Pharmacoepidemiological Research on N-Nitrosodimethylamine-Contaminated Ranitidine Use and Long-Term Cancer Risk: A Population-Based Longitudinal Cohort Study.

N-Nitrosodimethylamine (NDMA), a carcinogenic chemical, has recently been identified in ranitidine. We conducted a population-based study to explore ranitidine use and cancer emergence over time. Using the Taiwan National Health Insurance Research Database, a population-based cohort study was conducted. A total of 55,110 eligible patients who received ranitidine between January 2000 and December 2018 were enrolled in the treated cohort. We conducted a 1:1 propensity-score-matching procedure to match the ranitidine-treated group with the ranitidine-untreated group and famotidine controls for a longitudinal study. The association of ranitidine exposure with cancer outcomes was assessed. A multivariable Cox regression analysis that compared cancer risk with the untreated groups revealed that ranitidine increased the risk of liver (hazard ratio (HR): 1.22, 95% confidence interval (CI): 1.09-1.36, p < 0.001), lung (HR: 1.17, CI: 1.05-1.31, p = 0.005), gastric (HR: 1.26, CI: 1.05-1.52, p = 0.012), and pancreatic cancers (HR 1.35, CI: 1.03-1.77, p = 0.030). Our real-world observational study strongly supports the pathogenic role of NDMA contamination, given that long-term ranitidine use is associated with a higher likelihood of liver cancer development in ranitidine users compared with the control groups of non-ranitidine users treated with famotidine or proton-pump inhibitors.

The quantitative estimation of microvessels in microvascular networks.

A novel method is presented that greatly facilitates the determination of vessel segment number and density in both simple and complex microvascular networks. This approach was applied to microvascular networks represented by the Bra-Ket operator technique and accurately predicted the number of vessel segments in both tree-branched and loop-branched (arcade) networks. The method was then applied to the complex hexagonal array network described by Engelson et al. for gastrointestinal mucosa and accurately yielded an average vessel segment number of three around each hexagonal loop. This new method may be used for conveniently estimating tissue microvascular densities, such as vessel rarefaction or proliferation, and for the modelling of microvascular networks.

Analysis of the current distribution in bone produced by pulsed electro-magnetic field stimulation of bone.

Pulsed electromagnetic stimulation is being increasingly used by orthopaedic surgeons to treat non-unions and congenital pseudoarthrosis. In this paper a theoretical model is developed to analyze the distribution of induced current in bone due to a pulsed electromagnetic field, produced by a pair of Helmholtz coils. The result shows that the induced current density is dependent of the electrical properties of bone, geometry of the coils and their location.

Wave propagation characteristics in long bones to diagnose osteoporosis.

A mathematical model of stress wave propagation in bone is developed assuming a long bone to be a thick-walled, long cylindrical shell filled with a fluid. The calculated phase and group velocities in adult human femurs were found to be a function of the wave number and they were different for population groups of above and below 55 yr of age. The velocities were also sex dependent, being different for males and females of the same age group. Diagnostic methods based on the measurement of wave propagation characteristics may potentially be used to measure the structural changes in long bones due to osteoporosis.

Thermal analysis of the bone surface induced by laser radiation.

High energy laser has emerged to be an important surgical tool in medical technology. However, the application of laser energy to drill or cut a bone is still in an experimental state. In order to estimate the adequacy of laser heating of bone surface and at the same time minimize the damage to the bone tissue, we developed a mathematical model of the temperature distribution in bone due to laser irradiation. The thermal analysis shows that the temperature distribution depends on several parameters, including the density, the specific heat, and the thermal conductivity of the osseous tissue.

Substance P-like immunoreactivity in rat and cat carotid bodies: light and electron microscopic studies.

Substance P-immunoreactive (SP-1) structures in the carotid bodies of rats and cats were examined with the light and electron microscopes. In both species SP-I varicose nerve fibers were located singly in the interstitial connective tissue in close association with blood vessels. They were small unmyelinated fibers enveloped in a common Schwann cell sheath with other SP-negative fibers. Some of SP-I fibers contained large dense-cored granules and small clear vesicles in addition to microtubules and mitochondria and probably represented nerve fiber varicosities. The latter often were found incompletely invested by Schwann cell sheaths. SP-fibers were found occasionally in the envelopes of supporting cells at the periphery of parenchymal cell groups. However, none of the nerve terminals making synaptic contacts with glomus cells exhibited SP-like immunoreactivity. In cat carotid bodies some glomus cells showed moderate to intense SP-like immunoreactivity. The intense SP-I glomus cells displayed numerous dense-cored vesicles of 85 to 140 nm in diameter and frequently showed synaptic contacts with SP-negative nerve terminals. In rat carotid bodies we were unable to detect consistent SP-immunoreactivity in glomus cells. Our results do not favor the hypothesis that SP is a neurotransmitter/modulator in the chemoreceptor afferents synapsing on glomus cells in either the cat or rat carotid body. However our results support the hypothesis that SP in cat glomus cells may play a role in the modulation of chemoreceptor activity.

