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Rahul Gupta

Publications and source records attributed to Rahul Gupta.

At least 19 recordsLinked to original sources
PubMed2026

Mechanism of age-related accumulation of mtDNA mutations in human blood.

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.

Humans↗
PubMed2023

Low and differential polygenic score generalizability among African populations due largely to genetic diversity.

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.

Humans↗
PubMed2006

Lack of adaptation to random conflicting force fields of variable magnitude.

The concept of internal models has been used to explain how the brain learns and stores a variety of motor behaviors. A large body of work has shown that conflicting internal models could not be learned simultaneously; this suggests either a limited capacity or the unstable nature of short-term motor memories. However, it has been recently shown that multiple conflicting internal models of motor behavior could be acquired simultaneously if associated with appropriate contextual cues and random presentations. We re-examined this issue in a more complex environment in which the magnitude of the conflicting fields could vary randomly. Human subjects failed to show any evidence of learning the force fields themselves or the magnitude of the forces experienced, even with extended practice. Subjects did adapt to the applied perturbation when the field strength was kept constant but still did not form internal models. Our results show that neither random presentation nor specific contextual cues are sufficient for learning conflicting internal models when the magnitude of the forces is also unpredictable. The data suggest that multiple conflicting internal models cannot be learned in all environments, and provide support for the unstable nature or limited capacity of motor memories.

Adaptation, Physiological↗
PubMed2006

Endoscopic ultrasound as a first test for diagnosis and staging of lung cancer: a prospective study.

RATIONALE: Multiple tests are required for the management of lung cancer. OBJECTIVES: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was evaluated as a single test for the diagnosis and staging (thoracic and extrathoracic) of lung cancer. METHODS: Consecutive subjects with computed tomography (CT) findings of a lung mass were enrolled for EUS and results were compared with those from CT and positron emission tomography scans. RESULTS: Of 113 subjects with lung cancer, EUS was performed as a first test (after CT scan) for diagnosis in 93 (82%) of them. EUS-FNA established tissue diagnosis in 70% of cases. EUS-FNA, CT, and positron emission tomography detected metastases to the mediastinal lymph nodes with accuracies of 93, 81, and 83%, respectively. EUS-FNA was significantly better than CT at detecting distant metastases (accuracies of 97 and 89%, respectively; p = 0.02). Metastases to lymph nodes at the celiac axis (CLNs) were observed in 11% of cases. The diagnostic yields of EUS-FNA and CT for detection of metastases to the CLNs were 100 and 50%, respectively (p < 0.05). EUS was able to detect small metastases (less than 1 cm) often missed by CT. Metastasis to the CLNs was a predictor of poor survival of subjects with non-small cell lung cancer, irrespective of the size of the CLNs. Of 44 cases with resectable tumor on CT scan, EUS-FNA avoided thoracotomy in 14% of cases. CONCLUSIONS: EUS-FNA as a first test (after CT) has high diagnostic yield and accuracy for detecting lung cancer metastases to the mediastinum and distant sites. Metastasis to the CLNs is associated with poor prognosis. EUS-FNA is able to detect occult metastasis to the CLNs and thus avoids thoracotomy.

Aged↗
PubMed2006

Unusual presentations of craniovertebral junction tuberculosis: a report of 2 cases and literature review.

BACKGROUND: CVJ tuberculosis is a described entity requiring challenging ways of management. Severe neck pain, causing restricted neck movements and torticollis, is a characteristic presentation of neurologically asymptomatic suboccipital Pott's disease. CASE DESCRIPTION: Two patients with unusual CVJ tuberculosis form the basis for the present communication. The first patient presented with tubercular otitis media, causing progressive erosion of the petrous part of temporal bone, and destruction of the occipital condyle, along with the lateral mass of atlas, leading to CVJ instability. This is a first report of such a presentation, according to our knowledge. Detailed bony architectural destruction demonstrable on CT scan has been described. The second patient, with CVJ tuberculosis, presented with skull base syndrome and with multiple cranial nerve palsies. Both patients were managed without surgical intervention and showed clinical and radiological recovery. CONCLUSION: In such patients with unusual clinical presentations, histopathologic examination is necessary to arrive at a correct diagnosis. The management of patients with tubercular involvement of CVJ remains controversial. In the present communication, both the patients were managed successfully with full dose of antitubercular drugs and immobilization.

Adult↗
PubMed2006

True hemicranial decompression for severe pediatric cranial trauma: a short series of 4 cases and literature review.

BACKGROUND: Traumatic acute SDH in pediatric patients is a life-threatening situation. There is a severe increase in ICP caused by acute SDH or diffuse brain swelling or secondary to ischemic brain damage. In certain situations, conventional measures may fail to control such a rapid increase in ICP. CASE DESCRIPTION: The cases of 4 pediatric patients with cranial trauma with raised ICP, in whom hemicranial decompression was performed, are described. All patients had acute SDH with diffuse brain injury; in addition, 2 of them had associated massive infarcts. Three of them survived and had a favorable outcome. CONCLUSIONS: In certain situations, pediatric patients with cranial trauma may be offered hemicranial decompression as a surgical option. These children may have a better long-term outcome despite massive infarcts.

