Claudius Galen: from a 20th century genitourinary perspective.

PURPOSE: We review the life and contributions of Claudius Galen from a 20th century perspective and examine his genitourinary observations. MATERIALS AND METHODS: All obtainable English translations of Galen's works were explored in addition to relevant commentaries. RESULTS: Galen's remarkable observations and novel concepts expanded medical knowledge in general and contributed to fundamental genitourinary principles in particular. Galen was one of the first to describe correctly the function of kidneys and explain micturition. Among his many neologisms he coined the term ureter, and he was probably the first to recognize the value of a competent ureterovesical valve. Galen advocated catheterization for urinary obstruction. He was a teacher, practitioner and philosopher, and wrote voluminously. CONCLUSIONS: Galen's influence on medical theory, terminology and practice remained unquestioned in Europe and the Middle East throughout the Middle Ages and Renaissance.

Methionine intolerance: a possible risk factor for coronary artery disease.

Homocystinuria, an inherited disorder associated with premature atherosclerosis, represents a severe form of methionine intolerance. To analyze the importance of milder forms of methionine intolerance in the genesis of vascular disease, the relation between provokable methionine intolerance and coronary artery disease was investigated. In a group of 138 men, aged 31 to 65 years (mean 53), referred for cardiac catheterization, plasma homocystine was measured before and 6 hours after an oral l-methionine load (0.1 g/kg). Thirty-nine subjects found to have normal coronary arteries had a mean post-load plasma homocystine level of 0.59 +/- 0.37 mumol/liter. A criterion at the 95th percentile (1.64 SD above the mean) was selected and applied to the remaining 99 subjects with coronary artery disease (0.70 +/- 0.68 mumol/liter). Sixteen (16%) of 99 subjects with coronary artery disease exceeded this level as compared with 1 (2%) of 39 subjects without coronary artery disease (p less than 0.04). The risk of coronary artery disease in men with provokable methionine intolerance was increased sevenfold as estimated by the odds ratio. By correlation matrix and multivariate regression analyses, provokable homocystinemia was predictive of coronary artery disease and was independent of tobacco smoking, hypertension, diabetes mellitus, serum cholesterol and age. It is proposed that men with mild methionine intolerance exposed to the high methionine content of the Western diet may develop intermittent homocystinemia and thus may be at greater risk for the development of coronary artery disease.

Partial pyruvate decarboxylase deficiency with profound lactic acidosis and hyperammonemia: responses to dichloroacetate and benzoate.

We describe the successful use of sodium benzoate in a neonate with hyperammonemia associated with congenital lactic acidosis caused by a partial deficiency of the E1 component of pyruvate dehydrogenase (PDH); of note, this biochemical disturbance has not been previously described in PDH deficiency. The pyruvate dehydrogenase complex in skin fibroblasts had 48% of normal activity with a deficiency of the E1 component. The infant presented with rapid onset of a severe metabolic lactic acidosis, hyperventilation, hyperammonemia, and coma. At 30 hours of age continuous peritoneal dialysis was started; however, plasma NH3 concentrations remained in the 300-400 micrograms/dl range over the next 12 hours. Sodium benzoate, 250 mg/kg, was infused intravenously with a decrease in plasma ammonia of 25 micrograms/dl/hr. Hippurate was documented in the urine and peritoneal fluid after benzoate therapy. At 10.5 months of age, 50 mg/kg dichloroacetate was administered orally under fasting conditions, which resulted in a 56 and 62% reduction in the serum lactate and pyruvate levels, respectively; after 2 weeks on dichloroacetate his fasting levels were significantly decreased. Fibroblast PDH activity responded similarly to this drug. In our patient sodium benzoate was rapidly effective in producing a decline in plasma ammonia that was associated with clinical improvement. We feel that its use in organic acidemias deserves further evaluation and, furthermore, that any child with suspected PDH deficiency requires a clinical trial of dichloroacetate.

Improved diagnosis of classical vs atypical phenylketonuria by liquid chromatography.

Atypical phenylketonuria among infants with hyperphenylalaninemia must be promptly diagnosed and differentiated from classical phenylketonuria, because these patients require different treatment to prevent irreversible neurological damage. Measurement of pteridines in urine by liquid chromatography has been widely used for this purpose. Here we report a rapid, simplified liquid-chromatographic method for simultaneously measuring urinary biopterin, neopterin, and creatinine. Unlike previous methods, this method involves neither tedious cleanup procedures nor special equipment.

