Separation of the Toxic and Glutathione-Enhancing Effects of the Naturally Occuring Nitrile, Cyanohydroxybutene

Cyanohydroxybutene (CHB) is reported to be hepatotoxic in maleFischer 344 rats at an oral dose of 300 mg/kg and, while nolonger hepatotoxic, pancreatotoxic at 200 mg/kg. In addition,the 200 mg/kg dose causes a persistent elevation in hepaticand pancreatic glutathione (GSH). This study was conducted tode termine if smaller doses of CHB could cause GSH elevationin the absence of toxicity. A single oral dose of 100 mg/kgor multiple lower doses (50 mg/kg daily for 3 days or 30 mg/kgfor 6 days) caused a significant and persistent increase inpancreatic GSH, although hepatic levels were unchanged. Tenmilligrams per kilogram, even daily for 24 days, was withouteffect on hepatic or pancreatic GSH. Neither a single oral doseof 100 mg/kg nor multiple lower doses were associated with toxicity.However, when either 100 or 50 mg/kg were administered intravenously,pancreatic apoptosis was observed. In animals dosed with 100mg/kg iv, mixed histiocytic and suppurative inflammation andfrank pancreatic necrosis also developed and were associatedwith elevated plasma lipase and amylase. The animals receivingCHB intravenously also exhibited elevated GSH levels in bothpancreas and liver. This study shows that oral doses between30 and 100 mg CHB/kg can be used to elevate GSH levels withoutany pancreatotoxicity. However, a single 50 mg CHB/kg dose givenintravenously causes apoptosis, while 100 mg/kg causes severepancreatotoxicity with necrosis.     

Immunological properties of recombinant proteins of the transmission blocking vaccine candidate, Pfs48/45, of the human malaria parasite Plasmodium falciparum produced in Escherichia coli

A precondition for the development of a transmission blocking vaccine based on the sexual stage-specific surface antigen Pfs48/45 of Plasmodium falciparum is its heterologous synthesis in a native state. Here we describe the production of recombinant Pfs48/45 in Escherichia coli . Two recombinant proteins, of which one is a glutathione-S-transferase fusion protein, were produced. Enzyme-linked immunosorbent assays showed that at least a subfraction of the recombinant proteins had a conformation capable of binding transmission blocking monoclonal antibodies. However, despite the fact that both proteins were very immunogenic, they did not induce transmission blocking immunity in mice or rabbits. Immunological studies with congenic mouse strains demonstrated that immune responses could be boosted with gametocyte extracts and were not restricted to a particular class II major histocompatibility complex haplotype .     

POSTNATAL DEVELOPMENT OF RENAL FUNCTION IN PRE-TERM AND FULL-TERM INFANTS

ABSTRACT. Aperia, A., Broberger, B., Klinder, G., Herin, P. and Zetterström, R. (Department of Paediatrics, Karolinska Institute, St. Göran's Children's Hospital, Stockholm and Huddinge Hospital, Huddinge, Sweden). Postnatal deveopment of renal function in preterm and full-term infants. Acta Paediatr Scand, 70:183, 1981. –This study has been designed to examine the effect of gestational age (GA) on the postnatal development of renal function and has been performed in pre-term (PT) infants (GA=30–34 weeks) and in full-term (FT) infants (GA=39–41 weeks). Postnatal age has ranged from 1–35 days. From 8 hour urine samples collected after spontaneous voiding and a capillary blood sample, determinations have been made of the clearance of creatinine (C_Cr), the fractional excretion of β₂-microglobulin (FE_β2) and the fractional excretion of sodium (FE_Na). In some infants receiving fluid parenterally, simultaneous determinations were made of the clearance of creatinine and inulin. As judged from this study, C_Cr is a reliable indicator of the glomerular filtration rate (GFR). GFR was almost the same in newborn PT and FT, but from 0.3–1 week of age GFR increased significantly more rapidly in FT than in PT. From 1–5 weeks of age GFR increased at approximately the same rate in PT and FT infants. The absolute value for GFR in 3–5 weeks old infants was lower in PT than in FT. FE_β2 was higher in PT than in FT infants during the entire first month of life and FE_Na was higher in PT than in FT infants during the first week of life, suggesting a glomerular tubular imbalance at least at the level of the proximal tubule in PT infants. It is concluded that different stages of maturation will alter the preconditions for the renal adaptation to extrauterine life during at least the first month of life. Therefore special attention must be paid to the limited renal function in PT during their entire first month of life.     

