Precision of cellular magnesium assays.
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Cell Count↗
Biomedical subjects
S M Banks
Publications and source records attributed to S M Banks.
Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.
Infection with the hepatitis C virus may result in chronic liver disease for which no effective therapy is now available. We studied the effects of recombinant human interferon alfa in a prospective, randomized, double-blind, placebo-controlled trial in patients with well-documented chronic hepatitis C. Forty-one patients were enrolled in the trial, 37 of whom were later found to have antibody to hepatitis C virus. Twenty-one patients received interferon alfa (2 million units) subcutaneously three times weekly for six months, and 20 received placebo. The mean serum aminotransferase levels and the histologic features of the liver improved significantly in the patients treated with interferon but not in the patients given placebo. Ten patients treated with interferon (48 percent) had a complete response, defined as a decline in mean serum aminotransferase levels to the normal range during therapy; three others had a decrease in mean aminotransferase levels of more than 50 percent. After treatment ended, however, serum aminotransferases usually returned to pretreatment levels; 6 to 12 months after the discontinuation of interferon therapy, only two patients (10 percent) still had normal values. We conclude that interferon alfa therapy is beneficial in reducing disease activity in chronic hepatitis C; however, the beneficial responses are often transient.
Adult↗
Human T cell recognition of polymorphic epitopes from malaria circumsporozoite protein.
Lymphocytes obtained from forty individuals living in a malaria endemic area of West Africa were tested for in vitro proliferative responses to peptides representing variant regions of the immunodominant T cell domain of the circumsporozoite protein (amino acids 326 to 345, referred to as Th2R, and 361 to 380, referred to as Th3R) from three distinct strains of Plasmodium falciparum. A total of 83% of the individuals responded to at least one of the six peptides tested, confirming that these epitopes are immunodominant. A much greater number of individuals than expected by chance (32% of the responders to Th2R and 27% of the responders to Th3R) reacted to all three of the variant peptides for that epitope, indicating interdependency of the T cell responses, suggestive of cross-reactivity. Nevertheless, some subjects' T cells were clearly able to distinguish each variant peptide from the others. Using EBV transformed B cells, lymphocytes from 10 of the individuals were HLA typed. In this small group, HLA DRw13 was associated with a positive response to any of the peptides, whereas there was a negative association between DQw3 and response to any of the peptides. These results, although limited by the small sample size, suggest that recognition of T epitopes may be Ir gene linked. Our findings suggest that it may be possible to broaden the immunogenicity of an anti-sporozoite malaria vaccine.
Adult↗
Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock.
Survivors of both human and animal bacterial shock develop a characteristic pattern of progressive changes in cardiovascular function over a period of 7-10 d. In this present study, we examined whether endotoxin (a product of Gram-negative bacteria) or TNF (a cytokine released from macrophages) could reproduce the same complex cardiovascular changes observed in septic shock over a period of 7-10 d. To test this hypothesis, we implanted a thrombin-fibrin clot containing purified endotoxin from E. coli into the peritoneal cavity of eight dogs, and infused TNF into eight different dogs. Over the next 10 d, serial simultaneous heart scans and thermodilution cardiac outputs were performed in these awake nonsedated animals. By day 2 after challenge with either endotoxin or TNF, animals developed a decrease (p less than 0.05) in both mean arterial pressure and left ventricular ejection fraction. With fluid resuscitation, animals manifested left ventricular dilatation (increased [p less than 0.05] end diastolic volume index), increased or normal cardiac index, and decreased or normal systemic vascular resistance index. In surviving animals, these changes returned to normal with 7-10 d. The time course of these changes was concordant (p less than 0.05) with that previously described in a canine model of septic shock using viable bacteria. During the 10-d study, control animals receiving sterile clots or heat-inactivated TNF had not significant changes in hemodynamics. The results from this canine model demonstrate that either endotoxin or TNF alone can produce many of the same hemodynamic abnormalities seen in human septic shock and in a canine septic shock model induced by live bacteria. These findings support the hypothesis that the action of endogenous mediators (TNF) responding to bacterial products (endotoxin) is the common pathway that produces the serial cardiovascular changes found in septic shock.
Animals↗
Modified Box-Cox transform for modulating the dynamic range of flow cytometry data.
