Blood dolichol in lysosomal diseases.

Highly elevated serum total dolichol (free dolichol + dolichyl ester) concentrations have recently been found in two lysosomal storage diseases, aspartylglucosaminuria (AGU) and mannosidosis. The present study demonstrates that the increase of serum dolichol in AGU patients is caused by an increase of serum free dolichol. In 15 patients the mean serum level of free dolichol (227 +/- 16 ng/mL) was 1.9 times higher (p < 0.001) than that in healthy controls (120 +/- 6 ng/mL), while the amounts of dolichol fatty acid esters were similar in the patients and controls (110 +/- 9 vs. 118 +/- 6 ng/mL). In contrast, 10 patients with neuronal ceroid-lipofuscinosis (NCL) (three with infantile, four with juvenile, and three with variant late infantile NCL) had significantly (p < 0.01) lower mean serum levels of both free (79 +/- 5 ng/mL) and total (159 +/- 6 ng/mL) dolichol than age-adjusted healthy controls (free, 100 +/- 6 ng/mL; total, 206 +/- 14 ng/mL). Decreased blood dolichol has not been reported earlier for any other disease. We conclude that the increased serum free dolichol in AGU reflects disturbed lysosomal function and that the decreased free and esterified dolichols in NCLs speak against their presumed primary lysosomal nature.     

High levels of brain dolichols in neuronal ceroid-lipofuscinosis and senescence

Dolichols as unesterified alcohols were identified as significant components of lipid extracts from storage cytosomes isolated post-mortem from the brains of patients with the infantile, late infantile, and juvenile types of neuronal ceroid-lipofuscinosis (NCL). Very small amounts of dolichols were present in the corresponding subcellular fractions of non-NCL brains. The nuclear fraction from NCL cerebral cortex contained the highest dolichol content expressed per milligram protein or lipid, whereas the crude mitochondrial fraction was the richest in normal brain. Highly significant elevations of dolichol levels were found in human cerebral cortex of patients with NCL and Alzheimer's disease compared with age-matched controls, but the levels were normal in Pick's disease. In human non-NCL cerebral cortex, dolichols increased from 16 micrograms/g at age 5 to over 200 at age 81. Rat cerebral cortex showed a similar progressive increase in dolichol content with age. The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain. This is the first time a uniform biochemical abnormality has been found in all childhood forms of NCL, but the enzyme defect is still unidentified. It may lie on pathways where dolichols and retinyl compounds are recycled in Golgi membranes and derived organelles during the biosynthesis of glycoproteins.     

Rat testicular dolichols: distribution and accumulation with age

Dolichols, linear isoprenoids essential in the biosynthesis of N-glycosylated glycoproteins, are abundant in testicular tissue. This study investigated the distribution of dolichols among testicular cell and subcellular fractions. In addition, the accumulation of dolichol within the rat testis as a function of age was investigated. Dolichol content expressed either as total dolichol/testicle or as dolichol/mg protein exhibited a marked and continuous increase between 14 and 60 days of age. The 4-, 6-, 9-, and 12-mo-old animals exhibited only minor increases in testicular dolichol content. Mean value for retired breeders was 279 ng dolichol/mg protein. Although previous studies have suggested that dolichol synthesis occurs primarily within the spermatogenic cell, elutriation-purified spermatogenic cell fractions showed very low concentrations of dolichol. Pachytene spermatocyte and round spermatid fractions contained 25.8 and 36.5 ng dolichol/mg protein, respectively. Washed epididymal sperm also had a very low dolichol content (18.8 ng dolichol/mg protein). Recovery studies during elutriation purification of spermatogenic cells showed that the majority of dolichol was contained within the Sertoli-rich tubular fragments. Microsomal fractions isolated from whole testis exhibited a small enrichment (1.6-fold) in dolichol content, whereas Golgi apparatus fractions exhibited a large (12-fold) enrichment over that of the initial homogenate. These studies suggest that, although dolichols may be synthesized within the spermatogenic cell, they accumulate within the Sertoli cell.     

