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Biomedical subjects

G Jacob

Publications and source records attributed to G Jacob.

At least 19 recordsLinked to original sources
PubMed1999

Idiopathic orthostatic intolerance and postural tachycardia syndromes.

Upright posture imposes a substantial gravitational stress on the body, for which we are able to compensate, in large part because of the autonomic nervous system. Alteration in autonomic function, therefore, may lead to orthostatic intolerance. On one extreme, patients with autonomic failure caused by degenerative loss of autonomic function are severely disabled by orthostatic hypotension and may faint whenever they stand up. Fortunately, such patients are relatively rare. On the other hand, disabling orthostatic intolerance can develop in otherwise normal young people. These patients can be severely impaired by symptoms of fatigue, tachycardia, and shortness of breath when they stand up. The actual incidence of this disorder is unknown, but these patients make up the largest group of patients referred to centers that specialize in autonomic disorders. We will review recent advances made in the understanding of this condition, potential pathophysiological mechanisms that contribute to orthostatic intolerance, therapeutic alternatives currently available for the management of these patients, and areas in which more research is needed.

Autonomic Nervous System↗
PubMed1998

Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control.

BACKGROUND: Chronic orthostatic intolerance (COI) is a debilitating autonomic condition in young adults. Its neurohumoral and hemodynamic profiles suggest possible alterations of postural sympathetic function and of baroreflex control of heart rate (HR). METHODS AND RESULTS: In 16 COI patients and 16 healthy volunteers, intra-arterial blood pressure (BP), ECG, central venous pressure (CVP), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during 75 degrees tilt. Spectral analysis of RR interval and systolic arterial pressure (SAP) variabilities provided indices of sympathovagal modulation of the sinoatrial node (ratio of low-frequency to high-frequency components, LF/HF) and of sympathetic vasomotor control (LFSAP). Baroreflex mechanisms were assessed (1) by the slope of the regression line obtained from changes of RR interval and MSNA evoked by pharmacologically induced alterations in BP and (2) by the index alpha, obtained from cross-spectral analysis of RR and SAP variabilities. At rest, HR, MSNA, LF/HF, and LFSAP were higher in COI patients, whereas BP and CVP were similar in the two groups. During tilt, BP did not change and CVP fell by the same extent in the 2 groups; the increase of HR and LF/HF was more pronounced in COI patients. Conversely, the increase of MSNA was lower in COI than in control subjects. Baroreflex sensitivity was similar in COI and control subjects at rest; tilt reduced alpha similarly in both groups. CONCLUSIONS: COI is characterized by an overall enhancement of noradrenergic tone at rest and by a blunted postganglionic sympathetic response to standing, with a compensatory cardiac sympathetic overactivity. Baroreflex mechanisms maintain their functional responsiveness. These data suggest that in COI, the functional distribution of central sympathetic tone to the heart and vasculature is abnormal.

Adult↗
PubMed1998

Relation of blood volume and blood pressure in orthostatic intolerance.

A complex but crucial relationship exists between blood volume and blood pressure in human subjects; it has been recognized that in essential hypertension, renovascular hypertension, and pheochromocytoma, the relationship between plasma volume and diastolic blood pressure is an inverse one. This phenomenon has not been studied in individuals with low normal and reduced blood pressures. Orthostatic intolerance is a commonly encountered abnormality in blood pressure regulation often associated with tachycardia in the standing position. Most of these patients have varying degrees of reduced blood volume. We tested the hypothesis that the relationship previously found between plasma volume and diastolic blood pressure in pressor states would also hold in orthostatic intolerance. We studied 16 patients with a history of symptomatic orthostatic intolerance associated with an elevation in plasma norepinephrine in the upright posture and hypovolemia in 9 patients and normovolemia in 7 patients. Our studies demonstrate an inverse relationship between plasma volume and diastolic blood pressure in patients with orthostatic intolerance. This finding also holds for the change in diastolic blood pressure in response to upright posture. In this relationship, patients with orthostatic intolerance with high plasma norepinephrine resemble those with essential hypertension, renovascular hypertension, and pheochromocytoma. We conclude that in a variety of conditions at both ends of the blood pressure spectrum, the seemingly paradoxical association of hypovolemia and diastolic blood pressure is preserved.

