychiatric disorders; in 33 (75%) patients, the psychiatric diagnosis coincided with their unexplained motor symptoms. 31/59 (45%) patients had a personality disorder. Three subjects had developed new psychiatric illnesses at follow up, but in only one did the diagnosis account for the previous motor symptoms. Resolution of physical symptoms was associated with short length of symptoms, comorbid psychiatric disorder, and a change in marital status during follow up. CONCLUSIONS: Unlike Slater's study of 1965, a low incidence of physical or psychiatric diagnoses which explained these patients' symptoms or disability was found. However, a high level of psychiatric comorbidity existed.

Adolescent↗
PubMed1998

The health of overseas-born Australians, 1994-1996.

Analysis of mortality, hospital separations and self-reported health indicators by country of birth group has confirmed that overseas-born populations are generally in better health than their Australian-born contemporaries. The better health of the overseas-born may be reflected in both the willingness and eligibility of individuals to emigrate. Overseas-born individuals were placed into one of four groups according to place of birth. These included the United Kingdom and Ireland, Other Europe, Asia and Other. All population groups reported lower mortality and hospitalisation rates for all causes of disease combined. The Asian-born population had the lowest mortality rates with 38% less mortality for males and 30% less for females. Hospitalisation rates were also lower for the Asian-born, with males and females having 46% and 37% fewer hospital separations compared to the Australian-born population. However, diabetes mortality was greater for males and females from Other Europe, Asia and Other regions. Both males and females from the United Kingdom and Ireland group showed increased mortality from lung cancer. Mortality and hospitalisation for cervical cancer was also significantly higher for Asian-born and Other females. The mortality and hospitalisation data corresponded well with self-reported prevalence of health-related risk factors. For example, self-reported diabetes prevalence was higher for the Other Europe, Asia and Other groups. Asian and Other females reported significantly less use of regular Pap smear tests, reflecting their increased mortality and hospitalisation for cervical cancer. These results support the finding of past studies that the health of migrants is generally better than that of the Australian-born population and reflects a 'healthy migrant' effect.

Asia↗
PubMed1998

Status dystonicus: the syndrome and its management.

Patients with dystonic syndromes sometimes develop increasingly frequent and relentless episodes of devastating generalized dystonia which we call status dystonicus. Twelve cases of status dystonicus, of various underlying aetiologies, are presented. Possible precipitating factors were identified in only five cases: intercurrent infection (one); discontinuation of lithium (one) and tetrabenazine (one); and the introduction of clonazepam (two). Nine patients required mechanical ventilation and three others were sedated with intravenous chlormethiazole. Drug therapy used included benzhexol, tetrabenazine, pimozide, baclofen, chlorpromazine, haloperidol, carbamazepine and acetozolamide. Two patients underwent thalamotomies, one of whom improved. Two patients died, five returned to their pre-status dystonicus condition, two eventually made a full recovery and three were worse. Patients with status dystonicus should be managed on an intensive care unit as they may develop bulbar and respiratory complications which may require ventilation. Metabolic problems encountered can include rhabdomyolysis with acute renal failure. Drug therapy with benzhexol, tetrabenazine and pimozide or haloperidol may be beneficial in some cases.

Adolescent↗
PubMed1998

Comparative incidence of the rearrangements of TEL/AML1 and ALL1 genes in pediatric precursor B acute lymphoblastic leukemias in India.

The TEL/AML1 translocation, which is specific for pre B-cell leukemias is predictive of a favorable treatment outcome. In contrast, translocations involving the ALL1 locus which are associated with both B and non B leukemias predict a poor outcome. To determine the relative distribution of high and low risk molecular subtypes of ALL in India, we analyzed the relative frequencies of these two translocations. The study included a random selection of 46 newly diagnosed patients of childhood ALL from the Tata Memorial Hospital, Bombay, India. Similar to the frequency observed in other world regions, we found an All1 rearrangement in less than 7% (3/46) of pre B-ALL patients. In contrast to the 25% frequency reported for other regions the low risk molecular subtype characterized by the TEL/AML1 translocation represented a comparatively smaller fraction (4/46) in this study. These results provide a preliminary support for a lower frequency of molecular subgroup of leukemias with a potential for favorable clinical outcome in precursor B-ALL from India.

