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Biomedical subjects

B Venkatesh

Publications and source records attributed to B Venkatesh.

At least 37 records · Page 2Linked to original sources

Molecular synapomorphies resolve evolutionary relationships of extant jawed vertebrates.

The evolutionary relationships of gnathostomes (jawed vertebrates), which comprise chondrichthyans (cartilaginous fishes), lobe-finned fishes (coelacanths and lungfishes), tetrapods, and actinopterygians (ray-finned fishes), have been debated for almost a century. Phylogenetic analyses based on fossils, morphology, and molecular sequences have generated different models of relationships that remain unresolved. We identified 13 derived shared molecular markers (synapomorphies) that define clades in the vertebrate lineage and used them to resolve the phylogenetic relationships of extant jawed vertebrates. Our markers include the presence or absence of insertions and deletions in coding sequences, nuclear introns, and alternatively spliced transcripts. The synapomorphies identified by us are congruent with each other and give rise to a single phylogenetic tree. This tree confirms that chondrichthyans are basal to all living gnathostomes, that lungfishes (Dipnoi) are the closest living relatives of tetrapods, and that bichirs (Cladistia) are the living members of the most ancient family of ray-finned fishes. Our study also provides molecular evidence to support the monophyly of living tetrapods and teleosts.

Amino Acid Sequence↗

Conserved synteny between the Fugu and human PTEN locus and the evolutionary conservation of vertebrate PTEN function.

Mutations of PTEN, which encodes a protein-tyrosine and lipid phosphatase, are prevalent in a variety of human cancers. The human genome 'draft' sequence still lacks organization and much of the PTEN and adjacent loci remain undefined. The pufferfish, Fugu rubripes, by virtue of having a compact genome represents an excellent template for rapid vertebrate gene discovery. Sequencing of 56 kb from the Fugu pten (fpten) locus identified four complete genes and one partial gene homologous to human genes. Genes neighboring fpten include a PAPS synthase (fpapss2) differentially expressed between non-metastatic/metastatic human carcinoma cell lines, an inositol phosphatase (fminpp1) and an omega class glutathione-S-transferase (fgsto). We have determined the order of human BAC clones at the hPTEN locus and that the locus contains hPAPSS2 and hMINPP1 genes oriented as are their Fugu orthologs. Although the human genes span 500 kb, the Fugu genes lie within only 22 kb due to the compressed intronic and intergenic regions that typify this genome. Interestingly, and providing striking evidence of regulatory element conservation between widely divergent vertebrate species, the compact 2.1 kb fpten promoter is active in human cells. Also, like hPTEN, fpten has a growth and tumor suppressor activity in human glioblastoma cells, demonstrating conservation of protein function.

Amino Acid Sequence↗

Transient mesenteric ischaemic episodes tracked by continuous jejunal PCO2 monitoring during liquid feeding.

OBJECTIVE: To test the effect of liquid feeds on the responses to splanchnic ischaemia of a continuous rapid response PCO2 sensor inserted in the jejunum. DESIGN: Prospective experimental animal study in a university research laboratory. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Adult male Wistar rats (285-425 g) were anaesthetised with sodium pentobarbitone 60 mg/kg i.p. and ventilated with 100% oxygen and isoflurane via tracheostomy to a PaCO2 of 30-40 mmHg. A sensor was inserted into the mid-jejunum to record PCO2 every second. Distal aortic pressure was transduced. Four control rats received no feeds whilst in another four rats liquid feed was infused into the proximal jejunum at 3 ml/h. In each rat five episodes of splanchnic ischaemia were induced by 2-min elevations of an aortic sling to a mean distal aortic pressure of 30 mmHg. MEASUREMENTS AND MAIN RESULTS: PCO2 elevations were always detectable, usually less than a minute from the onset of splanchnic ischaemia in both fed and unfed rats, with no difference in mean times to detectable response. In the fed rats there was a small but significant increase in the time to peak sensor response (196+/-16 vs. 180+/-12 s) and a trend towards an elevated mean baseline luminal PCO2 (67+/-9 vs. 55+/-4 mmHg). CONCLUSIONS: Brief episodes of splanchnic ischaemia were tracked successfully by a rapid response jejunal continuous PCO2 sensor during the infusion of a proprietary liquid feed preparation despite minor changes in PCO2 response characteristics and a possible elevation in baseline luminal PCO2.

