A gravimetric assessment of the Gotthard Base Tunnel geological model: insights from a novel gravity terrain-adaptation correction and rock physics data.

The Gotthard Base Tunnel (GBT) is a 57 km long railway tunnel, constructed in the Central Alps in Switzerland and extending mainly North-South across numerous geological units. We acquired 80 new gravity data points at the surface along the GBT profile and used 77 gravity measurements in the tunnel to test and constrain the shallow crustal, km-scale geological model established during the tunnel construction. To this end, we developed a novel processing scheme, which computes a fully 3D, density-dependent gravity terrain-adaptation correction (TAC), to consistently compare the gravity observations with the 2D geological model structure; the latter converted into a density model. This approach allowed to explore and quantify candidate rock density distributions along the GBT modelled profile in a computationally-efficient manner, and to test whether a reasonable fit can be found without structural modification of the geological model. The tested density data for the various lithologies were compiled from the SAPHYR rock physical property database. The tested models were evaluated both in terms of misfit between observed and synthetic gravity data, and also in terms of correlation between misfit trend and topography of the target profile. The results indicate that the locally sampled densities provide a better fit to the data for the considered lithologies, rather than density data averaged over a wider set of Alpine rock samples for the same lithology. Furthermore, using one homogeneous and constant density value for all the topographic corrections does not provide an optimal fit to the data, which instead confirms density variations along the profile. Structurally, a satisfactory fit could be found without modifying the 2D geological model, which thus can be considered gravimetry-proof. From a more general perspective, the gravity data processing routines and the density-dependent corrections developed in this case study represent a remarkable potential for further high-resolution gravity investigations of geological structures. Supplementary Information: The online version contains supplementary material available at 10.1186/s00015-022-00422-z.

An historical review of rheumatoid arthritis treatment: 1948 to 1952.

OBJECTIVES: The early responses by practicing physicians to the discovery of the effect of cortisone (compound E) and adrenocorticotropic hormone (ACTH) on acute rheumatoid arthritis in 1948 and their reactions to the drugs' scarcity have been reviewed. METHODS: Review of the relevant literature in American, British, and European medical journals and some newspapers. RESULTS: Whereas the effect of the compound E and ACTH was stunning, their scarcity made them unavailable to most physicians. Nevertheless, practicing physicians took a lively interest in the new therapy, as witnessed by the large number of letters with comments and questions to professional journals from all over the world. As expected, most of these were about attempts to find a substitute for cortisone or a way to release it endogenously to a sufficient degree. A few alternative therapies were suggested too, some quite unorthodox. A lively interest was shown by the general public. CONCLUSIONS: No alternative therapy recommended to treat acute rheumatoid arthritis in lieu of cortisone proved to be effective. The era of scarcity was ended by the discovery of a more efficient method to manufacture cortisone.

Role of modeling in the design of experiments in carbohydrate metabolism.

Most publications on modeling present only the final product without describing the details as to how they were developed and tested. It is, however, by model development and testing that the true power of modeling as a research tool reveals itself. The purpose of this paper is to present a "behind the scenes" look at a set of experiments designed to study carbon atom transport in gluconeogenesis. In particular, it will be shown how the development of one model led to hypotheses for which another set of experiments was designed. The model which resulted from the second study contained in turn a number of new hypotheses for which further experiments remain to be designed. The second model supported the findings of the first, and yielded deeper insights into the exchange of carbon atoms among three metabolites. It is hoped this illustration will encourage other investigators to take advantage of the utilitarian value of modeling not only as a parameter generating tool, but also as a true research tool which can aid significantly to extract more information from available data.

Effect of stress on glucoregulation in physiology and diabetes.