Adolescent↗
PubMed1998

Effect of standing on neurohumoral responses and plasma volume in healthy subjects.

Upright posture leads to rapid pooling of blood in the lower extremities and shifts plasma fluid into surrounding tissues. This results in a decrease in plasma volume (PV) and in hemoconcentration. There has been no integrative evaluation of concomitant neurohumoral and PV shifts with upright posture in normal subjects. We studied 10 healthy subjects after 3 days of stable Na+ and K+ intake. PV was assessed by the Evans blue dye method and by changes in hematocrit. Norepinephrine (NE), NE spillover, epinephrine (Epi), vasopressin, plasma renin activity, aldosterone, osmolarity, and kidney response expressed by urine osmolality and by Na+ and K+ excretion of the subjects in the supine and standing postures were all measured. We found that PV fell by 13% (375 +/- 35 ml plasma) over approximately 14 min, after which time it remained relatively stable. There was a concomitant decrease in systolic blood pressure and an increase in heart rate that peaked at the time of maximal decrease in PV. Plasma Epi and NE increased rapidly to this point. Epi approached baseline by 20 min of standing. NE spillover increased 80% and clearance decreased 30% with 30 min of standing. The increase in plasma renin activity correlated with an increase in aldosterone. Vasopressin increased progressively, but there was no change in plasma osmolarity. The kidney response showed a significant decrease in Na+ and an increase in K+ excretion with upright posture. We conclude that a cascade of neurohumoral events occurs with upright posture, some of which particularly coincide with the decrease in PV. Plasma Epi levels may contribute to the increment in heart rate with maintained upright posture.

Adult↗
PubMed1997

Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.

BACKGROUND: Idiopathic orthostatic tachycardia (IOT) is characterized by an increase in heart rate (HR) with standing of > or = 30 bpm that is associated with elevated catecholamine levels and orthostatic symptoms. A dynamic orthostatic hypovolemia and alpha1-adrenoreceptor hypersensitivity have been demonstrated in IOT patients. There is evidence of an autonomic neuropathy affecting the lower-extremity blood vessels. METHODS AND RESULTS: We studied the effects of placebo, the alpha1-adrenoreceptor agonist midodrine (5 to 10 mg), the alpha2-adrenoreceptor agonist clonidine (0.1 mg), and I.V. saline (1 L) in 13 patients with IOT. Supine and upright blood pressure (BP) and HR were measured before and at 1 and 2 hours after intervention. Midodrine decreased both supine and upright HR (all HR values are given as bpm) at 2 hours (from 78+/-2 supine to 108+/-5 upright before treatment and from 69+/-2 supine to 95+/-5 upright after treatment, P<.005 for supine and P<.01 for upright). Saline decreased both supine and upright HR (from 80+/-3 supine to 112+/-5 upright before infusion and from 77+/-3 supine to 91+/-3 upright 1 hour after infusion, P<.005 for supine and P<.001 for upright). Clonidine decreased supine HR (from 78+/-2 to 74+/-2, P<.03) but did not affect the HR increase with standing. Clonidine very significantly decreased supine systolic BP (from 109+/-3 at baseline to 99+/-2 mm Hg at 2 hours, P<.001), and midodrine decreased supine systolic BP mildly. CONCLUSIONS: IOT responds best acutely to saline infusion to correct the underlying hypovolemia. Chronically, this can be accomplished with increased salt and water intake in conjunction with fludrocortisone. The response of patients to the alpha1-agonist midodrine supports the hypothesis of partial dysautonomia and indicates that the use of alpha1-agonists to pharmacologically replace lower-extremity postganglionic sympathetics is an appropriate overall goal of therapy. These findings are consistent with our hypothesis that the tachycardia and elevated catecholamine levels associated with IOT are principally due to hypovolemia and loss of adequate lower-extremity vascular tone.

Adolescent↗
PubMed1997

Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system.