Analysis of Variance↗

Molecular cloning and genomic structure of a gene encoding interferon regulatory factor in the pufferfish (Fugu rubripes).

Interferon regulatory factors (IRFs) are a large family of transcription factors involved in regulating the transcriptional response of vertebrates to interferons and viral infection. In this report we describe the cloning and genomic organization of an IRF gene from the pufferfish (Fugu rubripes). The fugu IRF gene spans 2.7 kb from the transcription start site to the polyadenylation signal. It consists of 10 exons and 9 introns and encodes a protein of 296 amino acids. The overall amino acid sequence of fugu IRF displays 55% identity to flounder IRF and approximately 44% identity to avian and mammalian IRF-1 and IRF-2. On the basis of the genomic structure and the absence of a transcriptional repression domain, we conclude that the fugu IRF is a member of the IRF-1 family. The fugu IRF gene is expressed in a wide range of tissues. While a single transcript of 1.4 kb was detected in most tissues, several larger transcripts generated using alternative polyadenylation signals were found in the gills.

Journal Article↗

Monitoring tissue oxygenation during resuscitation of major burns.

BACKGROUND: Because subcutaneous and splanchnic oxygenation indices are sensitive indicators of evolving hemorrhagic shock and adequacy of resuscitation, we postulated that these indices might have an equivalent role in the monitoring of severely burned patients. This observational study was undertaken to examine changes in tissue oxygenation indices during burn resuscitation. METHODS: Seven patients with major burns (54 +/- 21% total body surface area) were studied during the first 36 hours of fluid resuscitation. Silastic tubing was placed in the subcutaneous tissue just beneath both normal skin and deep partial thickness burn. Fiberoptic sensors inserted into the tubing measured subcutaneous oxygen and carbon dioxide tensions in the burnt skin (PO2scb and PCO2scb) and normal skin (PO2scn and PCO2scn) continuously. Gastric intramucosal pH (pHi) and the mucosal CO2 (PCO2m) gap were calculated using gastric tonometers. Mean arterial pressure, arterial pH, lactate, and pHi measurements were obtained for 36 hours. RESULTS: There were no significant differences in mean arterial pressure, arterial pH, or lactate concentrations throughout the study period, whereas indices of tissue oxygenation showed deterioration: pHi decreased from 7.2 +/- 0.1 to 6.7 +/- 0.3 (p = 0.06), the PCO2m gap increased from 12 +/- 17 to 108 +/- 123 mm Hg (p < 0.01), PO2scn decreased from 112 +/- 18 to 50 +/- 11 mm Hg (p < 0.01), PO2scb decreased from 62 +/- 23 to 29 +/- 16 mm Hg (p < 0.01), PCO2scn increased from 42 +/- 4 to 46 +/- 10 mm Hg (p = 0.2), and PCO2scb increased from 42 +/- 10 to 52 +/- 5 mm Hg (p = 0.05). CONCLUSION: Despite adequate global indices of tissue perfusion after 36 hours of resuscitation, tissue monitoring indicated significant deterioration in the splanchnic circulation and in the normal and burnt skin.

Adult↗

Procalcitonin in critical illness.

OBJECTIVE: To detail the biology and diagnostic usefulness of serum procalcitonin in critical illness. DATA SOURCES: A review of articles published in peer reviewed journals from 1990 to 2001 and identified through a MEDLINE search on procalcitonin. SUMMARY OF REVIEW: Procalcitonin (PCT) is a prohormone of calcitonin. Serum levels are elevated during sepsis and have been identified as a potential marker of infection in critical illness. However, its function and precise source of origin during sepsis remain unclear. The value of estimating serum PCT appears to be in the differentiation of infectious from non-infectious forms of systemic inflammatory response syndrome. A number of studies also point to its usefulness in distinguishing between bacterial and viral meningitis. However, there are a number of non-infectious conditions, where elevations in serum PCT occur, reducing its specificity. Its superiority as a marker of sepsis compared with other acute phase reactants continues to be debated. CONCLUSIONS: The utility of serum procalcitonin as a diagnostic test of sepsis is still under evaluation. Moreover, a number of unanswered questions remain regarding the biological role of PCT during sepsis, its target receptors and its protective value to the patient.

Journal Article↗

Acute myocardial ischaemia in the presence of thrombotic thrombocytopenic purpura: what are the treatment options?