Adolescent↗
PubMed1998

The health of Australian children and young adults: recent statistics.

The lack of reliable national statistics to monitor the health of Australian children and youths is well recognised (Commonwealth Department of Human Services and Health 1995). There is a clear need to develop this information through a nationally integrated and coordinated approach. The best way to achieve this would be to scope the fields of child and youth health information, identify data gaps and deficiencies, and catalogue the data requirements and needs. The framework within which this should occur, accompanied by a national child and youth health information development plan, also needs to be clearly defined. The Australian Institute of Health and Welfare is undertaking an analysis of the health of Australian children and youths and a review of available information in this area. Here we present early work on this project, providing a general picture of the health of Australian children and youths based on mortality, morbidity, reported health status and disability statistics. Some information on the health of indigenous children and young people is also included.

Adolescent↗
PubMed1998

Guidelines for the management of Parkinson's disease. The Parkinson's Disease Consensus Working Group.

Parkinson's disease is a chronic and disabling illness and there is currently wide variation in its management. This article presents the first UK-specific guidelines for the management of Parkinson's disease and it contains a treatment decision free to aid the physician in deciding when and how to treat patients. We hope this document will prove useful to all those involved in the planning and delivery of care to patients with Parkinson's disease.

Aged↗
PubMed1997

Perception of spatial orientation in spasmodic torticollis. Part I: The postural vertical.

Estimates of points of entering and exiting from upright posture were obtained from 25 seated, restrained patients with idiopathic spasmodic torticollis (ST) and matched normal subjects exposed to cycles of 1.5 degrees/s tilts in a flight simulator. Estimates were obtained for displacements in roll and pitch about upright and for yaw tilts about a rostrocaudal, "barbecue," axis with the subjects supinated. For both pitch and roll, normal subjects estimated entering upright when they were still approximately 1 degree from machine upright and perceived themselves to be upright through a mean arc of 6 degrees. In barbecue tilt, entering upright was estimated at 0.2 degree for an arc of 6 degrees. Patients estimated entering upright at 2.8 degrees in roll and 3 degrees in pitch but estimated exiting upright at the same tilt as normal subjects; that is, they were less specific in detecting verticality. Patients were normal in barbecue tilt. No relationship between tilt estimates and head deviation was found. There were no differences between normal subjects when tested with their head in normal posture and with an assumed tilt of 20 degrees. Normal subjects probably based their estimates on combined vestibular-somatosensory signals, whereas torticollis patients appeared to derive more from a vestibular signal. However, patients referred the vestibular signals to the trunk long axis when asked to indicate the whole-body vertical. The findings suggest disruption of the normal combined vestibuloproprioceptive mechanism for detecting body uprightness in ST.

Adult↗
PubMed1997

Perception of spatial orientation in spasmodic torticollis. Part 2: The visual vertical.