A mathematical representation for vessel network III.

The loop vascular network is found frequently within biological tissue, but a schematic characterization of the loop vascular network is at present difficult to describe. The reason is that the topographical feature of vessel loop can change during maturation. In this article, we treat the mathematical representation of the loop vessel network, and discuss the application of this to the increased vascular resistance in hypertensive animals resulting from microvascular rarefaction. On the other hand, the number of regions into which the tissue plane is divided by n bifurcational tree branches is derived from recurrence relation.

Microvascular alterations in the one-kidney, one-clip renal hypertensive rat.

The microcirculation was studied in one-kidney, one-clip renal hypertensive rats ( 1KG ) and uninephrectomized controls at 4-6 and 8-10 wk postoperation. Under chloralose-urethan anesthesia the gracilis muscle was transilluminated in situ with a light pipe. Measurements of arteriolar and capillary density and arteriolar diameter were made in three consecutive states: innervated, denervated, and vasodilated with nitroprusside. Arteriolar wall-to-lumen ratio was measured after vasodilation. At 4-6 wk vasoconstriction was significantly greater in 1KG and vasodilated arteriolar diameter was significantly smaller, partially because of an elevated wall-to-lumen ratio. Capillary density in 1KG was reduced in the innervated and denervated states compared with controls. At 8-10 wk in the 1KG , arteriolar vasoconstriction was no longer significantly elevated. However, the vasodilated arteriolar diameter was smaller, wall-to-lumen ratio had increased further, and rarefaction of arterioles and capillaries was present. Thus, with time, structural mechanisms for increasing vascular resistance were seen to displace the active mechanism of vasoconstriction.

Mathematical modeling of capillary density.

Capillary density is important as a determinant for total oxygen transport to tissue. Because both capillary morphology and fiber composition vary considerably from muscle to muscle, measurement of capillary morphology and fiber composition vary considerably from muscle to muscle, measurement of capillary density alone cannot provide the detailed information necessary for analyzing physical phenomena. In this report we consider the capillary:fiber ratio, fiber types, fiber diameters, and fiber composition as components of a unit to express capillary density. We have applied the hexagonal fiber array model to calculate capillary density in cat and dog striated muscle and compared this with experimental data in the literature. The results indicate that this model may be useful for predicting capillary densities from simple biopsy procedures.

A mathematical representation of the microvascular network in the bat's wing.

We previously have published a description of a mathematical representation for general vascular networks. In this paper we will illustrate the application of this operator representation to the microvascular network found in the wing web of the bat. We will show that this method follows the rules of vector algebra, it can be used for determination of Orthogonality of two vectors, and can be used in calculating resistance through the microvascular network. The method can also be used for representation of vessel networks in three dimensions.

A mathematical representation for vessel networks II.

The topographical features of vessel networks can influence the red cell hematocrit, red cell spacing and flow pattern, either directly or indirectly at any level from arteriole to venules. In this article, we continue to treat the mathematical representation for vessel networks. We have treated a vessel segment as a vector quantity and applied this representation to central artery of the gyrus in human brain. The flow mechanism of arteriolar arcades in the bat wing is discussed in this article.

Capillary pressure gradients in cremaster muscle of normotensive and spontaneously hypertensive rats.

The purpose of this investigation is to test the hypothesis that capillary pressure gradients are elevated in spontaneously hypertensive rats (SHR) and to determine the mechanism for the elevation. The cremaster muscle was prepared for microscopic examination under chloralose-urethane anesthesia in seven SHR and eight Wistar-Kyoto (WKY) rats 4-6 weeks of age. Capillary hematocrit, diameter, and red cell velocity were measured. Capillary flow induced by a time-varying pressure gradient was treated mathematically. A finite Hankel transformation was applied to the Navier-Stokes equation for capillary vessels. The solution was expressed as a Fourier-Bessel series, and the fluctuation of capillary flow induced by a time-varying pressure gradient was studied. It was shown that if the velocity fluctuation depended only on the pressure gradient, then the velocity fluctuation would be diminished almost instantly after the capillary started to flow. Capillary pressure gradient and shear stress were evaluated according to two different flow models, Newtonian and Casson. The capillary viscosity was obtained from the capillary hematocrit based on the empirical correlation of viscosity vs hematocrit. Calculations based on both flow models indicate that the capillary pressure gradient and shear stress of SHR is higher than in WKY, especially in vessels near 6 microns in diameter. The elevated pressure gradient is due to a combination of reduced capillary density, causing a higher red cell velocity and a tendency toward smaller capillary diameters in the SHR. Capillary hematocrit and viscosity were not elevated in the SHR.