To examine the glucoregulatory responses to stress and their impact on diabetes, we used the following models of stress: A) Hypoglycemia; B) Epinephrine infusion; C) intracerebroventricular (ICV) injection of carbachol, an analog of acetylcholine. A) Hypoglycemia induces release of all counterregulatory hormones. During acute hypoglycemia, glucose production increases initially mainly due to glucagon release but eventually also due to a very large increment in catecholamines. In newborn dogs, neither epinephrine nor glucagon respond to a decrease in plasma glucose. This lack of a safeguard against hypoglycemia may indicate that the brain in pups is less dependent on a normal supply of glucose as a fuel, than in adult dogs. Counterregulation is enhanced when the effects of endogenous opiates are blocked by naloxone, indicating that endogenous opiates play a regulatory role during hypoglycemia. However, beta-endorphins which can be released with epinephrine during various stress situations, potentiate the peripheral effect of epinephrine. Glucoregulatory responses, even to slight changes in plasma glucose, are greatly enhanced during glucocorticoid treatment. This apparently reflects the greater sensitivity of the liver to glucagon. In diabetic dogs, similar to human diabetics, the glucagon response is abolished and the response of the catecholamines is partially decreased. On the basis of histological studies, we proposed that the deficient glucagon response in diabetes could be related to an increase in the somatostatin-glucagon ratio in the diabetic pancreas. This ratio is further augmented when normoglycemia is maintained with insulin. In response to a decrease in plasma glucose, there is a biphasic increment in glucose production in normal dogs, which is missing in diabetes. When normoglycemia is restored in diabetic dogs with phlorizin treatment, the second but not the first increment in glucose production is restored. We postulated, therefore, that the toxic effect of hyperglycemia, in addition to the lack of glucagon response, is the main reason why in diabetes, glucose production cannot respond promptly to a decrease in plasma glucose. The low rate of metabolic clearance of glucose seen in diabetes in the post-absorptive state, also reflects, at least in part, the toxic effect of glucose, because with acute normalization of glucose with phlorizin, metabolic glucose clearance substantially improves. Hyperglycemia is the main reason for the decreased number of glucose transporters in diabetic muscle. B) Epinephrine infusion in normal dogs mimics some effects of stress, in that it increases glucose production, inhibits metabolic glucose clearance and increases lipolysis. These metabolic effects of epinephrine are independent of glucagon release.(ABSTRACT TRUNCATED AT 400 WORDS)

Distribution and kinetics of glucose in rats analyzed by noncompartmental and compartmental analysis.

The steady-state kinetics and distribution of glucose were assessed using noncompartmental and various two-compartment models in rats that were infused with insulin (+/- euglycemic clamping), methylprednisolone (MP), or phlorizin (PHL) as well as rats injected with protamine-zinc-insulin (PZI) or rendered diabetic. Decreases in clearance of glucose (PCR) were greatest with insulin infusion, followed by PHL, MP, and PZI treatments. PCR decreased in diabetes to 25% of normal. With hyperinsulinemia and euglycemia, turnover rates were 1.18 times the rate of glucose infusion. In normal rats the ratio of the contents of the two compartments was 0.6-0.8 (depending on the model). Significant increases, of between 2.8 and 5.2, were observed with insulin infusion and between 0.8 and 1.8 with PHL, again depending on the model. Because PHL-induced changes in PCR are renal, these data suggest that variations in glucose distribution depend on changes in PCR as well as insulin. The intercompartmental rate constant decreased, and the noncompartmental volume of distribution increased to reflect the above changes. In non-steady-state studies, glucose release increased in response to insulin but not to PHL in contrast to other species.

Phlorizin-induced normoglycemia partially restores glucoregulation in diabetic dogs.

The plasma concentration of glucagon (IRG), catecholamines, and hepatic glucose production (Ra) were followed in insulin-induced hypoglycemia in dogs before (normal) and at 14-21 and again at 89-119 days after the injection of alloxan (diabetic). Some diabetic dogs were also tested when euglycemia was restored by phlorizin. In the normal state plasma IRG and epinephrine were raised by a factor of 3 and 15, respectively. Ra increased in two phases, an early peak (350% basal) was followed by a plataeu at about twice basal. In diabetes, irrespective of its duration, plasma IRG was decreased in hypoglycemia, and the rise in plasma epinephrine was significantly reduced. Ra remained unchanged. In phlorizin-treated euglycemic diabetic dogs plasma IRG fell, and the response in plasma epinephrine remained blunted. There was no early rise in Ra, but the same elevated plateau was reached at the same time as in normal animals. In conclusion, the following is observed in diabetic dogs. 1) The sensitivity of alpha-cells to insulin is maintained, but that to hypoglycemia is lost. The concentration of plasma catecholamines is raised less than in normals. With no increase in plasma glucagon this rise is not sufficient to increase Ra. 2) Restoration of euglycemia with phlorizin does not restore normal IRG and epinephrine responses to hypoglycemia but restores the delayed increase of Ra. Thus the restoration of euglycemia in severely diabetic dogs partially restores the responses of the liver, but not of the alpha-cell or sympathetic discharge, to hypoglycemia.

Possible interactions between antibiotics and oral contraceptives.