Immunoglobulin G in cystic lesions of rat enamel organ following fluoride intoxication

Fluoride given as a high single dose to young rats with developing molars has earlier been shown to cause subameloblastic cysts with disorganized ameloblasts in the cystic wall and an irregular mineralization pattern of the underlying enamel. In the present study irnmunohist-ochemistry has been employed to determine if an increased permeability of the enamel organ occurred at the areas of cell disturbances. For this purpose 5-day-old rats were injected with 60 mg sodium fluoride per kg body weight. They were decapitated after 24 h, the maxilla prepared histologically and paraffin sections incubated for the demonstration of IgG according to the avidin-biotin-peroxidase complex method. Staining for IgG was present in the cystic lumina and in areas of disorganized ameloblasts. No reaction was observed in areas of unaffected ameloblasts. It was suggested that the fluoride-induced cell injury increased the permeability of the ameloblastic cell layer. Diffusion of IgG and most likely other substances as well, through the ameloblastic layer may have contributed to cyst formation and to the irregular mineral deposits that have been found in the ameloblastic layer and at the enamel surface.     

Construct validity of the Capacity Profile in preschool children with cerebral palsy

The Capacity Profile (CAP) classifies additional care needs, subdivided into five domains of body functions (physical health, motor, sensory, mental, and voice/speech) of children with stable conditions. Construct validity of the CAP was established in 72 children (56 males, 16 females) with cerebral palsy (CP); median age 2 years 7 months, range 2 years 6 months to 3 years; 34 unilateral and 37 bilateral spastic-type CP, one dyskinetic-type CP. Gross Motor Function Classification System (GMFCS) classification was 24 in level I, eight in level II, 18 in level III, 14 in level IV, and eight in level V. All CAP domains were significantly associated ( p <0.001) with the Functional Skills (rho=−0.42 to −0.85) and Caregiver Assistance scales (rho=−0.42 to −0.82) of the Dutch Paediatric Evaluation of Disability Inventory. The CAP-motor domain and GMFCS were strongly correlated (rho=0.91, p <0.001). Stepwise regression analysis demonstrated that the CAP domains contributed 74% to mobility (CAP-motor 66%, mental 6%, voice 2%); 75% to self-care (CAP-voice 61%, mental 12%, physical 2%); and 70% to social functionality (CAP-mental 68%, voice 2%). CAP demonstrated good construct validity in young children with CP. The independent contribution of CAP domains to daily function underscores the importance of comprehensive assessment with regard to all domains of body functions in heterogeneous conditions like CP.     

Alcoholism and the Patterning of Outcome: a multivariate analysis

This study takes a particular data set deriving from 10-year follow-up information on 68 male alcoholics as basis for exploring patterns of outcome in multivariate terms. A Principal Components Analysis demonstrates that degree of dependence is intrinsic to the patterning of outcome. The overall relationship between dependence and holistic outcome is a ‘Janus’ effect: high dependence may be related either to good or to bad outcome in different circumstances. When there is good outcome in terms simply of abstinence, dependence then further predicts within abstinent patients the overall quality of outcome which will be achieved. The need for a multivariate model is underlined.     

Diagnostic Specificity of Sucrose Hemolysis Test for Paroxysmal Nocturnal Hemoglobinuria

The diagnostic specificity of the various modifications of the sucrose hemolysis test for PNH was examined in detail. In whole blood screening tests thegreatest specificity was achieved using citrated or oxalated blood and roomtemperature incubation (23°). Defibrinated whole blood should not be usedsince "false positive" hemolysis may occur in blood disorders other than PNH.Mechanisms were suggested for this phenomenon. The validity of the confirmatory sucrose hemolysis test employing normal serum was further reported.Because of the clear, colorless character of serum-sucrose mixtures, an insignificant degree of hemolysis (i.e., less than 5%) is more readily visible thanin other PNH hemolytic tests employing undiluted serum. Definitive instructions and criteria for interpretation were given for both the whole bloodscreening test and the confirmatory sucrose hemolysis test.