Development of microvascular rarefaction in the spontaneously hypertensive rat.

Using stereological methods in vivo, we have investigated the rarefaction of arterioles and capillaries in male spontaneously hypertensive rats (SHR) and the Wistar-Kyoto controls (WKY) at 6-8, 12-14, and 16-18 wk of age. Under chloralose-urethan anesthesia, the gracilis muscle was isolated for microscopic observation. Vessel length and surface area per unit volume of tissue (density) were determined during three consecutive states: innervation, denervation, and vasodilation with nitroprusside. Arteriolar wall-to-lumen ratio was measured after vasodilation. At 6-8 wk capillary density was reduced in the SHR. At 12-14 wk there was a reduction of arteriole and capillary density under innervated and denervated conditions but not after vasodilation (a state of functional rarefaction). At 16-18 wk there was a reduction of arteriolar and capillary density under all three conditions (a state of anatomical rarefaction). At 12-14 and 16-18 wk there was an elevated level of arteriolar vasoconstriction in the SHR that was masked in any one state by the closure of the smaller arterioles. Arteriolar wall-to-lumen ratio was not elevated in the SHR at any time. Arteriolar closure was not reversed by acute denervation.

Dephosphorylation of glycogen synthase in rat heart extracts by E. coli alkaline phosphatase. Use of an exogenous phosphatase to study substrate-mediated regulation of dephosphorylation.

Regulation of the dephosphorylation of glycogen synthase in extracts from rat heart has been studied by adding exogenous phosphatase to the extract. These experiments were possible only because the endogenous protein phosphatase activity of the extract could be inhibited by KF under conditions where alkaline phosphatase activity was not. The concentration of substrate (glycogen synthase from the heart extract) and catalyst (purified E. coli alkaline phosphatase) could be varied independently, by adding known amounts of alkaline phosphatase to the KF-containing heart extracts. Alkaline phosphatase could completely dephosphorylate glycogen synthase while phosphorylase was unchanged. The rate of dephosphorylation was proportional to both the concentration of alkaline phosphatase added to the tissue extract and the amount of glycogen synthase in the extract. The Km for glycogen synthase was close to the concentration found in heart tissue. The Km and the maximum rate of dephosphorylation were both dependent on the phosphorylation state of the glycogen synthase. Less phosphorylated enzyme forms were dephosphorylated faster. These results indicate the necessity for precise control of many variables in studying the rate of glycogen synthase dephosphorylation. Alkaline phosphatase-catalyzed dephosphorylation could be inhibited by physiological concentrations of glycogen. Glycogen synthase dephosphorylation in extracts from fasted-refed rats was less sensitive to glycogen inhibition than in extracts from normal animals. The phosphorylation state of the glycogen synthase in these animals was assessed by kinetic studies to show that differences in phosphorylation state probably could not account for the observations. Fasting led to a decreased rate of dephosphorylation of glycogen synthase due to both an apparent change in kinetic properties of glycogen synthase as a substrate for alkaline phosphatase, and an increased inhibitory effect of glycogen. Stable modifications of glycogen synthase caused by altered nutritional states in the animals are thought to produce these effects.

Microvascular rarefaction in spontaneously hypertensive rat cremaster muscle.

We have investigated the neural and local vascular effects on vessel length and surface area per unit volume in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) by quantitative stereology. Fourteen SHR and 14 KWY (70-130 g) were anesthetized with chloralose-urethan, and the cremaster muscle was exposed for microscopic observation. The large arterioles entering the muscle were termed the first order, and consecutive branches were termed second-, third-, and fourth-order arterioles. The data were collected in three consecutive states: innervated, denervated, and vasodilated with nitroprusside. The third- and fourth-order arteriole and capillary lengths per unit volume in the SHR were less than those of the WKY in all three states. The vessel surface area per unit volume was also reduced in the SHR. Denervation and sodium nitroprusside (Nipride) resulted in larger percent increases in vessel length and surface area in the SHR than in the WKY. We conclude that in the SHR cremaster muscle there are fewer terminal arterioles and capillaries anatomically present, and, under resting conditions, a greater percentage but similar absolute number of them are closed to flow.