Accidental Falls↗
PubMed2006

Cerebellar aspergillosis in an infant: case report.

OBJECTIVE AND IMPORTANCE: Intracranial aspergillosis is occasionally seen among immunocompromised patients, the incidence increasing in consequence to large-scale use of chemotherapy against malignancies and immunosuppression after organ transplantation. Immunocompetent patients harboring invasive intracranial fungal infections still remain an elusive diagnosis. CLINICAL PRESENTATION: A 7-month-old immunocompetent infant who developed and harbored cerebellar aspergillosis until 3 years of age is reported. INTERVENTION: Radical surgical resection of posterior fossa mass (aspergilloma) and parenteral administration of Amphotericin B led to a successful outcome. CONCLUSION: The differential diagnosis at both stages of presentation and the possible mode of infection are discussed according to the radiological images. Preoperative diagnosis on the basis of imaging is difficult. The pathogenesis of such an infection remains uncertain. Parenteral Amphotericin B, followed by prolonged itraconazole therapy, remains the "gold standard" modality for central nervous system fungal infections in adjunct to aggressive surgical debridement.

Amphotericin B↗
PubMed2006

Tuberculosis of the craniovertebral junction: is surgery necessary?

OBJECTIVE: Tuberculosis of the craniovertebral junction is an uncommon entity and its optimal management remains controversial. In this study, we present the evolution of management protocol of this disease in our institute in the past 3 decades. METHODS: A total of 51 patients with craniovertebral junction tuberculosis presenting as atlantoaxial dislocation from 1978 through 2004 were reviewed. The disease was rated from Stage I to Stage III, depending on the radiological findings. All patients received antitubercular treatment for 18 months. In the initial period of this study (1978-1986), all patients (n = 10) underwent surgery, usually a posterior fusion. In the second period (1987-1998), patients with less severe disease (Stages I and II, n = 14) were managed with external rigid immobilization, whereas patients with severe disease (Stage III, n = 11) underwent either a transoral decompression with or without posterior fusion or posterior fusion alone. More recently (1999-2004), all patients (n = 16) in all stages (Stages I-III) have been managed without surgery by a rigid external immobilization. RESULTS: Except for two patients who died (one because of miliary tuberculosis, the other because of acute hydrocephalus), clinical recovery occurred in all. Follow-up imaging demonstrated radiological healing as well, with regrowth of the destroyed bone. CONCLUSION: The mainstay of management of tuberculosis of the craniovertebral junction is prolonged antitubercular treatment with a rigid external immobilization. Surgery is not necessary, even in patients with advanced stages of disease. Complete clinical and radiological healing occurs in all patients with conservative treatment.

Adolescent↗
PubMed2006

Plasmacytoma of the clivus: a case report.

A 60-year-old male presented with headache and diplopia for 2 months. Computed tomography of the head showed a heterogeneously enhancing expansile lytic lesion in clival region. The patient underwent surgery and histopathological examination revealed it to be plasmacytoma of the clivus. The multiple myeloma work-up was negative. Solitary plasmacytoma localized to the skull base is extremely rare. Prior to this, only three case reports of plasmacytoma of the clivus have been described in the English literature.

Cranial Fossa, Posterior↗
PubMed2005

Head CT evaluation in clinically stable motor vehicle collision patients.

PURPOSE: To assess the utilization of non-contrast head computed tomography (HCT) in clinically stable patients who were involved in motor vehicle collisions. Our goal is to identify patients in whom HCT may be safely excluded without altering clinical outcome. METHODS: Adult, front-seat passengers were retrospectively examined. All clinically stable patients involved in motor vehicle collisions and who subsequently underwent HCT were studied to determine the factors that increased the statistical likelihood of a negative examination. Seven factors relevant to passenger safety or clinical outcomes were measured. RESULTS: Eighteen of the 206 patients who met criteria for our study had positive HCT findings. Front-seat passengers were more likely to suffer traumatic head injury than drivers. Both Glasgow Coma Scale (GCS) and Injury Severity Score (ISS) individually had statistically significant correlations with positive HCT findings. Thirteen of the 18 patients had GCS scores of 13-15. Seatbelts, rollover collisions, gender, and airbag deployment demonstrated relatively decreased predictive values. CONCLUSION: The ISS emerged as the single most reliable predictor of positive HCT findings. Regarding multiple variable effects, the combinations of ISS and patient position or GCS and patient position are the most statistically significant clinical factors in identifying patients in whom HCT may be safely excluded.

Accidents, Traffic↗