Separation of dolichol and dolichyl-P in microsomal and lysosomal compartments of hepatocytes

The distribution, labeling and interrelationship of microsomal and lysosomal dolichol and dolichyl-P in rat liver was investigated. After membrane induction with phenobarbital, N-nitrosodiethylamine and diethylhexylphthalate, the amount of microsomal and lysosomal dolichols are modulated independently. Liposomal labeled dolichol injected into the portal vein appears only in lysosomes and even after 8 days is still limited to the lysosomes. After in vivo labeling with [3H]mevalonate, high initial labeling of dolichol and dolichyl-P is present in microsomes and the labeling in microsomes is greater than that in lysosomes even after 8 h. The results demonstrate compartmentalization of the intracellular dolichols in hepatocytes. These lipids may have independent roles at different membrane locations.     

Identification of variables influencing resistin serum levels in patients with type 1 and type 2 diabetes mellitus.

BACKGROUND: Resistin, a peptide hormone, has been discussed controversially as a missing link between obesity and insulin resistance. In contrast to resistin mRNA expression in adipose tissue, data on human serum levels in obesity and diabetes mellitus is scarce. The physiological range of serum resistin levels, reference values or adjusted percentiles have not yet been determined, making the interpretation of serum resistin concentrations quite difficult. METHODS: Resistin serum concentrations were measured systematically by ELISA in 216 healthy controls, 555 patients with type 2 diabetes and 114 patients with type 1 diabetes. Mean values, median, and range were determined, and BMI-, gender-, and disease-adapted percentiles were calculated for all subgroups. RESULTS: Age and gender did not have any influence on resistin levels. BMI and resistin levels were positively correlated in healthy controls (p = 0.02), albeit with a weak correlation coefficient. This correlation was absent in patients with type 1 and type 2 diabetes. In both genders, healthy controls had significantly higher resistin levels than patients with type 1 and type 2 diabetes (7.9 +/- 0.2 ng/ml vs. 5.7 +/- 0.2 ng/ml and 5.5 +/- 0.1 ng/ml, respectively; p < 0.0001). There was no correlation between resistin levels and occurrence of diabetic retinopathy or nephropathy. CONCLUSIONS: Serum resistin levels can be measured by ELISA over a broad range from 0.6 ng/ml up to 27.7 ng/ml, suggesting that percentiles might be helpful in the interpretation of an individuals resistin value. While age and gender do not influence resistin levels, BMI and occurrence of diabetes have to be considered.     

Systemic levels contribute significantly to increased intraocular IGF-I, IGF-II and IGF-BP3 [correction of IFG-BP3] in proliferative diabetic retinopathy.

Increased intraocular levels of angiogenic growth factors such as insulin-like growth factor I (IGF-I) have been demonstrated in proliferative diabetic retinopathy (PDR). It is unclear whether increased leakage of the blood retina barrier or local synthesis primarily determine intraocular levels of IGFs in man, which is of special interest regarding possible therapeutic options with somatostatin analogues in PDR. This is the first study investigating parallelly serum and vitreous levels of IGF-I/II, IGF-BP3 and the liver-derived permeability marker albumin to determine in vivo the amount of circulation-derived intraocular IGFs. A control group without retinal proliferation and patients with PDR were compared. Levels of IGF-I/II, IGF-BP3 and albumin were determined by immunological methods. Vitreous levels of albumin were 2.2-fold elevated in patients with PDR (254.1 +/- 37.2mg/dl; n = 27; p = 0.0027) compared to controls (115.7 +/- 36.2mg/dl; n =10), whereas serum levels were slightly decreased in diabetes patients (5049 +/- 196 mg/dl vs. 4330 +/- 186 mg/dl; p = 0.0283). This was comparable to an increase of IGF-I/11 and IGF-BP3 in vitreous from PDR patients (IGF-I: 2.3 +/- 1.1 ng/ml p = 0.005. IGF-II: 37.9 +/- 4.9 ng/ml; p = 0.0003. IGF-BP3: 97.9 +/- 26.9 ng/ml; p = 0.0001; n = 34) compared to controls (IGF-I: 0.7 +/- 0.1 ng/ml. IGF-II: 21.3 +/- 4.2 ng/ml. IGF-BP3: 31.3 +/- 4.9 ng/ml: n = 19). Serum levels did not differ significantly among the groups regarding IGF-I, II and IGF-BP3. Intraocular albumin and IGF-I levels calculated as percentage of the respective serum levels correlated significantly (r = 0.42; p = 0.012). This study demonstrates that influx of IGF-I, II and IGF-BP3 in PDR quantitatively parallels influx of the liver derived serum protein albumin suggesting that leakage of the blood retina barrier and serum levels of IGF primarily determine intravitreal IGF levels rather than local synthesis. Suppression of systemic IGF levels by new, highly effective somatostatin-analogues therefore provides a promising approach to prevent PDR.     

