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The design of load-critical human-machine systems presumes thorough modelling and analysis of interaction profiles the systems are meant to withstand at peak loads. The need for mathematical modelling of interactions is often ignored due to significant modelling effort and lack of relevant tools. We propose an algorithm for automatic learning a subclass of Uppaal timed automata models from system and its environment interaction logs. The learning method relies on synchronous communication assumption that is characteristic to communication protocols of networked HMS distributed components. The method is demonstrated on IEEE1394 protocol learning example. Beside enhancing automatic test generation, the learned model allows verifying test feasibility and test optimization already in early phases of test design.

A concise, convergent multikilogram synthesis of CI-1034 (1), a potent endothelin receptor antagonist, is described. A 15-step preparation from commercially available o-vanillin and benzenesulfonyl chloride employs a remarkably robust Suzuki coupling between a boronic acid and an aromatic sulfonate ester as the key synthetic step. A scalable route capable of producing multikilogram quantities of CI-1034 with no chromatographic steps is described in this contribution. Improvements to the process included using a 4-fluorobenzenesulfonate ester as a suitable substitute for the triflate group in the Suzuki reaction and the use of MgCl2 as a substitute for TiCl4 in a Dieckmann condensation to provide the benzothiazine dioxide core.

The investigation was designed to determine whether the renal loss of bicarbonate contributes significantly to the acidosis of hypothermia. The excretion of bicarbonate during hypothermia was studied in five infused (6% creatinine in saline at 0.4 ml/minute) and five non-infused dogs. All animals were anesthetized and artificial respiration was not used. The rectal temperature was gradually reduced to the 26–27 °C range by approximately 4 hours of exposure to ice packing. After control, clearance periods of 30 minutes' duration were conducted serially and continually through the experiment. There was no significant increase in bicarbonate excretion during hypothermia in the non-infused group. The urinary pH remained at control levels of about 6.2. The fall in arterial pH was not due to urinary bicarbonate loss. The urinary pH in the infused group, which had a higher urine flow, increased to pH 6.7 due to increased excretion of bicarbonate. The urine pH in three animals with highest urine flows in this latter group approached plasma levels. The excretion rate of bicarbonate in the infused group, however, was similarly insufficient to account for the decrease in arterial pH. The hypothermic kidney is quite effective in reabsorbing bicarbonate.

Hydrogen ion secretion by the kidneys of anesthetized hypothermic dogs was measured to ascertain if the hypothermic kidney helps to compensate for the acidosis which develops during exposure to cold. Artificial respiration was not used. Total hydrogen ion excretion was measured as the sum of total titratable acid and ammonia excreted. A constant saline infusion of 2 ml/min was employed to maintain a urine flow adequate for analysis procedures. Though anaerobic arterial pH, corrected to body temperature, fell significantly from 7.41 during control to 7.27 at 27 °C, urinary pH remained at control levels of approximately 6.8. Neither titratable acid nor ammonia excretion increased in response to the hypothermic acidosis as would have occurred during normothermia with a similar low pH. Total titratable acid excretion fell from a control value of 0.011 meq/min to 0.005 meq/min at 27 °C. Ammonia excretion, after a mild increase from a control value of 0.008 meq/min, fell to 0.006 meq/min at 27 °C. The failure of the hypothermic kidney to excrete additional hydrogen ions in the face of acidosis indicates that the renal acidification mechanism is temperature-dependent.

The effect of both mild and severe acute alkalosis, due to intravenous sodium bicarbonate infusion, on glomerular filtration rate, renal plasma flow, and sodium and potassium clearance was investigated on 12 anesthetized dogs. The maximum load used was over 50 grams of NaHCO3administered intravenously in 4 hours, at a rate of 2.5 meq/minute. On a weight basis, in a 70-kg man, this would be equivalent to a load of 195 grams of NaHCO3given at the rate of nearly 10 meq/minute. The plasma potassium fell from 3.8 meq/l. to 2.7 meq/l. and the plasma sodium increased from 144.4 to 170.8 meq/l. with maximum NaHCO3loading. There was no apparent acute detrimental renal effect. No depression of GFR or RPF was seen in any series although the pH increased from 7.32 to 7.61. Similarly no significant effect was seen on blood pressure, hematocrit, filtration fraction, heart rate, or rectal temperature in any series. Urine flow and urine pH increased significantly with higher loading rates and concentrations.

The handling of sodium and potassium by the renal tubules at various levels of hypothermia was studied. Fourteen dogs were anesthetized with 30 mg/kg sodium pentobarbital. After suitable control clearance measurements, the rectal temperature was lowered progressively by ice-packing to about 25 °C while renal clearances were continuously measured. Artificial respiration was not used. No change in plasma sodium was detected but plasma potassium fell significantly from a control value of 4.1 ± 0.09 meq/1. at 38 °C to 3.4 ± 0.12 meq/1. at 25 °C. Urine sodium concentration fell during exposure to cold while potassium concentration increased slightly. In spite of the marked fall in glomerular nitration rate (69.0 ± 3.1 ml/minute control to 17.0 ± 3.6 ml/minute at 25 °C) the final urine flow at 25 °C was slightly greater than that of control. The clearance ratios (in percentage) increased significantly, reflecting the marked decrease in tubular reabsorption: water, 0.49 ± 0.05 at 38 °C to 2.02 ± 0.25 at 25 °C; sodium, 0.47 ± 0.12 to 1.13 ± 0.27; potassium, 18.0 ± 2.6 to 54.0 ± 12.0. The difference in clearance ratio alterations is a reflection of the dissimilar effect of hypothermia on particular renal regulations.