Submitted on June 18, 1969 Accepted on December 8, 1969     

Urinary excretion of prostaglandin F2α and 6-keto-prostaglandin F1α during volume expansion in man

Renal function and the urinary excretion of immunoreactive prostaglandin F_2α (PGF_2α) and 6-keto-prostaglandin F_1α (6-keto-PGF_1α) were investigated during volume expansion (VE) in 9 healthy young adults. The studies were started after at least 17 h of food and fluid deprivation. Volume expansion (3% of body weight) was achieved by a continuous infusion of Ringer's solution (0.22 ml/kg/min). This increased the urinary excretion of sodium from 195±25 to 714±55 μmol/min/1.73 m²(mean ± S.E.) and decreased the excretion of potassium by 24% and plasma renin activity by 60% (P<0.01). The clearance of inulin increased slightly (from 102.4±3.7 to 114.5±6.2 ml/min/1.73 m², P<0.025), whüe clearance of PAH did not change. The excretion of immunoreactive PGF_2α decreased in 8 out of 9 individuals during VE, from 1.58±0.15 to 0.97±0.10 ng/min/1.73 m²(P<0.01). In contrast, excretion of immunoreactive 6-keto-PGF_1α increased in 8 out of 9 subjects, from 2.32±0.20 to 3.47±0.48 ng/min/1.73 m²(P<0.05). Urinary excretion of PGF_2α and 6-keto-PGF_1α may reflect renal synthesis of prostaglandins (PGs) and prostacyclin (PGI₂), respectively. The results indicate that synthesis of PGs is decreased and that of PGI₂ is increased during VE in man. However, no simple relationship could be found between the prostaglandins and the renal functional parameters.     

Quantitative Comparison of Temporal and Spatial High-Resolution Recordings of Terminal QRS

Beat-by-Beat Recording of Terminal QRS. Introduction: Beat-by-beat recordings of quasiorthogonal leads were performed in 82 normal subjects (35 male and 47 female) with normal standard electrocardiograms (ECGs) in order to: (1) establish normal values for parameters that were similar to those used in signal-averaged ECG; (2) compare these data with the signal-averaged ECG; and (3) assess the noise level in beat-by-beat recording. Methods and Results: Low-noise recordings were achieved by special instrumentation, preparation of subjects, and screening recording sites for an optimal magnetic field at 60 Hz or its harmonics without using a shielded room. Using a 40-Hz bidirectional high-pass filter, 95% of normal subjects had a beat-by-beat duration of vector magnitude complex ≤ 107 msec, a duration of low-amplitude signal under 40 μV ≤ 37 msec, and a root mean square (RMS) voltage of last 40 msec ≥ 24.1 μV. Significant difference was found in duration of vector magnitude complex (P < 0.0001) between gender groups; this difference disappeared after normalization for height (P > 0.3). Although the beat-by-beat and signal-averaged data were highly correlated in all three parameters, the beat-by-beat recordings exhibited a shorter duration of low-amplitude signal (P < 0.0004) and a higher RMS voltage of last 40 msec (P < 0.002), and no significant variation in duration of vector magnitude complex (P > 0.2). The mean RMS noise in the vector magnitude lead from the normal group was 1.52 ± 0.65 μV (mean ± SD) while over 80% of the subjects had RMS noise under 1 μV in an individual lead. Conclusion: The normal values from beat-by-beat recordings are correlated to but different from those of signal-averaged ECGs. Every-beat high-resolution recordings of terminal QRS are stable and reproducible in normal subjects. Also, the use of individual lead (s) with lower noise is recommended for better detection of low-level terminal QRS. (J Cardiovasc Electrophysiol, Vol. 3, pp. 109–118, April 1992)