Soluble tumour necrosis factor-alpha receptor I and interleukin-6 as markers of activity in thyrotoxic Graves' disease.

Autoimmune thyroid diseases are thought to be mediated by pro-inflammatory cytokines such as TNFalpha and IL-6. Serum levels of cytokines may indicate activity levels of immune functions. We investigated serum levels of IL-6 and of the soluble receptor of TNFalpha in patients with newly diagnosed onset of Graves' hyperthyroidism. The predominantly female group consisted of 39 patients, mean fT4 was 47.6 pg/ml (normal values 7.5=19.0 pg/ml). After diagnosis, all patients were treated with anti-thyroid drugs. Soluble Tumour Necrosis Factor Receptor I (TNF-RI) serum levels were found significantly increased (mean 3.7+/-1.3 ng/ml; p<0,01) compared to a matched group of apparent healthy individuals (mean sTNF-RI 1.8+/-0.5 ng/ml) and to a matched group of patients with treated Graves' disease (mean sTNF-RI 1.9+/-0.6 ng/ml). When IL-6 was assessed only 4 of the 39 patients exhibited increased serum levels. Our finding may indicate that sTNF-RI and possibly its ligand, TNFalpha, could play an important role in the onset of the acute stage of Graves' disease.     

Changes in circulating levels of immunoreactive follicle stimulating hormone, luteinizing hormone, and testosterone during sexual development in the rhesus monkey, Macaca mulatta

Basal serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) and the responsiveness of these hormones to a challenge dose of luteinizing hormone releasing hormone (LHRH), were determined in juvenile, pubertal, and adult rhesus monkeys. The monkey gonadotrophins were analyzed using RIA reagents supplied by the World Health Organization (WHO) Special Programme of Human Reproduction. The FSH levels which were near the assay sensitivity in immature monkeys (2.4 +/- 0.8 ng/ml) showed a discernible increase in pubertal animals (6.4 +/- 1.8 ng/ml). Compared to other two age groups, the serum FSH concentration was markedly higher (16.1 +/- 1.8 ng/ml) in adults. Serum LH levels were below the detectable limits of the assay in juvenile monkeys but rose to 16.2 +/- 3.1 ng/ml in pubertal animals. When compared to pubertal animals, a two-fold increase in LH levels paralleled changes in serum LH during the three developmental stages. Response of serum gonadotrophins and T levels to a challenge dose of LHRH (2.5 micrograms; i.v.) was variable in the different age groups. The present data suggest: an asynchronous rise of FSH and LH during the pubertal period and a temporal correlation between the testicular size and FSH concentrations; the challenge dose of LHRH, which induces a significant rise in serum LH and T levels, fails to elicit an FSH response in all the three age groups; and the pubertal as compared to adult monkeys release significantly larger quantities of LH in response to exogenous LHRH.     