We describe a case of severe myocardial ischaemia in the setting of thrombotic thrombocytopoenic purpura (TTP). In this report, we discuss the potential difficulties in the diagnosis and management of acute myocardial ischaemia with TTP, particularly relating to the use of antiplatelet agents. We also highlight the importance of careful monitoring during plasma exchange for TTP when acute myocardial ischaemia is present. The potential role for novel therapies in the management of TTP related myocardial ischaemia is also discussed.

Journal Article↗

Fugu: a compact vertebrate reference genome.

At 400 Mb, the Japanese pufferfish, Fugu rubripes, has the smallest vertebrate genome but has a similar gene repertoire to other vertebrates. Its genes are densely packed with short intergenic and intronic sequences devoid of repetitive elements. It likely has a mutational bias towards DNA elimination and is probably close to a 'minimal' vertebrate genome. As such it is a useful reference genome for gene discovery and gene validation in other vertebrates. Its usefulness in the discovery of conserved regulatory elements has already been demonstrated. The Fugu genome sequence is a good complement to genetic studies in other vertebrates.

Animals↗

Subcutaneous oxygen tensions provide similar information to ileal luminal CO2 tensions in an animal model of haemorrhagic shock.

OBJECTIVES: The cutaneous and splanchnic circulations undergo early vasoconstriction in shock. Methodological problems and insufficient information on subcutaneous carbon dioxide partial pressures limit the usefulness of previous studies on splanchnic and subcutaneous gas tensions in shock. Little comparative data exist on the responses of these tissues to shock and resuscitation. We therefore compared continuous subcutaneous PO2 (PO2sc) and PCO2 (PCO2sc) with simultaneous continuous gut luminal PCO2 (PCO2gi) in an animal model of haemorrhagic shock and resuscitation. DESIGN: Prospective observational study. SETTING: Intensive care laboratory in a teaching hospital. SUBJECTS: Five anaesthetised rats. INTERVENTIONS: Electrochemical-fiberoptic gas sensors inserted into Silastic tubing placed in the subcutaneous tissue and in the ileal lumen measured PCO2sc, PO2sc and PCO2gi continuously in five anaesthetised rats. After steady state conditions, hypotension [mean arterial blood pressure (MAP) 40 mmHg] was induced by controlled haemorrhage. The rats were allowed to remain hypotensive for 15 min and then resuscitated with shed blood and crystalloids. Arterial plasma lactate concentrations were measured at defined periods during the study. MEASUREMENTS AND MAIN RESULTS: Hypovolaemia resulted in a significant decrease in PO2sc (P < 0.01) and a significant increase in PCO2gi and PCO2sc (P < 0.05). These values returned to baseline with resuscitation. PO2sc appeared to respond to haemorrhage earlier than PCO2gi and PCO2sc (P = 0.02). PO2sc was inversely correlated with PCO2gi (r2 0.7, P < 0.001). There were no significant changes in arterial plasma lactate concentrations. CONCLUSIONS: In our rat model, subcutaneous oxygen tension provided similar information to ileal luminal PCO2 and was more rapidly responsive than subcutaneous carbon dioxide tensions and arterial lactate during evolving haemorrhagic shock and resuscitation.

Animals↗

Blood in the gastrointestinal tract delays and blunts the PCO2 response to transient mucosal ischaemia.

OBJECTIVE: To determine whether the presence of blood in the gastrointestinal tract impairs the detection of splanchnic mucosal ischaemia by reducing the rate and magnitude of rise in gut luminal PCO2. DESIGN: Prospective observational study. SETTING: University Research Laboratory. SUBJECTS: Four adult male Wistar rats with four controls from a concurrent study. INTERVENTIONS: Four adult male Wistar rats were anaesthetised with sodium pentobarbitone and ventilated with oxygen and isoflurane to an initial PaCO2 of 30-40 torr. Electrochemical-fiberoptic gas sensors inserted into silastic tubing placed in the ileal lumen measured luminal PCO2 at 1-s intervals. Distal aortic pressure was monitored continuously. Six 2-min episodes of aortic hypotension were induced in each rat to a mean pressure of 30 mmHg by intermittent elevation of a silk sling placed around the proximal aorta. Before the last three episodes in each rat 0.75-1.0 ml blood was injected into the ileal lumen via a 25-gauge needle. Four control rats from a concurrent experiment were treated in an identical fashion except that the rats were subjected to five ischaemic episodes, and there was no intraluminal injection of blood, although a 20-gauge cannula was placed in the proximal ileal lumen. MEASUREMENTS AND MAIN RESULTS: The presence of blood in the lumen significantly decreased the ischaemic deltaPCO2 response from 33 +/- 8 to 15 +/- 4 torr (P < 0.001) and also significantly increased the peak response time from 188 +/- 12 to 227 +/- 24 s (P < 0.001). The corresponding measurements in the concurrent controls differed only from the values after blood injection in the experimental group. CONCLUSIONS: In this animal model the presence of intraluminal blood significantly delayed the rate and the amplitude of luminal PCO2 increases in response to transient ischaemia. This raises questions about the validity of luminal CO2 measurements as an indicator of splanchnic ischaemia in the presence of gastrointestinal haemorrhage.

