Iscoms with different quillaja saponin components differ in their immunomodulating activities.

In this study we demonstrate that iscoms made with different defined fractions of quillaja saponins (fractions A and C) exhibit strikingly different immunomodulatory activities. Fraction A has a potent immunomodulatory activity by enhancing antigen specific proliferation and production of IL-2 and IFN-gamma, interestingly, this is not reflected by increased levels of IgG2a. The C-fraction on the other hand strongly enhance antibody production and has the ability to modulate the IgG subclass pattern towards IgG2a, in spite of the fact that C-iscoms induce only low levels of IFN-gamma. Iscoms containing both fractions A and C (Iscoprep703) induced higher serum antibody responses than iscoms made of either of the fractions alone and showed an enhanced ability to modulate the serum subclass pattern towards IgG2a compared to C-iscoms.     

Steric hindrance is not required for n-alkanol cutoff in soluble proteins.

A loss of potency as one ascends a homologous series of compounds (cutoff effect) is often used to map the dimensions of binding sites on a protein target. The implicit assumption of steric hindrance is rarely confirmed with direct binding measurements, yet other mechanisms for cutoff exist. We studied the binding and effect of a series of n-alkanols up to hexadecanol (C16) on two model proteins, BSA and myoglobin (MGB), using hydrogen-tritium exchange and light scattering. BSA binds the n-alkanols specifically and, at 1 mM total concentration, is stabilized with increasing potency up to decanol (C10), where a loss in stabilizing potency occurs. Cutoff in stabilizing potency is concentration-dependent and occurs at progressively longer n-alkanols at progressively lower total n-alkanol concentrations. Light scattering measurements of n-alkanol/BSA solutions show a smooth decline in binding stoichiometry with increasing chain length until C14-16, where it levels off at approximately 2:1 (alkanol:BSA). MGB does not bind the n-alkanols specifically and is destabilized by them with increasing potency until C10, where a loss in destabilizing potency occurs. Like BSA, MGB demonstrates a concentration-dependent cutoff point for the n-alkanols. Derivation of the number of methylenes bound at K(D) and the free energy contribution per bound methylene showed that no discontinuity existed to explain cutoff, rendering steric hindrance unlikely. The data also allow an energetic explanation for the variance of the cutoff point in various reductionist systems. Finally, these results render cutoff an untenable approach for mapping binding site sterics in the absence of complementary binding measurements, and a poor discriminator of target relevance to general anesthesia.     

Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis

BACKGROUND: Pouchitis is the major long-term complication after ileal pouch-anal anastomosis for ulcerative colitis. About 15% of patients have a chronic, treatment-resistant disease. AIMS: To evaluate the efficacy of an antibiotic combination for chronic active, treatment-resistant pouchitis. PATIENTS AND METHODS: Eighteen patients were treated orally with rifaximin 1 g b.d. + ciprofloxacin 500 mg b.d. for 15 days. Symptoms assessment, endoscopic and histological evaluations were performed at screening and after 15 days using the Pouchitis Disease Activity Index (PDAI). Improvement was defined as a decrease of at least 3 points in PDAI score, and remission as a PDAI score of 0. Systemic absorption of rifaximin was determined by high performance liquid chromatography. Faecal samples were collected before and after antibiotic treatment for stool culture. RESULTS: Sixteen out of 18 patients (88.8%) either improved (n=10) or went into remission (n=6); the median PDAI scores before and after therapy were 11 (range 9-17) and 4 (range 0-16), respectively (P < 0.002). No side-effects were reported. Rifaximin plasma levels and urinary excretion were negligible, confirming its mainly topical activity. A significant decrease in total anaerobes and aerobes, enterococci, lactobacilli, bifidobacteria and bacteroides in faecal samples was observed, while the reduction in number of coliforms and Clostridium perfringens did not reach a statistical significance. CONCLUSIONS: A combination of rifaximin and ciprofloxacin was effective in patients with active chronic, treatment-resistant pouchitis, suggesting the need, in these patients, for treatment using antibiotic agents with wide antibacterial spectrum of activity.     

Measuring the cultural inflation of morbidity during the decline in mortality

The author replies to an article by James C. Riley concerning Johansson's earlier work on the cultural determinants of the health transition.     

Lethal deformation of cancer cells in the microcirculation: a potential rate regulator of hematogenous metastasis.

The hypothesis has been advanced that deformation-induced lethal mechanical trauma, resulting in surface-membrane rupture, is inflicted on circulating cancer cells trapped in the microcirculation, and that this rapid cell-killing mechanism is a potentially important rate regulator for hematogenous metastasis. We describe and discuss an in vivo test of this hypothesis. Vital fluorescence microscopy was performed on the microcirculation of cremaster muscle preparations in mice, following retrograde injections into the femoral artery of acridine orange-stained sarcoma cells. Cancer cells having mean diameters of 16.5 microns in suspension, were deformed from spheres into cylinders having a mean length of 53 microns, in 7-microns diameter capillaries. Most of these cells were dead several minutes after injection. It was estimated that sphere-to-cylinder shape-transitions of this magnitude required an average increase of 52% in apparent cell surface area. Evidence is presented that most of this apparent increase was achieved by non-lethal surface "unfolding", utilizing membrane "excess". That cancer-cell deformation of the magnitude observed in vivo is the direct cause of lethal, surface-membrane rupture was indicated by the observed loss of membrane integrity in cells deformed from spherical to cylindrical shape in vitro, by aspiration into micropipettes of capillary dimensions. The experimental observations are therefore consistent with the hypothesis.     