Twenty-nine patients with idiopathic spasmodic torticollis (ST) and matched normal control subjects were asked to align a target line to perceived earth vertical [visual vertical (VV)]. Settings were made against a whole-field random-dot background that was either stationary or rotating around the line of sight, and subjects performed the task upright and lying horizontally on their sides. Normal subjects were tested both head upright and after assuming a voluntary head tilt. Patients with ST set the VV close to true upright with a minimal deviation toward tilt of the head in contrast to normal subjects assuming a head tilt who set the VV in the opposite direction to the head tilt (Müller "E" effect). Settings against the spinning disk were biased in the direction of rotation similarly for both subject groups. Settings made against static or spinning disk performed when subjects lay horizontally were tilted in the direction of recumbence (Aubert "A" effect) similarly for both subject groups. When attempting to set the target line parallel to the long axis of the face, patients with head tilt set the line to upright, whereas normal subjects correctly estimated their tilts. One hypothesis offered to explain these results is that the patients referenced only their upright trunk for vertical and did not make use of neck proprioceptive or vestibular signals of head tilt so that all settings were made as if the trunk and head were upright. Alternatively, patients may have used only otolith signals as the reference for upright, and these are recalibrated in ST patients with head tilt. The pathological deviation becomes accepted as upright posture, and VVs and facial orientation are estimated as if the head were upright. In either case the findings indicate abnormal processing of the perception of visual verticality in ST patients.

Adult↗
PubMed1997

Intraclonal molecular heterogeneity suggests a hierarchy of pathogenetic events in Burkitt's lymphoma.

BACKGROUND: Burkitt's lymphoma is a B-cell neoplasm characterized by a chromosomal translocation involving the c-myc gene. BL may carry, besides the c-myc translocation, several other lesions including a) mutations in c-myc, b) mutations in bcl-6, c) mutations in p53 and d) EBV genomes. In this report we describe a unique study of the timing of these genetic lesions during the evolution and progression of Burkitt's lymphoma. MATERIALS AND METHODS: From each of two patients with Burkitt's lymphoma, we established three different cell lines from different sites or at different times in the clinical course of the disease (diagnosis and relapse). Chromosomal aberrations were analyzed by karyotyping and the presence of molecular lesions determined by Southern blot, PCR, SSCP and sequence analyses. RESULTS: In each patient all the clones carry identical c-myc translocations, identical bcl-6 status (wild type or mutant) and the same productive VDJ rearrangement. However, within each individual patient, we could demonstrate the presence of intraclonal variation with respect to EBV, p53 mutations and c-myc mutations. CONCLUSIONS: c-myc translocation and bcl-6 mutations appear to be early events, mutations in the coding region of c-myc occur early but are an ongoing event, while mutations in the p53 gene seem to occur later. Discrete clonal bands reflecting independent EBV infection were observed in the cell lines from one HIV-associated Burkitt's lymphoma, suggesting the possibility that EBV infection may occur as a late event, at least in some HIV associated lymphomas.

Adult↗
PubMed1997

Postural responses to vibration of neck muscles in patients with idiopathic torticollis.

Vibration of the dorsal muscles of the neck, simulating lengthening, in standing man causes a visible forwards tilt of the body shown on posturography as a tonic sagittal sway deviation. According to the theory that posture is organized with respect to a 'body schema' this deviation is a result of an interpretation of the concurrent neck afferent and vestibular signals. Considering the hypothesis that neck afferent signals may be misinterpreted in patients with spasmodic torticollis (ST) causing abnormal postural responses, we recorded body sway induced by unilateral dorsal neck muscle vibration in 22 idiopathic ST patients (19 treated with botulinum toxin) during upright stance with eyes closed. Comparison groups were 19 normal subjects and 11 patients with bilateral loss of vestibular function (labyrinthine defective, LD) in whom neck afference should be intact. Both treated and untreated ST and LD patients had absent or diminished sway deviations. When sway deviation did occur, it was sagitally oriented as with normal subjects and unrelated to ST head turns. In most ST and LD patients, neck vibration induced neck extension, an effect which is observed in normal subjects only if the torso is retrained. The results suggest that neck proprioceptive input retains local postural functions in ST, however, it is relatively ignored in the context of the whole body postural control and spatial orientation. The mild disorders of vestibular function reported in torticollis patients may be due to an inability to calibrate vestibular signals by reference to corroborative signals from neck proprioception.

Achilles Tendon↗
PubMed1997

Sequence variations in EBNA-1 may dictate restriction of tissue distribution of Epstein-Barr virus in normal and tumour cells.