We describe an algorithm, Vout = Integer ([2(12)-1/2(12 lambda)-1] V lambda in-1) + 1; lambda greater than 0 based upon Box-Cox transformations as an alternative to nonlinear electronic amplifiers to expand or compress high- or low-amplitude flow cytometer-derived signals. If the indexing parameter lambda less than 1, input channels in the high-amplitude input range are compressed in the output range as occurs when an electronic logarithmic amplifier is used. However, if lambda greater than 1, input channels in the low-amplitude input range are compressed in the output range as occurs when an electronic power amplifier is used. Our modified Box-Cox transform can be implemented either during data collection or off-line for the transformation of previously collected raw data. The transform is the equivalent of an infinite class of nonlinear amplifiers. As the transform is implemented in software, it does not suffer from many of the disadvantages of nonlinear electronic amplifiers.
Algorithms↗
The pathophysiology of rhinitis. III. The control of IgG secretion.
To examine the sources of IgG in nasal secretions, nasal provocation tests with histamine (H) and methacholine (MC) were performed on 22 subjects. Nasal lavages were assayed for IgG, total protein, albumin (Alb), nonsecretory IgA (nonsIgA), and secretory IgA (sIgA). H stimulation dramatically increased the secretion of IgG, nonsIgA, and Alb and also increased the proportion of these proteins compared to total protein. H-induced protein secretion was significantly inhibited by nasal pretreatment with chlorpheniramine maleate but was unaffected by atropine sulfate. sIgA was also stimulated by H challenge, but unlike IgG and other vascular proteins, the proportion of sIgA to total protein (sIgA percent) decreased after H challenges. MC stimulation also increased secretion of IgG, Alb, nonsIgA, and sIgA but did not alter their proportions, compared to total protein. Topical atropine significantly inhibited secretion of all proteins, suggesting a mode of transportation mediated by glandular muscarinic receptor stimulation. Thus, MC can increase the amount of IgG secretion, whereas H increases both the amount and relative proportion of IgG in nasal secretions. These data suggest that pharmacologic stimulation of IgG into nasal secretions may be used as a total to modulate mucosal immunity.
Administration, Topical↗
Follicular fluid-induced acrosome reaction distinguishes a subgroup of men with unexplained infertility not identified by semen analysis.
We compared the ability of sperm to undergo follicular fluid-induced acrosome reaction in vitro in fertile men and patients with unexplained infertility. After capacitation under optimum conditions, 28% of sperm from fertile men undergo acrosome reaction after follicular fluid exposure, whereas only 7% of the cells react spontaneously. In 15 men with unexplained infertility, 6 patients showed lack of acrosome reaction, whereas 9 men had sperm acrosome reactions similar to that of fertile men. However, in this cohort under study, semen characteristics of AR(+) and AR(-) patients were similar. In addition to inducing sperm acrosome reaction, follicular fluid also promoted significant changes in motion characteristics of capacitated sperm. Sperm curvilinear velocity (Vc) increased significantly after exposure to follicular fluid though linearity remained unchanged. The largest difference in cumulative Vc occurred at 90 microns/s. Assessing the ability of capacitated sperm to acrosome react may have clinical significance in predicting whether such sperm are capable of fertilizing an ovum.
Acrosome↗
Sperm motion characteristics in men with isolated hypogonadotropic hypogonadism treated with gonadotropin.
The authors compared curvilinear velocity (Vc) and linearity (L) of sperm from fertile oligospermic men with isolated hypogonadotropic hypogonadism (IHH) to Vc and L of sperm from fertile normal men in order to determine if sperm motion analysis is better than sperm density as an indicator of fertility potential. Nine fertile men with IHH treated with exogenous gonadotropins and 20 fertile normal men were studied. Sperm density was significantly lower in the men with IHH compared with normal men (15.5 +/- 4.8 x 10(6)/ml versus 92.4 +/- 9.7 x 10(6)/ml; mean +/- standard error of the mean [SEM]; P less than 0.01) as was percent motility (51.4 +/- 4.7 versus 73.4 +/- 3.1; P less than 0.01). While a small but significant difference in Vc was noted between the groups at the 40 micron/second cumulative distribution point (P less than 0.01), no difference in L was found between the two groups. When the men with IHH were subgrouped according to sperm density (greater than 20 x 10(6)/ml versus less than or equal to 20 x 10(6)/ml, no differences in Vc were found between the subsets, but for L sperm were somewhat less directional for the subgroup with a density less than or equal to 20 x 10(6)/ml (P = 0.05). Coanalysis using both Vc and L parameters indicated that sperm from IHH patients were distributed similarly to sperm from normal men. However, sperm motion characteristics in men with unexplained infertility were different from values measured in normal men and IHH patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Diagnosis, Computer-Assisted↗
Low acrosin activity in a subgroup of men with idiopathic infertility dose not correlate with sperm density, percent motility, curvilinear velocity, or linearity.