The incidence and manifestation of drug interaction decreasing ther action of contraceptive tablets have been examined in 79 women receiving antibiotic therapy concurrently with the use of oral contraceptives. The antagonistic interaction of antibiotics manifested itself in intermenstrual spotting, rarely in break-through bleeding, but it did not completely inhibit the contraceptive action (pregnancy). Drug interaction occurred individually and, in the majority of cases, it showed reciprocal relation to the hormone content of the used oral contraceptive. Though the exact mechanism of interaction is not known, it has to be considered in the course of therapy since both drug types are widely used.

Gluconeogenesis from glycine and serine in fasted normal and diabetic rats.

1. Non-anaesthetized normal and diabetic rats were fasted for 1 day, and [U-14C]glycine, or [U-14C]serine, or [U-14C]- plus [3-3H]-glucose was injected intra-arterially. The rates of synthesis de novo/irreversible disposal for glycine, serine and glucose, as well as the contribution of carbon atoms by the amino acids to plasma glucose, were calculated from the integrals of the specific-radioactivity-versus-time curves in plasma. 2. The concentrations of both glycine and serine in blood plasma were lower in diabetic than in fasted normal animals. 3. The rates of synthesis de novo/irreversible disposal of both amino acids tended to be lower in diabetic animals, but the decrease was statistically significant only for serine (14.3 compared with 10.5 mumol/min per kg). 4. Of the carbon atoms of plasma glucose, 2.9% arose from glycine in both fasted normal and diabetic rats, whereas 4.46% of glucose carbon originated from serine in fasted normal and 6.77% in diabetic rats. 5. As judged by their specific radioactivities, plasma serine and glycine exchange carbon atoms rapidly and extensively. 6. It was concluded that the turnover of glycine remains essentially unchanged, whereas that of serine is decreased in diabetic as compared with fasted normal rats. The plasma concentration of both amino acids was lower in diabetic rats. Both glycine and serine are glucogenic. In diabetic rats the contribution of carbon atoms from glycine to glucose increases in direct proportion to the increased glucose turnover, whereas the contribution by serine becomes also proportionally higher.

Glucose and lactate turnover and gluconeogenesis in chronic metabolic acidosis and alkalosis in normal and diabetic dogs.

The turnover rate of glucose, the irreversible disposal rate of lactate, and the rate of gluconeogenesis from lactate were calculated by tracer methods in four normal and four alloxan-diabetic dogs under control conditions as well as in chronic, stable metabolic acidosis and alkalosis. Acidosis was produced by feeding dogs 0.8-1 g.kg-1.day-1NH4Cl over 1 week, alkalosis was produced by feeding dogs a chloride-free diet and injections of furosemide. Mean plasma pH in the three states were 7.28 +/- 0.013, 7.40 +/- 0.024, and 7.51 +/- 0.015 in normal dogs, and 7.22 +/- 0.025, 7.42 +/- 0.009, and 7.49 +/- 0.002 in the diabetic dogs. Respective mean plasma bicarbonate levels were 14.6 +/- 0.88, 22.0 +/- 0.80, and 32.4 +/- 1.88 mequiv. in normal dogs, and 12.3 +/- 1.30, 22.6 +/- 0.66, and 35.0 +/- 1.14 mequiv. in diabetic animals. In normal dogs shifts in acid-base balance had no effect on the level of plasma glucose or the turnover rate of glucose. In diabetic dogs plasma glucose level was significantly elevated by alkalosis. Plasma lactate was positively correlated with plasma pH (r = 0.69, p less than 0.01) and was in general higher in diabetic than in normal animals. The increment in concentration was due to a decreased clearance of lactate from the plasma. The irreversible disposal rate was not changed by the acid-base status. Whereas a larger fraction of lactate removed from the plasma appeared in glucose in diabetic animals, this fraction was not changed significantly by shifts in the acid-base status.(ABSTRACT TRUNCATED AT 250 WORDS)

Gluconeogenesis from acetone in diabetic rats.

Previous investigations have demonstrated that acetone is a true, if minor precursor of glucose in vivo. In diabetic rats 1.30% of the carbon atoms of circulating glucose arises from acetone, whereas 0.67% does in normal 3-day fasted animals. Calculated from these fractions and the turnover rate of glucose, 48 micrograms/kg. min acetone-carbon is converted to glucose-carbon in diabetic and 16 micrograms/kg. min in normal rats. In both groups of rats the labelling of plasma lactate was stronger than that of glucose. In view of these results we conclude that: the transfer of C-atoms from acetone to glucose increases in diabetes; acetone remains a minor source of glucose even in ketonemic diabetic rats.

