Cardiotoxic effects of the combined use of caffeine and isoproterenol in the minipig

Beta agonists such as isoproterenol are widely used in the treatment of acute asthmatic attacks. It would not be unexpected that some patients receiving isoproterenol might have ingested caffeine as an over-the-counter drug or beverage. This study explores the possible interaction between these two drugs. Anesthetized minipigs were injected with 0.5 mg/kg caffeine iv followed by a 10-min infusion of 1 microgram/kg.min isoproterenol. Heart rate, EKG, respiration, and blood pressure were recorded continuously and the animals were sacrificed at 72 h. The two drugs in combination produced subtle changes in heart rate and blood pressure with significant alteration in the EKG tracing (premature ventricular contractions and extrasystoles). These changes persisted for 8 to 24 h. At autopsy both gross and microscopic lesions were noted in 10 of the 13 minipig hearts receiving the combination of drugs. This was not true of the six minipigs given only caffeine or the eight minipigs receiving only the infusion of isoproterenol. No changes in EKG tracings or pathologies were noted with caffeine and only two of eight animals infused with isoproterenol showed any lesions. Results indicate that doses of caffeine equivalent to that expected from drinking a cup of coffee appear to increase the toxicity of isoproterenol to a point that EKG changes and myocardial pathologies are observed.     

Brain neurotransmitter receptor alterations in offspring of rats exposed to phenobarbital, phenytoin or their combination during pregnancy

Neurotransmitter receptor binding was studied in the progeny of rats exposed to phenobarbital (80 mg/kg), phenytoin (80 mg/kg) or their combination daily from 5 to 20 days of gestation. At 22 days postnatally, female pups in all treated groups showed decreased binding of [3H]spiroperidol to striatal membranes. A decreased binding of [3H]diazepam to frontal cortical membranes was observed in the female pups of rats exposed to phenytoin or the combination. The Scatchard analysis of data from the affected groups revealed a decrease in the maximum number of dopamine and benzodiazepine receptor sites and no change in their affinities. The binding of [3H]spiroperidol or [3H]diazepam was not altered significantly in any of the drug-treated male pups. Also, no significant change in the binding of [3H]serotonin or [3H]quinuclidinyl benzilate to frontal cortical membranes was observed in any of the treated groups. At 60 days postnatally, no significant change in the binding of any of the above ligands was evident. The above prenatal drug exposures appear to cause transitory subsensitivity of dopamine and benzodiazepine receptors in rats.     

Morphology and ultrastructure of human vitreous fibers

Significant alterations in vitreous structure occur with aging and disease. There is controversy as to the nature of the normal structure of the vitreous and no studies have correlated macroscopic structure with ultrastructure in the same eyes. Twenty-eight fresh, untreated human eyes were examined after removal of the sclera, choroid and retina. Dark-field slit illumination of the whole vitreous revealed the presence of macroscopic fibrous structures. The fibers had an antero-posterior orientation with anterior insertions at the vitreous base and posterior insertions in the premacular vitreous cortex. Transmission electron microscopy demonstrated the presence of collagen fibrils and no membraneous structures. Parallel collagen fibrils packed in bundles were also detected. Macroscopic vitreous fibers most likely result from alteration of the hyaluronic acid-collagen complex with aggregation of collagen fibrils into bundles as seen on electron microscopy. Identifying the mechanisms underlying this process of fiber formation could clarify the pathogenesis of vitreous liquefaction and the pathophysiology of posterior vitreous detachment.     

Expression of HLA-DR antigens by thyroid cells: the effect of Graves' IgG

We have investigated factors which influence HLA-DR expression on thyroid cells. While bTSH (100 mU/ml) did not enhance HLA-DR expression, it increased when brought about by IFN-gamma. Graves' IgG showed a dose-dependent (0.1-2 mg/ml) increase in DR expression and at a concentration of 2 mg/ml prolonged the time for which DR was expressed. The pathway of DR induction by Graves' IgG apparently differs from that by IFN-gamma. The humoral response in Graves' disease, by inducing DR expression, may be instrumental in propagating thyroid specific autoimmunity.     