Identification of serum endoglin as a novel prognostic marker after acute myocardial infarction

Endoglin is a proliferation-associated and hypoxia-inducible protein expressed in endothelial cells. The levels of soluble circulating endoglin and their prognostic significance in patients with acute myocardial infarction (AMI) are not known. In this observational prospective study serum endoglin levels were measured by ELISA in 183 AMI patients upon admission to hospital and 48 hrs later and in 72 healthy controls. Endoglin levels in AMI patients on admission were significantly lower than in healthy controls (4.25 +/- 0.99 ng/ml versus 4.59 +/- 0.87 ng/ml; P= 0.013), and decreased further in the first 48 hours (3.65 +/- 0.76 ng/ml, P < 0.001). Upon follow-up (median 319 days), patients who died had a significantly greater decrease in serum endoglin level over the first 48 hrs than those who survived (1.03 +/- 0.91 versus 0.54 +/- 0.55 ng/ml; P= 0.025). Endoglin decrease was an independent predictor of short-term (30 days) (hazard ratio 2.33;95% CI = 1.27-4.23; P= 0.006) cardiovascular mortality, and also predicts overall cardiovascular mortality during the follow-up (median 319 days) in AMI patients (hazard ratio 2.13;95% CI = 1.20-3.78; P= 0.01). In conclusion, early changes in serum endoglin may predict mortality after AMI.     

A novel family of longer chain length dolichols present in oleate-induced yeast Saccharomyces cerevisiae

The typical size of the yeast dolichol family ranges from 14 to 19 isoprene units D((14-19)) with dolichol(16) being the dominating species. Induction of peroxisome proliferation by growing the cells in medium containing oleate as carbon source induces the synthesis of an additional family of longer dolichols D((19-24)) with D(21) being the most prominent. This phenomenon is abolished in the peroxisome biogenesis deficient strain in which the PEX1 gene (encoding Pex1p peroxin) has been disrupted. The total amount of dolichols in pex1Delta cells is lower than in the wild-type cells, as is the amount of phosphatidylcholine. Moreover, the levels of 3-hydroxy-3-methylglutaryl CoA reductase and farnesyl diphosphate synthase, two key enzymes in dolichol biosynthesis, are decreased in the absence of a functional PEX1 gene. The presence of longer dolichols in oleate-induced Saccharomyces cerevisiae cells, the absence of this additional family in peroxisome deficient cells, and a decrease of the total amount of dolichols in these cells indicate the involvement of peroxisomes in the biosynthesis of dolichols in this organism.     

Nutrition and somatomedin. XIX. Molecular regulation of insulin-like growth factor-1 in streptozotocin-diabetic rats

Poor growth in diabetes involves low circulating levels of somatomedins/insulin-like growth factors (IGFs), largely reflecting decreased growth factor release by the liver. To define regulatory mechanisms, circulating IGF-1 was compared with levels of a high mol wt putative hepatic IGF-1 precursor and hepatic IGF-1 mRNA in a model of progressive severity of diabetes in rats. Streptozotocin administered at 36, 72, 144, and 288 mg/kg produced graded metabolic decompensation 2 days later, from minimal hyperglycemia with continued weight gain at 36 mg/kg, to marked hyperglycemia, ketonemia, and weight loss at 288 mg/kg (all P less than 0.001). Total serum IGF-1 measured by RIA was unchanged with the 36 and 72 mg/kg doses of streptozotocin (471 +/- 19 and 439 +/- 27 ng/ml, respectively, vs. 517 +/- 27 ng/ml in controls) despite serum glucose greater than 400 mg/dl. With streptozotocin 144 and 288 mg/kg, serum IGF-1 fell to 131 +/- 27 and 142 +/- 10 ng/ml, respectively (both P less than 0.005 vs. controls). Serum IGF-1 was correlated strongly with serum beta-hydroxybutyrate and body weight (r = -0.88 and 0.91, respectively, P less than 0.0001), and less strongly with serum glucose (r = -0.59, P less than 0.0002). Extractable hepatic content of a high mol wt form of immunoreactive IGF-1 (a putative precursor) was unchanged at the two lowest doses of streptozotocin (68 +/- 4 and 83 +/- 9 ngeq/g vs. 67 +/- 4 in controls), but decreased to 16 +/- 3 and 29 +/- 4 ng/g at the two highest doses (both P less than 0.001 vs. controls).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in the tumor marker concentration in female patients with hyper-, eu-, and hypothyroidism