Relationship between protein and energy in the feeding of preterm infants during the first month of life.

Energy and protein quantity and quality in the diet are factors regulating the rate of growth in the preterm infant. In the present study twenty infants 31-36 weeks of gestational age were fed with identical test formulas which varied only in the content of energy. One formula (F-81) contained 3.1 g protein (60 bovine whey: 40 bovine caseins) and 81 kcal per dl. The second formula (F-94) contained the same amount of protein but 94 kcal per dl. At an intake of 150 ml/kg/d the infants received 4.6 g protein/kg/d and either 121 or 141 kcal/kg/d. The infants on F-94 had a significantly higher rate of weight gain, but growth of length and head circumference was equal in the two groups. Significant differences were found in the plasma concentrations of glutamine and alanine between the two feeding groups. The other plasma amino acids were not statistically different in the two groups of infants. Urine excretion of threonine, serine, glycine, alanine, histidine, tyrosine, glutamine and cystathionine was significantly increased in the high caloric, F-94-group. The results indicate that increasing the caloric intake above 120 kcal/kg/d in preterm infants on a relatively high protein intake does not increase linear growth but does produce increased weight gain. The biochemical results provide indirect evidence that this weight increase is the result of increased fat accretion.

Methylene unit calibration for analysis of organic acids by gas--liquid chromatography/mass spectrometry.

We describe a method for automatic computation of "methylene unit" retention-time indices in real time on a computer-controlled gas chromatograph/mass spectrometer system. The calculation is based on the exponential relationship between the methylene unit values of hydrocarbon reference standards and the oven temperature at their elution. Using this mathematical relationship, we calculated calibration factors, which eliminates the need to include a set of methylene unit reference standards with each run and simplifies and speeds identification of unknown peaks in chromatograms. Long-term stability and good precision of the calibration factors were observed during the six-month period of study.

Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome.

A 2-year-old boy had acute fever, malaise, and somnolence with hepatomegaly, increased blood ammonia content (338 microM), high SGOT, low blood glucose content, and mild acidosis. A liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes, and abnormal urinary metabolites included beta-hydroxy-beta-methyl glutarate (HMG), beta-methylglutaconate, beta-hydroxyisovalerate, and beta-methylglutaric and glutaric acids. In cultured skin fibroblasts and liver, beta-hydroxy-beta-methyl glutaryl CoA lyase activity was about 10% of normal. Therefore, a genetic deficiency of HMGCoA lyase activity can cause a clinical syndrome similar to that of Reye syndrome when the patient is stressed by an acute viral infection.

Capillary column gas chromatography--mass spectrometry in studies on rheumatoid arthritis.

A method is described for determining the organic acid profile of synovial fluid. The method requires 50--100 microgram of sample and involves ion exchange for isolation of the acids followed by combined capillary column gas chromatography--mass spectrometry. Normal synovial fluid and synovial fluid from patients with rheumatoid arthritis show a similar qualitative pattern of acids (mainly fatty acids) resembling the pattern found in serum. The concentrations of the organic acids in the abnormal synovial fluids are 5--10 times higher than those in the fluid from the normal joints. In patients receiving treatment with gold thiomalate, free thiomalate was excreted in the urine. The release of this thiol upon gold therapy is of consequence for the further understanding of the mechanism of action of certain drugs against rheumatoid arthritis.

Proline recycling during collagen metabolism as determined by concurrent 18O2-and 3H-labeling.

In a previous study where rat skin collagen was labeled with 180 in the hydroxyl group of the collagen hydroxyproline we noticed that the decat rate of this label was much faster than had been observed when the skin collagen hydroxyproline was labeled with oH in the prolyl ring. In this study a ratwas labeled concurrently with [1802] and [3H] proline and the rate of decline of both labels was determined in rat skin collagen hydroxyproline. After correction for growth dilution of the skin collagen the [180] hydroxyproline was found to have a half-life of 27 days while the [3H] hydroxyproline had a half-life of 53 days. The decay rate of the [180] hydroxyproline represents the true turnover rate of collagen since there is no possibility of recycling this label. Hence, the difference between this and the [3H] hydroxyproline decay rate is due to recycling of L-[3H] proline into new collagen. The efficiency of recycling of proline from catabolized collagen into new collagen was about 93%.