Prediction of gall-stone pancreatitis by computer.

The clinical features at presentation of 53 patients admitted with primary acute pancreatitis due to gall stones were compared with those of 31 patients in whom the disease was due to other causes. Between these two groups 10 significant differences existed. By listing the frequency of symptoms and signs for each group a computer data base was prepared and incorporated into a program used in the differential diagnosis of acute abdominal pain. A program written to predict the presence of gall stones in patients with acute pancreatitis was accurate in 92% of the patients studied. A predictive index devised from the presence of three of the significantly differing clinical features correctly identified 82% of patients with gall-stone pancreatitis. Predicting the presence of gall stones on admission by analysing the presenting symptoms and signs with a computer had an accuracy comparable to that of ultrasonography or radiology and may be of value in the management of patients with acute pancreatitis.     

The effect of several diphosphonates on acid phosphohydrolases and other lysosomal enzymes.

Diphosphonates are known to inhibit bone resorption in tissue culture and in experimental animals. This effect may be due to their ability to inhibit the dissolution of hydroxyapatite crystals, but other mechanisms may be important. Since lysosomal enzymes have implicated in the process of bone resorption, we have examined the effect of several phosphonates and of a polyphosphate (P20,2) on lysosomal hydrolases derived from rat liver and rat bone. Dichloromethylene diphosphonate strongly inhibited acid beta-glycerophosphatase (EC 3.1.3.2) and acid p-nitrophenyl phosphatase (EC 3.1.3.2) and to a lesser degree (in descending order) acid pyrophosphatase (EC 3.1.3.-), arylsulfatase A (EC 3.1.6.1), deoxyribonuclease II(EC 3.1.4.6) and phosphoprotein phosphatase (EC 3.1.3.16) of rat liver. Inhibition of acid p-nitrophenyl phosphatase and arylsulfatase A was competitive. Ethane-1-hydroxy-1, 1-diphosphonate did not inhibit any of these enzymes, except at high concentrations. Neither dichloromethylene diphosphonate nor ethane-1-hydroxy-1, 1-diphosphonate had any effect on beta-glucuronidase (EC 3.2.1.31), arylesterase (EC 3.1.1.2) and cathepsin D (EC 3.4.23.5). Of several other phosphonates tested only undec-10-ene-1-hydroxy-1, 1-diphosphonic acid inhibited acid p-nitrophenyl phosphatase strongly, the polyphosphate (P20, I) had little effect. Acid p-nitrophenyl phosphatase in rat calvaria extract behaved in the same way as the liver enzyme and was also strongly inhibited by dichloromethylene diphosphonate, but not by ethane-1-hydroxy-1, 1-diphosphonate. It is suggested that the inhibition of bone resorption by dichloromethylene diphosphonate might be due in part to a direct effect of this diphosphonate on lysosomal hydrolases.     

Chemical pathology of neurofibrils. Neurofibrillary tangles of Alzheimer's presenile-senile dementia.

A subcellular fraction enriched in twisted tubules was obtained by differential centrifugation of a homogenate of neurons isolated from areas of the brain with many neurofibrillary tangles from patients with Alzheimer's presenile-senile dementia. A unique protein (molecular weight 50,000 daltons) which does not co-migrate with either of the two tubulin monomers of the major neurofilament protein, both purified from human brain, was found in this subcellular fraction on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Similarly processed tissue from areas of the brain poor in neurofibrillary tangles contained low levels of this new protein. The new protein band could not be seen in control patients.     

The location of proteins labeled by the 125I-lactoperoxidase system in the NIL 8 hamster fibroblast.

NIL 8 hamster fibroblast cells were labeled by lactoperoxidase-catalyzed iodination. Their membranes were fractionated by sedimentation-rate and isopycnic zonal centrifugation. All the iodinated proteins except the very prominently labeled high molecular weight protein (greater than 200,000 daltons) were located in a fraction identified enzymically and compositionally as plasma membrane. The high molecular weight protein that was previously shown to be sensitive to virus transformation (Hynes, 1973) is concentrated in a very high density particle (rho equals 1.253-1.259) which contains mainly carbohydrate and protein and very low levels of lipid. 5'-nucleotidase was the only enzyme reproducibly demonstrated in this fraction, and electron micrographs revealed a predominantly amorphous morphology together with a few membraneous structures. The iodine label in this fraction was very sensitive to trypsinization prior to homogenization. All the available evidence indicates that this fraction is derived from the surface coat. Mitochondria, nuclei, and soluble protein were labeled to an insignificant extent. The presence of the iodinated surface proteins associated with the endoplasmic reticulum fraction is discussed in the light of these results.     

Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine

Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.     

Clearance of bacteria and non-antigenic markers following intra-uterine inoculation into maiden mares: Effect of steroid hormone environment

Uterine response to inoculation with Streptococcus zooepidemicus organisms (antigenic markers) and 15-mum microspheres and charcoal (non - antigenic markers) was determined in seasonally acyclic maiden mares treated with either progesterone (P) n = 4, estradiol (E) n = 4 or oil vehicle (C) n = 4. At 3, 7 and 15 d after inoculation with bacteria and the 2 non - antigenic markers, uteri were flushed and the clearance of these materials, as well as the number of white blood cells and immunoglobulin concentration, determined. P-treated mares had higher numbers of bacteria and IgA and a greater volume of purulent fluid in the uterus than E- or C-treated mares at 7 d after inoculation. Clearance of inoculated materials began within 2 h in E-treated mares, and the non-antigenic markers were completely cleared in E- and C-, but not in P-treated mares, in 3 d. This suggests that in the P-dominated uterus, reduced physical clearance may contribute to an increased susceptibility to uterine infection.     

Modeling of drug delivery into tissues with a microneedle array using mixture theory

In this paper, we apply mixture theory to quantitatively predict the transient behavior of drug delivery by using a microneedle array inserted into tissue. In the framework of mixture theory, biological tissue is treated as a multi-phase fluid saturated porous medium, where the mathematical behavior of the tissue is characterized by the conservation equations of multi-phase models. Drug delivery by microneedle array imposes additional requirements on the simulation procedures, including drug absorption by the blood capillaries and tissue cells, as well as a moving interface along its flowing pathway. The contribution of this paper is to combine mixture theory with the moving mesh methods in modeling the transient behavior of drug delivery into tissue. Numerical simulations are provided to obtain drug concentration distributions into tissues and capillaries.