Hydrogen ion secretion by the kidneys of anesthetized hypothermic dogs was measured to ascertain if the hypothermic kidney helps to compensate for the acidosis which develops during exposure to cold. Artificial respiration was not used. Total hydrogen ion excretion was measured as the sum of total titratable acid and ammonia excreted. A constant saline infusion of 2 ml/min was employed to maintain a urine flow adequate for analysis procedures. Though anaerobic arterial pH, corrected to body temperature, fell significantly from 7.41 during control to 7.27 at 27 °C, urinary pH remained at control levels of approximately 6.8. Neither titratable acid nor ammonia excretion increased in response to the hypothermic acidosis as would have occurred during normothermia with a similar low pH. Total titratable acid excretion fell from a control value of 0.011 meq/min to 0.005 meq/min at 27 °C. Ammonia excretion, after a mild increase from a control value of 0.008 meq/min, fell to 0.006 meq/min at 27 °C. The failure of the hypothermic kidney to excrete additional hydrogen ions in the face of acidosis indicates that the renal acidification mechanism is temperature-dependent.

The effect of both mild and severe acute alkalosis, due to intravenous sodium bicarbonate infusion, on glomerular filtration rate, renal plasma flow, and sodium and potassium clearance was investigated on 12 anesthetized dogs. The maximum load used was over 50 grams of NaHCO3administered intravenously in 4 hours, at a rate of 2.5 meq/minute. On a weight basis, in a 70-kg man, this would be equivalent to a load of 195 grams of NaHCO3given at the rate of nearly 10 meq/minute. The plasma potassium fell from 3.8 meq/l. to 2.7 meq/l. and the plasma sodium increased from 144.4 to 170.8 meq/l. with maximum NaHCO3loading. There was no apparent acute detrimental renal effect. No depression of GFR or RPF was seen in any series although the pH increased from 7.32 to 7.61. Similarly no significant effect was seen on blood pressure, hematocrit, filtration fraction, heart rate, or rectal temperature in any series. Urine flow and urine pH increased significantly with higher loading rates and concentrations.

The handling of sodium and potassium by the renal tubules at various levels of hypothermia was studied. Fourteen dogs were anesthetized with 30 mg/kg sodium pentobarbital. After suitable control clearance measurements, the rectal temperature was lowered progressively by ice-packing to about 25 °C while renal clearances were continuously measured. Artificial respiration was not used. No change in plasma sodium was detected but plasma potassium fell significantly from a control value of 4.1 ± 0.09 meq/1. at 38 °C to 3.4 ± 0.12 meq/1. at 25 °C. Urine sodium concentration fell during exposure to cold while potassium concentration increased slightly. In spite of the marked fall in glomerular nitration rate (69.0 ± 3.1 ml/minute control to 17.0 ± 3.6 ml/minute at 25 °C) the final urine flow at 25 °C was slightly greater than that of control. The clearance ratios (in percentage) increased significantly, reflecting the marked decrease in tubular reabsorption: water, 0.49 ± 0.05 at 38 °C to 2.02 ± 0.25 at 25 °C; sodium, 0.47 ± 0.12 to 1.13 ± 0.27; potassium, 18.0 ± 2.6 to 54.0 ± 12.0. The difference in clearance ratio alterations is a reflection of the dissimilar effect of hypothermia on particular renal regulations.

The investigation was designed to determine whether the renal loss of bicarbonate contributes significantly to the acidosis of hypothermia. The excretion of bicarbonate during hypothermia was studied in five infused (6% creatinine in saline at 0.4 ml/minute) and five non-infused dogs. All animals were anesthetized and artificial respiration was not used. The rectal temperature was gradually reduced to the 26–27 °C range by approximately 4 hours of exposure to ice packing. After control, clearance periods of 30 minutes' duration were conducted serially and continually through the experiment. There was no significant increase in bicarbonate excretion during hypothermia in the non-infused group. The urinary pH remained at control levels of about 6.2. The fall in arterial pH was not due to urinary bicarbonate loss. The urinary pH in the infused group, which had a higher urine flow, increased to pH 6.7 due to increased excretion of bicarbonate. The urine pH in three animals with highest urine flows in this latter group approached plasma levels. The excretion rate of bicarbonate in the infused group, however, was similarly insufficient to account for the decrease in arterial pH. The hypothermic kidney is quite effective in reabsorbing bicarbonate.

Reaction of the nitrothioxanthen‐9‐ones (I) with the aminoalkylhydrazine (II) gives the 5‐nitrobenzothiopyranoindazoles (III) which are reduced, forming the corresponding amino compounds (IV).