Characteristics of tetrahydrocannabinol (THC)-produced discrimination in rats

Rats were trained in a T-shaped maze to discriminate the effects produced by i.p. injections of tetrahydrocannabinol (THC) and the no-drug state (state-dependency, StD). Several doses of both ⁸-THC (range: 0.75–5.0 mg/kg) and ⁹-THC (range: 0.75–10.0 mg/kg) were used in order to compare the number of sessions required by the animals until reaching criterion performance. An additional group of rats had to discriminate pentobarbital sodium (20.0 mg/kg) from the no-drug state.Results: THC discrimination was proportional to dose i.e., animals that had to differentiate high doses of THC from no drug acquired the T-maize task faster than animals trained with the lower doses of THC. Acquisition data further suggest that ⁸-THC is somewhat less potent than the ⁹-isomer. ⁹-THC (10.0 mg/kg) produces strong StD, as defined by Overton (1971), since both this group and the barbiturate group reached the criterion within the first 10 training sessions. Time and dose testings suggest that stimulus properties of drugs vary in a quantitative way and that the calculated ED₅₀ values are mainly determined by the training dose used. It was found that the higher the training dose used the higher was the corresponding ED₅₀ value. Hashish smoke can maintain drug responding among THC-trained rats. A lowered content of brain catecholamines and/or serotonin, induced by AMPT (150 mg/kg) and PCPA (310–350 mg/kg), did not lessen ⁹-THC (2.5 mg/kg) discrimination.Portions of the results were presented at the Fourth Scandinavian Meeting on Physiology and Behavior, Oslo May 22–24, 1975.     

Unrestricted pore area (A0/Deltax) is a better indicator of peritoneal membrane function than PET

BACKGROUND: How to measure the peritoneal exchange in uremic patients treated with peritoneal dialysis (PD) is still a matter of controversy. Most clinics use the peritoneal equilibration test (PET), but from a theoretical point of view, it would be more appropriate to determine the "area" parameter, A0/Deltax. The latter reflects the total unrestricted pore area per centimeter diffusion distance and can be obtained by three-pore analysis using, for example, the PD capacity test (PDC). To evaluate the different estimates of peritoneal function, PET data and the A0/Deltax parameters were compared with the independently determined uptake of a small diffusible tracer, iohexol (molecular weight of 821 D), from the abdominal cavity to blood. METHODS: Fourteen patients on routine PD underwent determinations of PET and A0/Deltax using PDC. Within a month, the two-hour uptake of iohexol (6 mg/mL) was also determined from the plasma iohexol concentration following abdominal filling. RESULTS: A strong correlation was found between the rate of iohexol plasma concentration increase (k30-120) and A0/Deltax (A0/Deltax = 76,300. k30-120 - 1.56; r2 = 0.799; N = 14) for the 2 L dwell, while the PET data were far less related to iohexol uptake (D/DPurea, r2 = 0.409; D/Pcreatinine, r2 = 0.436; and D/D0glucose, r2 = 0.015, respectively). CONCLUSION: The "area" parameter, A0/Deltax, is superior to the more widely used routine PET as an indicator of peritoneal membrane function. In addition, the concept of A0/Deltax has the virtue of supplying quantitative information about the peritoneal pathophysiology and physiology.     

Involvement of deprivation and environmental lead in neural tube defects: a matched case-control study

OBJECTIVE: To analyse the prevalence of neural tube defects in small geographical areas and seek to explain any spatial variations with reference to environmental lead and deprivation. SETTING: The Fylde of Lancashire in the north west of England. DESIGN: Cases were ascertained as part of a prospective survey of major congenital malformations in babies born in the Fylde to residents there between 1957 and 1981. A matched case-control analysis used infants with cardiovascular system, alimentary tract, and urinary system malformations as controls. Conditional logistic regression was used to assess the effects of more than 10 micrograms/l lead in drinking water and the Townsend deprivation score. RESULTS: The prevalence of neural tube defects in 1957-73 was higher in Blackpool, Fleetwood, and North Fylde, whereas the three control groups showed no significant spatial variation. In 1957-81 mothers living in electoral wards with either a higher proportion of houses with more than 10 micrograms/l lead in the water or a higher deprivation score had a greater risk of having a baby with a neural tube defect. For spina bifida and cranium bifidum alone, this was also true. For anencephaly, deprivation was less important although the effect of lead was still seen. In some neural tube defects, lead may act independently of other possible factors associated with deprivation. It seemed unlikely that lead levels changed significantly during the survey. The percentage of houses with 10 micrograms/l or more of lead in the water in 1984-5 was similar to that found in Great Britain 10 years previously. CONCLUSION: There is evidence to suggest that lead is one cause of neural tube defects, especially anencephaly. This could link the known preventive actions of hard water and folic acid. Calcium is a toxicological antagonist of lead. One cause of a deficiency of folic acid is impaired absorption secondary to zinc deficiency, which may be produced or exacerbated by lead.     

Tuberous sclerosis complex and Wolff-Parkinson-White syndrome

This report highlights the association between tuberous sclerosis and Wolff-Parkinson-White syndrome. Ten patients with concurrent diagnoses of Wolff-Parkinson-White syndrome and tuberous sclerosis were identified. Wolff-Parkinson-White syndrome presented early in life, nine cases being diagnosed in the first year. Eight of the 10 cases were male. In eight cases, the syndrome was associated with supraventricular tachycardias, and in nine with cardiac rhabdomyomata. One child died from cardiac failure secondary to obstruction of the left ventricular outflow tract by a rhabdomyoma. Five of nine survivors showed resolution of Wolff-Parkinson-White syndrome on follow up. The accessory pathway was localised in nine patients from surface electrocardiograms: six children had left sided pathways and three had right sided pathways.