In seropositive individuals Epstein-Barr virus (EBV) establishes a virus reservoir in peripheral blood lymphocytes (PBLs). Transmission from one individual to another occurs via saliva due to a lytic (virion productive) phase of infection in the oropharynx. EBNA-1 is responsible for maintaining viral episomes in the host cell and could, therefore, also affect the persistence of the virus in different cell lineages. Based on sequence analysis of EBNA-1 we now demonstrate that (i) in addition to the prototype EBNA-1 (identical to the B95.8 virus EBNA-1), EBV in normal individuals encompasses multiple EBNA-1 subtypes, both in PBLs and in oral secretions; (ii) although EBV with prototype EBNA-1 is the predominant virus in normal individuals, it is very rarely associated with either nasopharyngeal carcinoma (NPC) or Burkitt's lymphoma (BL); (iii) EBV with an EBNA-1 subtype (V-val) frequently associated with NPC is also selectively detected in oral secretions and not in PBLs; (iv) EBV with the EBNA-1 subtype V-pro is restricted to PBLs, while a mutated version of this subtype is present in BL, but not in NPC. These findings suggest that the variations in EBNA-1 may be relevant to the ability of EBV to persist in different cell types, and hence relevant to its oncogenic potential.

Amino Acid Sequence↗
PubMed1996

Variation in the sequence of Epstein Barr virus nuclear antigen 1 in normal peripheral blood lymphocytes and in Burkitt's lymphomas.

We have examined sequence variations in the EBNA-1 protein of EBV in normal peripheral blood lymphocytes (PBL) and Burkitt's lymphomas (BL). We find two EBNA-1 strains P (prototype) and V (variant) which differ by 15 amino acids. Each strain has two subtypes defined by the amino acid at position 487 (P-ala, P-thr, V-pro and V-leu). In PBLs from 32 normal individuals, up to three of these subtypes were found in each sample, but the V strain did not occur in the absence of P strain viruses, nor was the V-leu subtype ever observed in normal PBL. In BLs only a single subtype was observed in each tumor. The P-thr and V-leu subtypes were more frequently seen than the P-ala and V-pro subtypes, which occurred in only two and one of the 36 tumor samples respectively. The P-thr was the most commonly observed subtype in peripheral blood of both American and African lymphocytes as well as in African tumors. However, in 11 of 12 American tumors, the EBNA-1 subtype was V-leu. These data indicate that some EBNA-1 subtypes are more likely to lead to oncogenesis, and one subtype, V-leu, appears only to occur in tumors.

Amino Acid Sequence↗
PubMed1996

Use of Epstein-Barr virus nuclear antigen-1 in targeted therapy of EBV-associated neoplasia.

To target expression of toxic genes to Epstein-Barr virus (EBV)-associated tumor cells, we have developed an EBV-driven enzyme prodrug system (EDEPS) that takes advantage of the trans-activating properties of EBNA1, a latent protein expressed in all EBV-containing cells, to direct expression of cytosine deaminase (CD) at high levels in those cells only. Plasmids were constructed in which the CD gene or a luciferase reporter gene were cloned downstream of the herpes simplex virus thymidine kinase (tk) promoter and the family of repeats (FR) sequence from the oriP region of EBV. Analysis of luciferase activity after transient transfection into a panel of EBV-negative or -positive human cell lines showed that the presence of the FR element enhanced transcription from the tk promoter in all EBV-positive cell lines, whereas transcription from tk was repressed in all EBV-negative cell lines, including B, T, and fibroblast cell lines. In clonogenicity assays following transfection with the CD vector, the presence of 5-fluorocytosine (5-FC) in the culture medium completely abolished cell growth in EBV-positive cell lines, but did not affect the growth of EBV-negative cell lines. This vector system should have wide applicability in that it allows targeted expression of any gene of interest to tumors that carry EBV, irrespective of the role EBV plays in their pathogenesis.

Antigens, Viral↗