Cytoplasmic membrane potential of mouse lymphocytes is decreased by cyclosporins

Membrane potential of mouse lymphocytes was investigated in the presence and absence of cyclosporin A (CsA) and cyclosporin G (CsG) by flow cytometry and fluorescence spectroscopy. A carbocyanine dye, dihexyloxacarbocyanine iodide [DIOC6(3)], was applied as a membrane potential probe. A dose-dependent decrease in the membrane potential of T and B lymphocytes was observed in the presence of CsA and CsG. However, pretreatment of lymphocytes with insulin reduced the effect of the cyclosporins. Mobile ionophores, such as valinomycin, ionomycin and A23187 were less effective in changing the membrane potential of lymphocytes in the presence of CsA. The channel forming ionophore, gramicidin or high extra-cellular potassium concentration (160 mM) strongly reduced the membrane potential regardless of the absence or presence the CsA. These observations suggest incorporation of CsA into the cytoplasmic membrane causing changes in ion fluxes. Other reported biochemical effects of CsA may be secondary to the observed membrane potential changes. The membrane potential change induced by CsA may have selective biological consequences in a certain subpopulation of lymphocytes.     

Enterolith Ileus Resulting from Small Bowel Diverticulosis

Small intestine diverticula are infrequent. These acquired pulsion diverticula are postulated to be a result of intestinal dyskinesis. Usually asymptomatic, they can produce a variety of disorders such as malabsorption, hemorrhage, diverticulitis, and perforation. The rarest complication appears to be enterolith formation and obstruction. It is postulated that dyskinesis and stasis leads to bacterial overgrowth causing decomposition of bile salts allowing precipitation and concretion. Presented is an ileal obstruction from a small bowel enterolith. A literature review revealed 25 other cases of obstruction. Most of these cases were treated with simple removal, some with small bowel resection. Results are good and recurrences have not been observed.     

Relationship between plasma lipoprotein (a), apolipoprotein (a) phenotypes, and other coronary heart disease risk factors in a Melbourne South Asian population

BACKGROUND: High plasma lipoprotein(a) [Lp(a)] level is a strong and important risk factor for cardiovascular disease (CVD). Small-sized apolipoprotein(a) [apo(a)] isoforms (F, B, S1, and S2) are inversely correlated with the high levels of Lp(a) in plasma and significantly associated with CVD. Although the effects of apo(a) phenotypes and various risk factors on Lp(a) status in South Asian population may have been studied in other countries, there are no reports involving these risk factors in Australia. METHODS AND RESULTS: Factors contributing to variation in Lp(a) were surveyed in 402 (216 males and 186 females) South Asian Melburnians. There was a negative relationship between low alcohol beer per day and Lp(a) in men (P < 0.05). Approximately 21% of the variance of Lp(a) concentration in men and 6% in women were explained by age. Age was positively associated with Lp(a) concentrations in men but negatively in women. The most commonly occurring phenotype was apo(a) S3. In this phenotype, Lp(a) concentrations ranged from non-detectable to 811 mg/l. After adjusting for age, an inverse correlation was observed between Lp(a) concentration and apo(a) phenotypes (P < 0.01). CONCLUSIONS: Although Lp(a) has been reported to be genetically determined, there are clearly other factors contributing to variations in Lp(a) concentrations in a South Asian population.     

Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Dysregulation of neuropeptides may play an important role in aging‐induced impairments. Among them, pituitary adenylate cyclase‐activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue‐damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life and the well‐known general cytoprotective effects of PACAP lead to age‐related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre‐senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age‐related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal, and esophageal involvement. Mass spectrometry‐based proteomic analysis, reconfirmed with immunohistochemistry, revealed that apolipoprotein‐AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age‐related degeneration with amyloid deposits in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro‐inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene‐deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.