The levels of 6 circulating tumor markers were evaluated in a total of 131 female subjects with altered thyroid states; 36 normal subjects, 46 hyperthyroid patients with Graves' disease, and 49 primary hypothyroid patients. The mean CEA concentration was observed to be significantly higher (p less than 0.02) in hypothyroid patients than in normal and hyperthyroid patients (1.1 +/- 0.1 ng/ml, 0.8 +/- 0.1 ng/ml and 0.8 +/- 0.1 ng/ml, respectively). Similarly, the mean serum CA 125 concentration in hypothyroid patients was higher (p less than 0.02) than in normal and hyperthyroid patients (13.0 +/- 2.6 U/ml, 7.6 +/- 1.1 U/ml and 5.5 +/- 0.8 U/ml, respectively), and the mean serum CA 15-3 concentration in hypothyroid patients was significantly higher than in normal subjects (p less than 0.01) and hyperthyroid patients (p less than 0.001) (16.2 +/- 0.9 U/ml, 13.9 +/- 0.6 U/ml and 10.6 +/- 0.5 U/ml, respectively). No statistical difference was found in mean CA 19-9 in the three subject groups. AFP in the hypothyroid patients (3.6 +/- 0.3 ng/ml) was significantly higher (p less than 0.05) than in normal subjects (2.6 +/- 0.2 ng/ml) and hyperthyroid patients (1.7 +/- 0.2 ng/ml) (p less than 0.01). On the other hand, serum ferritin was low in the hypothyroid patients (65.9 8.0 ng/ml) and significantly increased (69.1 +/- 9.0 ng/ml) (p less than 0.02) with the normalization of thyroid function. In hyperthyroidism, serum ferritin (70.2 +/- 7.0 ng/ml) was significantly higher than in the hypothyroid patients (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of thecal androstenedione production by exogenous progesterone in the cyclic hamster

Implants of progesterone on the day of dioestrus II in the hamster induced on the following day an increase in circulating levels of progesterone (6.0 +/- 0.7 ng/ml, N = 8; sesame oil controls, less than 0.5 ng/ml, N = 6) and a decline in serum levels of LH (5.3 +/- 0.4 ng/ml; controls 12 +/- 2 ng/ml) and oestradiol (10 +/- 2 pg/ml; controls 69 +/- 5 pg/ml). The production of androstenedione and oestradiol by antral follicles in vitro was reduced in progesterone-treated hamsters when compared with controls, but progesterone production was not affected. Aromatizing activities of antral follicles were the same in progesterone-treated and sesame oil-treated hamsters. Androstenedione production by theca was significantly less in progesterone-treated hamsters than in controls. On dioestrus II, LH replacement therapy (200 micrograms ovine LH by osmotic minipump inserted s.c.) prevented the decline in follicular androstenedione and oestradiol production induced by progesterone alone, and also prevented the decline in thecal androstenedione production in vitro. The results indicate that exogenous progesterone on dioestrus II lowers circulating levels of LH by the following day, inhibits thecal androstenedione production and thus reduces follicular oestradiol production without alteration in aromatizing ability.     