Analysis of Variance↗

Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage.

OBJECTIVES: We studied the incidence of myocardial injury in aneurysmal subarachnoid hemorrhage (SAH) using the more sensitive cardiac troponin I (cTnI) assay, correlated changes in cTnI with creatine kinase, MB fraction (CK-MB), myoglobin, and catecholamine metabolite assays, and examined the predictive value of changes in cTnI for myocardial dysfunction. BACKGROUND: Myocardial injury in aneurysmal SAH as evidenced by elevated CK-MB fraction has been reported. Little published data exist on the value of cTnI measurements in aneurysmal SAH. METHODS: Thirty-nine patients were studied for seven days. Clinical cardiovascular assessment, electrocardiographic (ECG), echocardiography, cTnI, CK, CK-MB and CK-MB index, myoglobin and 24-h urinary catecholamine assays were performed in all patients. The ECG abnormalities were defined by the presence of ST-T changes, prolonged QT intervals, and arrhythmias. An abnormal echocardiogram was defined by the presence of wall-motion abnormalities and a reduced ejection fraction. The severity of SAH was graded clinically and radiologically. RESULTS: Eight patients demonstrated elevations in cTnI (upper limit of normal is 0.1 microg/liter with the immunoenzymatic assay and 0.4 microg/liter with the sandwich immunoassay), while five had abnormal CK-MB levels (upper limit of normal is 8 microg/liter). Patients with more severe grades of SAH were more likely to develop a cTnI leak (p < 0.05). Patients with cTnI elevations were more likely to demonstrate ECG abnormalities (p < 0.01) and manifest clinical myocardial dysfunction (p < 0.01) as evidenced by the presence of a gallop rhythm on auscultation and clinical or radiological evidence of pulmonary edema as compared to those with CK-MB elevations. The sensitivity and specificity of cTnI to predict myocardial dysfunction were 100% and 91%, respectively, whereas the corresponding figures for CK-MB were 60% and 94%, respectively. Elevations in myoglobin levels (upper limit of normal <70 microg/liter) and urinary catecholamine metabolites (urinary vanilmandelate/creatinine ratio upper limit of normal, 2.6) are a nonspecific finding. CONCLUSIONS: Measurements of cTnI reveal a higher incidence of myocardial injury than predicted by CK-MB in aneurysmal SAH, and elevations of cTnI are associated with a higher incidence of myocardial dysfunction. Thus, cTnI is a highly sensitive and specific indicator of myocardial dysfunction in aneurysmal SAH.

Adult↗

Cerebrospinal fluid in critical illness.

OBJECTIVE: To detail the physiology, pathophysiology and recent advances in diagnostic analysis of cerebrospinal fluid (CSF) in critical illness, and briefly review the pharmacokinetics and pharmaco-dynamics of drugs in the CSF when administered by the intravenous and intrathecal route. DATA SOURCES: A review of articles published in peer reviewed journals from 1966 to 1999 and identified through a MEDLINE search on the cerebrospinal fluid. SUMMARY OF REVIEW: The examination of the CSF has become an integral part of the assessment of the critically ill neurological or neurosurgical patient. Its greatest value lies in the evaluation of meningitis. Recent publications describe the availability of new laboratory tests on the CSF in addition to the conventional cell count, protein sugar and microbiology studies. Whilst these additional tests have improved our understanding of the pathophysiology of the critically ill neurological/neurosurgical patient, they have a limited role in providing diagnostic or prognostic information. The literature pertaining to the use of these tests is reviewed together with a description of the alterations in CSF in critical illness. The pharmacokinetics and pharmacodynamics of drugs in the CSF, when administered by the intravenous and the intrathecal route, are also reviewed. CONCLUSIONS: The diagnostic utility of CSF investigation in critical illness is currently limited to the diagnosis of an infectious process. Studies that have demonstrated some usefulness of CSF analysis in predicting outcome in critical illness have not been able to show their superiority to conventional clinical examination. With further advances in our understanding of neurological function and refinement in biochemical analysis there remains the possibility of useful cerebrospinal fluid diagnostic and prognostic markers in the future.