PURPOSE: Orthostatic intolerance is the cause of significant disability in otherwise normal patients. Orthostatic tachycardia is usually the dominant hemodynamic abnormality, but symptoms may include dizziness, visual changes, discomfort in the head or neck, poor concentration, fatigue, palpitations, tremulousness, anxiety and, in some cases, syncope. It is the most common disorder of blood pressure regulation after essential hypertension. There is a predilection for younger rather than older adults and for women more than men. Its cause is unknown; partial sympathetic denervation or hypovolemia has been proposed. METHODS AND MATERIALS: We tested the hypothesis that reduced plasma renin activity, perhaps from defects in sympathetic innervation of the kidney, could underlie a hypovolemia, giving rise to these clinical symptoms. Sixteen patients (14 female, 2 male) ranging in age from 16 to 44 years were studied. Patients were enrolled in the study if they had orthostatic intolerance, together with a raised upright plasma norepinephrine (> or = 600 pg/mL). Patients underwent a battery of autonomic tests and biochemical determinations. RESULTS: There was a strong positive correlation between the blood volume and plasma renin activity (r = 0.84, P = 0.001). The tachycardic response to upright posture correlated with the severity of the hypovolemia. There was also a correlation between the plasma renin activity measured in these patients and their concomitant plasma aldosterone level. CONCLUSIONS: Hypovolemia occurs commonly in orthostatic intolerance. It is accompanied by an inappropriately low level of plasma renin activity. The degree of abnormality of blood volume correlates closely with the degree of abnormality in plasma renin activity. Taken together, these observations suggest that reduced plasma renin activity may be an important pathophysiologic component of the syndrome of orthostatic intolerance.

Adolescent↗
PubMed1997

Profile of ocular trauma in Papua New Guinea.

BACKGROUND: Ocular trauma is a significant cause of blindness in Papua New Guinea (PNG). This study was done to determine the pattern and rates of ocular and adnexal injuries so as to determine the size and extent of the problem. METHODS: A retrospective study of 4157 cases presenting with ocular trauma in three regions of PNG was carried out. The data were analysed with respect to the age, sex, province, type and cause of injury, time interval between injury and presentation to the hospital and the final visual outcome after treatment. RESULTS: Ocular trauma rates in PNG were alarmingly high (39.1 per 100,000). The commonest cause of injury in the younger age group was due to lime. Alcohol-related violence and fights resulted in injuries in the adult age group. Most of the injuries were grievous and 60.7% of patients were left with a visual acuity of less than 6/60 in the injured eye. In addition, 78.7% of the patients were under 30 years of age. CONCLUSIONS: Ocular injuries in PNG are an important cause of visual disability. Some specific injuries, such as those due to lime in children, can easily be prevented by health education.

Adolescent↗
PubMed1997

Experimental study in bile duct-ligated rats of vasopressin and preoperative volume loading to prevent hypotensive crises.

BACKGROUND: Systemic hypotension may result in postoperative renal failure in jaundiced patients. Attenuated responsiveness to catecholamines and hypovolaemia has been reported in jaundiced animals and may be a mechanism contributing to the increased susceptibility of jaundiced patients to haemorrhagic shock. This suggests that an alternative to vasoactive amines to control perioperative hypotension could be desirable. METHODS: This study evaluated the pressor response to vasopressin in normovolaemic 3-day bile duct-ligated rats and in 3-day bile duct-ligated rats after an acute controlled haemorrhage. It also evaluated the response after volume loading with 0.9 per cent saline, 7.5 per cent saline, colloid and mannitol before controlled haemorrhage. In addition, blood volume was measured using radiolabelled albumin. All the data obtained from bile duct-ligated rats were compared with data from sham-operated animals. RESULTS: Attenuated pressor responses to vasopressin were not observed in either normotensive bile duct-ligated rats or in the bile duct-ligated rats subjected to controlled haemorrhage. Volume loading with the four fluids over the dosing range 2.5-7.5 microliters per g body-weight in bile duct-ligated rats reversed the susceptibility to haemorrhagic hypotension. CONCLUSION: Although no reduction in blood volume was demonstrated, bile duct-ligated rats may have a reduced effective blood volume manifesting itself as a latent hypovolaemia and/or tendency to hypotension. Preoperative fluid loading could be beneficial because it corrects hypovolaemia and improves cardiovascular function, as well as improving the cardiovascular response to haemorrhage.