Reinitiation of ovulatory cycles in incubating female turkeys by an inhibitor of serotonin synthesis, P-chlorophenylalanine

Nest deprivation of incubating turkeys caused a decrease in serum prolactin (Prl) levels from 1184.5 +/- 116.4 ng/ml to 896.8 +/- 83.0 ng/ml 1 day after initiation of deprivation, with a further decline to 156.5 +/- 111.7 ng/ml at the end of the 22-day experimental period. Serum luteinizing hormone (LH), progesterone and estradiol levels following nest deprivation were similar to those in birds allowed to incubate (controls). Oral administration of p-chlorophenylalanine (PCPA, 50 mg/kg) to incubating turkeys for 3 consecutive days reduced nesting frequency (P less than 0.05) on the 4th day after initiation of treatment and the nesting virtually ceased by the 9th day. Pretreatment Prl was 1655 +/- 210 ng/ml and declined (P less than 0.05) after PCPA administration to a low of 28.6 +/- 2.8 ng/ml. In addition, PCPA caused a sustained rise in serum LH peaking (5.59 +/- 1.09 ng/ml) 3 days after treatment initiation. Contrary to nest deprivation, serum levels of progesterone and estradiol increased (P less than 0.05) as a consequence of PCPA treatment. Seven of 8 PCPA-treated birds later came into lay when their Prl levels and nesting frequency increased again. The results suggest a role for serotonin (5-HT) in incubation behavior, and Prl and LH secretion in turkeys.     

Testicular responsiveness to long-term administration of hCG and hMG in patients with hypogonadotrophic hypogonadism

Steroidogenic responsiveness and amelioration of sperm number and motility following long-term intramuscular hCG and hMG administration were evaluated in 18 males with hypogonadotrophic hypogonadism (HH). The patients consisted of 13 patients with isolated gonadotrophin deficiency (IGD) and 5 patients hypophysectomized at an early or middle pubertal period. Basal serum levels of testosterone and 17 beta-estradiol were within prepubertal range in all patients before the treatment. Serum testosterone levels reached the normal adult male levels within 12-24 months of the treatment in only 2 of 7 younger patients and 1 of 6 older patients with IGD, whereas in all hypophysectomized patients serum levels of both testosterone and 17 beta-estradiol increased to the levels found in normal adult males within 6 months of the treatment. The mean peak levels of serum testosterone and 17 beta-estradiol, respectively, during the treatment were 2.1 +/- 0.8 (SD) ng/ml and 10.8 +/- 4.9 (SD) pg/ml in younger patients with IGD, 1.4 +/- 0.9 ng/ml and 9.7 +/- 5.1 pg/ml in older patients with IGD and 6.0 +/- 1.2 ng/ml and 34.2 +/- 14.8 pg/ml in hypophysectomized patients. Quantitative improvement in both sperm density and sperm motility were found in 4 of 7 younger patients, 1 of 6 older patients with IGD and all hypophysectomized patients, but only 3 of hypophysectomized patients (3 of 18 patients) could become fertile.     

Increased serum levels of endopeptidase 24.11 ('enkephalinase') in patients with end-stage renal failure

Endopeptidase 24.11, a widely distributed membrane-bound peptidase is found in low levels in the serum of normal individuals. Although increased levels of the enzyme have been found in sera of patients with sarcoidosis and adult respiratory distress syndrome, the cellular origin of circulating endopeptidase 24.11 remains unknown. As the brush border of the proximal tubular epithelial cells have the highest endopeptidase specific activity, we investigated the possible contribution of the kidney to the release of endopeptidase 24.11 in the systemic circulation. Therefore, we measured serum levels of the enzyme in patients with end-stage renal failure (ESRF) treated by haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Increased serum levels of endopeptidase 24.11 were observed both in HD patients (mean +/- SEM: 74.6 +/- 20.9 ng/ml) and in CAPD patients (mean +/- SEM: 45.1 +/- 8.1 ng/ml) as compared to normal individuals (mean +/- SEM: 13.6 +/- 1.4 ng/ml). Endopeptidase levels remain stable during haemodialysis sessions on two different dialysis membranes. Finally, serum levels of the enzyme in anephric patients tend to be lower than in ESRF patients, suggesting that the kidney may contribute to the generation of the circulating form of endopeptidase 24.11.     