The authors compared sperm acrosin activity with sperm density and cell motion characteristics in 21 normal fertile men and 25 patients with unexplained infertility. Under standardized and optimized conditions of abstinence and semen sample processing, we measured sperm acrosin activity in washed sperm from direct aliquots of semen and in aliquots of semen filtered through glasswool to remove dead cells and debris. Using washed sperm from semen, sperm acrosin levels in infertile men (median, 44 microIU/10(6) sperm) were significantly lower than values measured in fertile men (median, 67 microIU/10(6) sperm, P less than 0.01). After glasswool filtration, sperm acrosin activity was higher for both fertile and infertile men. Using washed sperm, 7 of 25 patients had acrosin activity consistently below values measured for fertile men; after glasswool filtration, values for 8 of 14 patients were below the normal range. For either fertile or infertile men, sperm acrosin activity showed no correlation with sperm density, percent motility, or either motion characteristic of curvilinear velocity (Vc40 microns/sec) or linearity (L3); and further, the low sperm acrosin activity of some infertile patients did not correlate with the motion co-characteristics measured at Vc40/L3, and the majority of patients with slower and/or less directional sperm had normal acrosin activity. From our data, we therefore conclude that sperm acrosin activity is independent of sperm motion characteristics.
Acrosin↗
Structure-kinetic relationships of choriogonadotropin and related molecules.
To assess how profound differences in carbohydrate and/or polypeptide structures affect parameters of plasma disappearance of glycoprotein hormones, we calculated and compared the initial volume of distribution, rate constants, and metabolic clearance rates of several highly purified human choriogonadotropin (hCG) analogues in monkeys. hCG, deglycosylated hCG, desialylated hCG, or core fragment of hCG-beta purified from pregnancy urine (beta-core) was administered as a rapid intravenous injection to adult male cynomolgus monkeys (n = 3/group). The metabolic clearance rates of deglycosylated hCG, beta-core fragment, and desialylated hCG were increased 15-, 47-, and 152-fold, respectively, over that of hCG. Their corresponding initial volumes of distribution, however, remained essentially unchanged compared with that of hCG and approximated the estimated plasma volume. In contrast, the fast and slow rate constants of plasma disappearance of the hCG analogues were increased as much as 18- and 23-fold, respectively, relative to those of hCG. These studies of structure-kinetic relationships in primates show that major carbohydrate and polypeptide modifications of a glycoprotein hormone cause profound changes in the rate constants of the disappearance curves without changes in the initial volume of distribution.
Animals↗
The pathophysiology of rhinitis. II. Assessment of the sources of protein in histamine-induced nasal secretions.
Nasal provocation tests were performed on nine atopic and 15 nonatopic subjects in order to assess the sources of protein in histamine-induced secretions and to examine the bilateral secretory response to unilaterally applied topical histamine (the nasonasal reflex). Nasal lavages were assayed for the following proteins: albumin, total protein, secretory IgA (sIgA), nonsecretory IgA (serum IgA), and total IgA. Histamine stimulation produced a profound ipsilateral protein secretion enriched in the serum proteins albumin and nonsecretory IgA. Histamine also produced a smaller contralateral protein secretion (about 15% as large as the ipsilateral response) which contained disproportionately elevated concentrations of the glandular protein sIgA. Topical pretreatment with chlorpheniramine (an H-1 antihistamine) completely abrogated the ipsilateral nasal secretory response to histamine. Nasal pretreatment with atropine (a muscarinic antagonist) had no significant effect on ipsilateral nasal secretion and did not alter the capacity of histamine to stimulate contralateral secretions (the nasonasal reflex). Histamine therefore stimulates secretion by both a direct action that increases plasma protein extravasation and by an indirect reflex mechanism that stimulates glandular secretion.
Adult↗
Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock.
Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses of viable or formalin-killed bacteria. Cardiovascular function of conscious animals was studied using simultaneous radionuclide heart scans and thermodilution cardiac outputs. Serial plasma endotoxin levels were measured. S. aureus produced a pattern of reversible cardiovascular dysfunction over 7-10 d that was concordant (P less than 0.01) with that of E. coli. Although this cardiovascular pattern was not altered by formalin killing (S. aureus and E. coli), formalin-killed organisms produced a lower mortality and less myocardial depression (P less than 0.01). S. aureus, compared to E. coli, produced higher postmortem concentrations of microorganisms and higher mortality (P less than 0.025). E. coli produced significant endotoxemia (P less than 0.01), though viable organisms (versus nonviable) resulted in higher endotoxin blood concentrations (P less than 0.05). Significant endotoxemia did not occur with S. aureus. Thus, in the absence of endotoxemia, S. aureus induced the same cardiovascular abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality.
Animals↗
Cardiac morphologic and functional changes induced by epirubicin chemotherapy.
Cardiac toxicity was evaluated in 24 patients who received epirubicin as a single chemotherapeutic agent, in doses of either 30 mg/m2 every week (11 patients) or 90 mg/m2 every 3 weeks (13 patients). The total doses of epirubicin ranged from 180 mg/m2 to 918 mg/m2 (mean, 491 +/- 187). No patient had prior heart disease, hypertension, mediastinal irradiation, or chemotherapy with other anthracycline agents. None of the patients developed overt heart failure, significant arrhythmias, ECG alterations, or roentgenographic changes in heart size. There was no significant change in the mean value of echocardiographic percent fractional shortening before and after epirubicin therapy. Patients receiving epirubicin doses less than 450 mg/m2 had minimal hemodynamic disturbances; however, no cut-off point separating two significantly different subpopulations could be demonstrated. Endomyocardial biopsy was performed on all patients; 20 biopsies were evaluable. Histologic and ultrastructural changes were similar to those caused by other anthracycline agents. A strong correlation was demonstrated between total dose of epirubicin and pathologic change as quantified using the Billingham scale (r = .7, P = .0006). A cut-off point beyond which there was a probability of increased pathologic damage was statistically defined at 450 mg/m2 of epirubicin. Severe pathologic alterations and moderate hemodynamic changes were observed in only one patient, who received 918 mg/m2 of epirubicin. Patients who are expected to receive epirubicin in excess of 450 mg/m2 should be monitored for cardiac toxicity, and continuation of epirubicin therapy beyond 900 mg/m2 should be based on the results of monitoring.
Adult↗
Stimulation of testosterone production in the cynomolgus monkey in vivo by deglycosylated and desialylated human choriogonadotropin.
Modifications of carbohydrate structures of hCG, such as deglycosylation or desialylation, have been shown to reduce the biological activity of the hormone derivatives in vivo. We posed the question of whether deglycosylated hCG (dg-hCG) and desialylated hCG (ds-hCG) would behave as agonists at the LH/CG receptor in the primate in vivo, as this would bear on their potential clinical utility as LH/CG agonists or antagonists. Thus, we administered large doses (approximately 3 nmol) of highly purified dg-hCG, ds-hCG, hCG, or normal saline as a rapid iv injection to adult male cynomolgus monkeys (n = 3/group). Mean areas under the curves of plasma T over the first 6 h achieved with dg-hCG and ds-hCG were about 5-fold, significantly (P less than 0.05) greater than that in the saline controls and not significantly (P greater than 0.05) different from that in hCG-injected animals. Despite comparable plasma T responses in the first 6 h, mean plasma concentrations of ds-hCG, dg-hCG, and hCG differed dramatically among the groups. Plasma ds-hCG and dg-hCG levels were undetectable by 15 and 180 min, respectively, while the mean plasma hCG level was more than 2.10 nmol/L at 360 min. These data indicate that 1) dg-hCG is a full agonist at the LH/CG receptor in the primate in vivo, despite having minimal intrinsic activity in the rat Leydig cell adenyl cyclase assay and being able to near-completely antagonize hCG action therein; and 2) ds-hCG is a full agonist in the monkey in vivo, capable of stimulating a full testicular response over 6 h, despite being cleared from the circulation in 15 min. We conclude that the signal transduction system at the monkey LH/CG receptor is capable of achieving full steroidogenesis despite dramatically shortened exposure to stimulus or exposure to a stimulus with markedly reduced adenyl cyclase-stimulating activity in vitro.
Animals↗
Sensitisation of preruminant calves and piglets to antigenic protein in early weaning diets: control of the systemic antibody responses.