Animals↗
PubMed1996

Clinical models of cardiovascular regulation after weightlessness.

After several days in microgravity, return to earth is attended by alterations in cardiovascular function. The mechanisms underlying these effects are inadequately understood. Three clinical disorders of autonomic function represent possible models of this abnormal cardiovascular function after spaceflight. They are pure autonomic failure, baroreflex failure, and orthostatic intolerance. In pure autonomic failure, virtually complete loss of sympathetic and parasympathetic function occurs along with profound and immediate orthostatic hypotension. In baroreflex failure, various degrees of debuffering of blood pressure occur. In acute and complete baroreflex failure, there is usually severe hypertension and tachycardia, while with less complete and more chronic baroreflex impairment, orthostatic abnormalities may be more apparent. In orthostatic intolerance, blood pressure fall is minor, but orthostatic symptoms are prominent and tachycardia frequently occurs. Only careful autonomic studies of human subjects in the microgravity environment will permit us to determine which of these models most closely reflects the pathophysiology brought on by a period of time in the microgravity environment.

Autonomic Nervous System↗
PubMed1995

Detection of hypoglycemic drugs in human urine using micellar electrokinetic chromatography.

Micellar electrokinetic chromatography (MEKC) is evaluated as a potential analytical method for the separation and detection of a series of sulfonylurea drugs used in the treatment of hyperglycemia. These drugs are often surreptitiously abused, producing extremely low blood glucose levels and symptoms indistinguishable from those associated with an insulin-secreting tumor. Separation buffer containing 50 mM sodium dodecyl sulfate (SDS) was found to be adequate for the MEKC separation of the third generation drugs (glipizide and glyburide) but not the second generation drugs (acetohexamide chlorpropamide, tolazamide, and tolbutamide). At a pH of 8.5 in the presence of 20 mM borate/20 mM phosphate and 150 mM SDS, all seven components were adequately resolved with an analysis time of 17 min. Altering the concentration of the buffering components to either 5 mM borate/5 mM phosphate or 40 mM borate alone reduced the analysis time to less than 10 min with no observable loss in resolution. A series of other micelle-forming surfactants were evaluated, and only sodium cholate provided an improvement over the SDS-based system. Optimal separation was obtained with 75 mM sodium cholate and led to complete analysis with baseline resolution of all seven components in less than 8 min. These conditions were shown to be adequate for the detection of the hypoglycemic drugs spiked into normal urine and in patients taking these drugs. The precision associated with nine consecutive injections of six samples (n = 54) was found to be acceptable with percent coefficient of variance for absolute migration times (MTabs) for all peaks averaging 0.89 with peak area and peak height being 8.49 and 8.26, respectively. The between-sample precision was found to average 0.92% for MTabs and 8.56% and 8.45%, respectively, for the relative peak area and peak height. With a detection limit for the drugs in urine (following extraction) in the 50 ng/mL range, the potential exists for an MEKC-based assay for the detection of sulfonylurea drugs in urine.

Chromatography, High Pressure Liquid↗
PubMed1995

DNA inhibits the catalytic activity of the alpha subunit of protein kinase CK2.

The recombinant alpha subunit of protein kinase CK2 (casein kinase 2) from Xenopus laevis is inhibited by the addition of single stranded or double stranded DNA. This inhibition is competitive with the casein substrate, having an apparent Ki of 160 nM for an 86 bp DNA fragment. Assays with a fragment containing the putative promoter of the human CK2 beta gene indicated that the affinity of CK2 for this fragment was not greater than that of other unrelated DNA. The inhibitory capacity of DNA toward the protein phosphorylating activity of CK2 alpha is greatly reduced by the presence of the beta subunit which can completely reverse the inhibition. The interaction of CK2 alpha with DNA can also be assayed by the nitrocellulose filter binding assay. This assay demonstrates that the interaction of CK2 alpha with the tested DNAs is not sequence specific and that the beta subunit can also greatly diminish the binding of CK2 alpha to DNA. Casein at substrate concentrations also is inhibitory to CK2 alpha DNA binding. Likewise, polyanionic inhibitors of the CK2 catalytic activity, such as heparin, poly(U), and copoly(Glu:Tyr) polypeptides, can compete for and inhibit the binding of DNA to CK2 alpha. However, quercetin, which also inhibits CK2 phosphorylation activity, and ATP do not affect DNA binding. A mutant CK2 alpha in which glutamic acids replace two lysine residues in positions 75 and 76 of the alpha peptide chain is less susceptible to DNA inhibition, indicating that this basic region of the molecule is involved in its interaction with DNA.