Influence of hormonal imprinting on hormone level. Permanent receptor damaging effect of pituitary hormones administered to newly-hatched cockerels.

The overlapping effect of TSH and FSH on the gonad and on the thyroid gland can be demonstrated in cockerels even at the age of five weeks. These hormones influence the secretion of testosterone in a similar way and to a similar extent, while on the thyroxine level the influence of the specific hormone is more pronounced. Neonatal FSH and TSH treatment considerably decreased the basal testosterone level measured at the age of five weeks. Neonatal FSH treatment increased the basal T4 level while TSH treatment decreased it. The effect of TSH treatment administered at the age of five weeks in increasing the testosterone level was weakened after neonatal pretreatment with any iodine hormone. The effect of TSH treatment could only be inhibited by neonatal FSH pretreatment. Neonatal pretreatment with any of the trophormones caused a diminution of the T4 level augmenting of FSH and TSH administered at the age of five weeks.

The effect of insulin-induced hypoglycaemia on the secretion of glucagon and hepatic glucose production in pancreatectomized dogs.

The concentration of plasma glucose in insulin deprived pancreatectomized dogs was decreased from the basal 385 +/- 44 to 65 +/- 12 mg/dL by the infusion of 7 mU X kg-1 X min-1 insulin. During the infusion, the plasma concentration of immunoreactive glucagon (IRG) did not change and hepatic glucose production was decreased. This is in contrast to earlier findings in alloxan diabetic dogs in which plasma IRG decreased in hypoglycaemia. The hypothesis is put forward that, in contrast to pancreatic alpha cells in which the effect of insulin prevails, neither insulin nor a decrease in the ambient concentration of glucose exerts any effect on the secretion of glucagon from extrapancreatic alpha cells.

Susceptibility of the human promyelocytic cell line HL-60 to an endogenous antileukaemic factor in suspension cultures.

HL-60 human leukaemic cell line a suitable homogeneous target population for the selective endogenous inhibitor of myelopoiesis, isolated in our laboratory, was submitted to multiparameter analysis of cell proliferation in suspension cultures. As detected by 3H-TdR incorporation, a single dose of the regulator elicited a 6 to 8 hours arrest of DNA synthesis. The inhibition could be prolonged by repeated applications. As affected by the factor, alteration of population kinetics is characterized, revealed by flow cytofluorometric analysis, in G1 arrest of a fraction of cells, and diminishing those in hyperdiploid and tetraploid stage. 51Cr-release detection of vitality proved, that the endogenous factor, chemically determined as nucleopeptide, affected non-toxically and reversibly HL-60 cell proliferation.

Glucoregulation in alloxan-diabetic dogs.

In order to establish whether a prolonged subnormal secretion of insulin may affect glucoregulation against hypoglycemic stimuli, the level of plasma glucose was decreased in alloxan-diabetic dogs by the infusion of either 50 micrograms/kg . min phlorizin (PHL), ie, reducing the concentration of plasma glucose without hyperinsulinemia; or with 7 mU/kg . min insulin (combined hyperinsulinemia and hypoglycemia). The concentration of glucose, immunoreactive glucagon (IRG), and insulin (IRI) and catecholamines were followed in the plasma. Hepatic glucose production (Ra) and the overall rate of glucose removal from the circulation were calculated by a tracer method. During a 200-minute infusion of PHL plasma glucose fell from 328 +/- 29 to 114 +/- 16 mg/dl, while IRG rose from a mean of 470 +/- 123 to 623 +/- 200 pg/mL, however this increase was significant only in 3 out of 6 dogs. There was no change in the plasma level of epinephrine. Plasma IRI decreased significantly, the IRI/IRG ratio remained low, and Ra did not increase. When the animals were treated with insulin for one week, plasma glucose was restored to normal, while plasma IRI and the IRI/IRG ratio were raised above the normal level. Under these circumstances the infusion of PHL increased plasma IRG significantly from 59 +/- 5 to 110 +/- 32 pg/mL, decreased IRI slightly, and increased Ra by an average of 50 +/- 16%. No measurable change in plasma glucose was observed indicating the restoration of nonhypoglycemic glucoregulation. In diabetic dogs during a 95-minute infusion of insulin, plasma glucose dropped from a mean of 338 +/- 5 to 74 +/- 24 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)