The immune response stimulated by dietary protein was studied in preruminant calves and piglets. Calves receiving dietary soya developed high serum titres of soya-specific IgG which did not decline with prolonged feeding. IgG1 and IgG2 subclasses showed a parallel rise although IgG1 predominated. Levels of antibody evoked by a combination of oral and parenteral sensitisation with soya protein were significantly greater than by parenteral sensitisation alone. These results suggest that the calves failed to develop oral tolerance. Passively acquired maternal soya-specific antibody did not influence the response to oral or parenteral sensitisation with soya. By contrast, piglets weaned onto a soya-containing diet became hyporesponsive to injection with soya protein. Thus, calves and piglets appear to differ in their ability to control adverse immune responses to dietary antigens. This could influence the severity of gastrointestinal disorders associated with early weaning diets.
Animal Feed↗
Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism.
Men with the complete form of isolated hypogonadotropic hypogonadism (initial mean testes volume less than 4 mL) require 2 or more yr of exogenous gonadotropin therapy combining hCG and human menopausal gonadotropin (hMG) to achieve maximal, but subnormal, testis size and sperm output. To test whether pulsatile GnRH therapy, which more closely mimics normal hormonal stimulation, would accelerate or further augment testicular growth, hasten the onset of sperm production, and/or increase sperm output more than occurs during conventional exogenous gonadotropin therapy, we administered either hCG/hMG or GnRH from the inception of therapy to 2 comparable groups of men with complete IHH (initial testicular volume, less than 4 mL) and compared their testicular responses during the first 2 hr of therapy. Five men were treated with pulsatile GnRH in doses of 143-714 ng/kg every 2 h, sc, while 11 other men received hCG (2000 IU) and hMG (75 IU FSH and 75 IU LH) im 3 times/week. In the GnRH-treated men, the mean plasma total and free testosterone levels during therapy rose to within the normal range, but were significantly lower (P less than 0.01 and P less than 0.02, respectively) than those in the hCG/hMG-treated men. The mean plasma estradiol concentrations during therapy were within the high normal range and were similar in the two groups. The mean plasma FSH levels achieved in the GnRH-treated men were significantly (P less than 0.01) and 1.3- to 3.2-fold higher than those in the hCG/hMG-treated men. The mean testicular size achieved in the GnRH-treated men was not significantly different from that in the hCG/hMG-treated men (P = 0.08); the mean testicular volumes after 2 yr were 4.8- and 4.3-fold the pretreatment values in the GnRH and hCG/hMG groups, respectively. After 12 months of therapy, sperm production had occurred in one man in the GnRH group and in no subject in the hCG/hMG group. After 24 months, two men in the GnRH group and eight men in the hCG/hMG group produced sperm. Thus, 40% of the GnRH-treated men and 80% of the hCG/hMG-treated men (P = NS) produced sperm after 2 yr of therapy. The sperm concentrations in all men were below 5 million/mL and were comparable in the two groups (P = NS). These results suggest that pulsatile sc GnRH therapy for the first 2 yr does not accelerate or enhance testicular growth, hasten the onset of sperm production, or increase sperm output significantly compared to hCG/hMG.
Adult↗
HLA and survival in lung cancer.
HLA A and B antigens were determined in a study of 125 patients with lung cancer. Differences between antigen frequencies in cancer and control populations were determined by chi 2 analysis or Fisher's exact test. Survival data were analyzed using the Cox model for censored data. Cancer patients had an increased frequency of the antigen Aw33 (relative risk = 10.5, P less than 0.016). The Cox model (D. R. Cox, J. R. Stat. Soc. B, 34, 187, 1972) indicated that four covariates had a significant effect on mean survival time independently: the presence of A3 (P less than 0.005) and of Aw33 (P less than 0.05) increased mean survival time of the cancer population; patients with anaplastic carcinoma and stage three of any histological type of cancer had a decreased mean survival time. The determination of HLA phenotypes, cancer type, and the stage of the disease can provide the expected mean survival time of any particular patient. This could be of importance for evaluating prognosis. The effect of Aw33 and A3 on survival time may be related to HLA closely linked genes, possibly coding for resistance to the disease.
HLA Antigens↗
The validity of assessing mental health needs with social indicators.
Selection of the appropriate number and types of social indicators for use in mental health planning has been a perennial problem. Social indicators have been associated with several concepts (quality of life, community disorganization, populations at risk) of varying relevance for planning mental health services, and abstracting social indicators from these conceptual domains poses a variety of validity issues. The issues are discussed, and the viability of social indicators in mental health planning is reexamined.
Catchment Area, Health↗