Amino Acid Sequence↗
PubMed1995

Orthostatic hypotension: epidemiology, pathophysiology and management.

Orthostatic hypotension is characterized by low upright blood pressure levels and symptoms of cerebral hypoperfusion. Whereas orthostatic hypotension is heterogeneous, correct pathophysiologic diagnosis is important because of therapeutic and prognostic considerations. Although therapy is not usually curative, it can be extraordinarily beneficial if it is individually tailored. Management of the Shy-Drager syndrome (multiple-system atrophy) remains a formidable challenge.

Humans↗
PubMed1995

Differential suppression of serum prostatic acid phosphatase and prostate-specific antigen by 5-alpha-reductase inhibitor.

OBJECTIVE: To evaluate the effect of finasteride (Proscar) on the serum levels of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) in patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Thirty patients on finasteride therapy for BPH formed the study group. Serum PSA and PAP levels were monitored for 2 years while the patients were receiving finasteride. RESULTS: During 12 months of finasteride therapy the serum PSA was suppressed but serum PAP was unaffected. The baseline mean PAP value was 1.303 ng/mL prior to finasteride therapy; this changed to 1.510 ng/mL (P = 0.195) at 6 months and 1.166 ng/mL (P = 0.383) at 12 months. The serum PSA was 2.630 ng/mL at baseline, 1.757 ng/mL (P < 0.001) at 6 months and 1.545 ng/mL (P = 0.001) at 12 months. CONCLUSIONS: Further studies are warranted to determine if PAP has a role as a tumour marker in patients whose PSA is suppressed as a result of finasteride therapy.

Acid Phosphatase↗
PubMed1994

Utility of preoperative serum prostate-specific antigen concentration and biopsy Gleason score in predicting risk of pelvic lymph node metastases in prostate cancer.

OBJECTIVES: To determine the accuracy of the preoperative serum concentration of prostate-specific antigen (PSA) plus the Gleason pathology score of biopsy specimens in predicting the presence of disease in the pelvic lymph nodes in patients with prostate cancer. METHODS: The medical records of all patients treated for prostate cancer at eight medical centers from January 1988 to June 1993 were reviewed. There were 932 patients with newly diagnosed prostate cancer for whom all relevant data were available who had undergone pelvic lymphadenectomy with (n = 912) or without (n = 20) radical prostatectomy. The rate of false-negative predictions of metastases based on combined preoperative biopsy Gleason score and serum PSA concentration was analyzed. A multivariate logistic regression analysis was performed to assess the value of preoperative serum PSA and biopsy Gleason scores individually and in combination in predicting pelvic lymph node metastases. RESULTS: The false-negative rate of metastases was 0% for preoperative PSA concentrations < or = 6 ng/mL and biopsy Gleason scores < or = 5 (n = 142) and 1.0% for PSA concentrations < or = 10 ng/mL and Gleason scores < or = 6 (n = 388). The 95% upper confidence limit for the rate of false negativity at this PSA cut-off level was 2.0%. A combination of preoperative serum PSA levels and biopsy Gleason scores provided the best prediction for the false-negative rates. CONCLUSIONS: For patients with newly diagnosed prostate cancer who have biopsy Gleason scores < or = 6 and preoperative PSA concentrations < or = 10 ng/mL (42% of our series), a staging pelvic lymphadenectomy appears to be unnecessary. The substantial cost associated with both cross-sectional imaging and staging lymphadenectomy may therefore be avoidable in this group of patients.

Biopsy↗