Journal Article↗

Late changes in spliceosomal introns define clades in vertebrate evolution.

The evolutionary origin of spliceosomal introns has been the subject of much controversy. Introns are proposed to have been both lost and gained during evolution. If the gain or loss of introns are unique events in evolution, they can serve as markers for phylogenetic analysis. We have made an extensive survey of the phylogenetic distribution of seven spliceosomal introns that are present in Fugu genes, but not in their mammalian homologues; we show that these introns were acquired by actinopterygian (ray-finned) fishes at various stages of evolution. We have also investigated the intron pattern of the rhodopsin gene in fishes, and show that the four introns found in the ancestral chordate rhodopsin gene were simultaneously lost in a common ancestor of ray-finned fishes. These changes in introns serve as excellent markers for phylogenetic analysis because they reliably define clades. Our intron-based cladogram establishes the difficult-to-ascertain phylogenetic relationships of some ray-finned fishes. For example, it shows that bichirs (Polypterus) are the sister group of all other extant ray-finned fishes.

Amino Acid Sequence↗

The continuous measurement of cerebrospinal fluid gas tensions in critically ill neurosurgical patients: a prospective observational study.

OBJECTIVE: To determine the feasibility and usefulness of continuous cerebrospinal fluid pH and gas tension monitoring in critically ill neurosurgical patients. DESIGN: Prospective, observational study. SETTING: Neurosurgical intensive care unit in a teaching hospital. PATIENTS: Five critically ill neurosurgical patients (GCS < 8) requiring intensive care intracranial pressure monitoring and intermittent positive pressure ventilation. INTERVENTIONS: Placement of a Paratrend 7 sensor into the external ventricular drain. MEASUREMENTS AND MAIN RESULTS: The cerebrospinal fluid (CSF) pH, PCO2 and PO2 were recorded at 1-min intervals. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were recorded at 15-min intervals. The mean baseline CSF pH, O2 and PO2 values were 7.28 +/- 0.08 pH units, 44 +/- 6 torr and 43 +/- 27 torr, respectively. The ranges of CSF pH, PCO2 and PO2 observed during the study were 6.3-7.8 pH units, 37-150 torr and 4-150 torr, respectively. A statistically significant correlation between ICP, CPP and CSF gas tensions occurred in patient 3. Significant changes in CSF PO2 and pH were observed with augmentation of CPP and preceded clinical improvement in patient 4. There were no complications attributable to sensor placement. CSF gas tensions and pH values obtained from patients 3 and 4 suggest that these measurements may be an indicator of cerebral perfusion. CONCLUSIONS: Continuous CSF gas tension measurements in critically ill patients are possible and may be an indicator of adequacy of cerebral perfusion. The relative merits and limitations of the technique are discussed.

Adult↗

Fourier transform Raman approach to structural correlation in hemoglobin derivatives.

In order to obtain information on the structural aspects of hemoglobin (Hb), Fourier transform Raman (FT-R) measurements on various ferrous, ferric derivatives and nickel reconstituted Hb (NiHb) has been made. FT-R spectra for these derivatives were obtained by laser excitation in the near infrared region (NIR) (1064 nm) whereby the wave-number region (600-1700 cm-1) related to both porphyrin ring modes and some globin modes were monitored. Comparison of various modes was made based on previous resonance Raman (RR) results. The wave-number shifts with respect to changes in oxidation state and spin state are very similar to those observed by RR. Additional bands at 1654, 1459, and 1003 cm-1 for deoxyHb and at 1656, 1454, and 1004 cm-1 for oxy Hb can be correlated to globin modes. The shift in the position of these bands for the binding of oxygen can be related to changes in conformation during the transformation. The presence of two distinct sites in NiHb could be monitored by the use of FT-R technique.

Carboxyhemoglobin↗