Relation of leptin and tumor necrosis factor alpha to body weight changes in patients with pulmonary tuberculosis

In this study we investigated whether leptin and TNFalpha levels change with improvement in body weight with antituberculotic therapy in active tuberculosis patients. 30 patients (8 females and 22 males) with active pulmonary tuberculosis formed the patient group, and 25 sex- and age-matched healthy subjects (8 females and 17 males) served as the control group. Body weight, body mass index (BMI) and serum leptin and plasma TNFalpha levels are measured before and in the sixth month of therapy in all patients. Before the initiation of therapy, BMI of the patients was significantly lower than BMI of the controls (20.2 +/- 1.6 vs. 25.2 +/- 2.7 kg/m(2), respectively; p < 0.05). After treatment, BMI of the patients increased significantly to 21.4 +/- 1.9 kg/m(2) (p < 0.05), but was still lower than that of the controls (p < 0.05). Pretreatment serum leptin (4.5 +/- 0.9 vs. 2.1 +/- 0.2 ng/ml, respectively; p < 0.05) and plasma TNFalpha (27.9 +/- 3.4 vs. 23.9 +/- 3.0 pg/ml, respectively; p < 0.05) levels of the patients were significantly higher than those of the controls. After treatment, serum leptin levels increased to 6.7 +/- 2.2 ng/ml, but this rise was not statistically significant (p > 0.05). Treatment did not result in any significant change in TNFalpha levels, either. Delta leptin was highly related to Delta BMI in patients with tuberculosis (r = 0.68, p = 0.02). In the pretreatment period, there was a significant correlation between leptin and TNFalpha levels in the whole patient group (r = 0.78, p < 0.001), and in female (r = 0.74, p < 0.001) and male patients separately (r = 0.74, p = 0.035). In conclusion, leptin and TNFalpha may be responsible for the weight loss in pulmonary tuberculosis patients, but their levels do not change with improvement in body weight with antituberculotic treatment.     

Low serum reverse T3 levels in patients with primary hyperparathyroidism

Although patients with primary hyperparathyroidism (1 degree HPT) were euthyroid, we measured serum thyroid hormone levels in 16 patients with 1 degree HPT together with 17 patients with hypercalcemia due to malignant diseases (HCM). In patients with 1 degree HPT, serum levels of T3, T4 and T3U were within normal range, but serum rT3 (reverse T3) levels (205 +/- 37 pg/ml, mean +/- SD) were significantly decreased as compared with those in normal controls (276 +/- 44 pg/ml, P less than 0.01). A significant inverse correlation was observed between the serum levels of rT3 and parathyroid hormone (PTH) (r = 0.54, P less than 0.05). After parathyroidectomy, serum rT3 levels were significantly elevated (240 +/- 56 pg/ml) compared to preoperative levels (P less than 0.01). Low levels of serum rT3 seemed to be attributed to the high levels of serum PTH. On the other hand, serum levels of T3 and T4 were low and serum rT3 levels were high in patients with HCM. Low serum rT3 allows for the differentiation of patients with 1 degree HPT from those with HCM.     

Aspartylglycosaminuria: biochemistry and molecular biology

Aspartylglucosaminuria (AGU, McKusick 208400) is an autosomal recessive lysosomal storage disease caused by defective degradation of Asn-linked glycoproteins. AGU mutations occur in the gene (AGA) for glycosylasparaginase, the enzyme necessary for hydrolysis of the protein oligosaccharide linkage in Asn-linked glycoprotein substrates undergoing metabolic turnover. Loss of glycosylasparaginase activity leads to accumulation of the linkage unit Asn-GlcNAc in tissue lysosomes. Storage of this fragment affects the pathophysiology of neuronal cells most severely. The patients notably suffer from decreased cognitive abilities, skeletal abnormalities and facial grotesqueness. The progress of the disease is slower than in many other lysosomal storage diseases. The patients appear normal during infancy and generally live from 25 to 45 years. A specific AGU mutation is concentrated in the Finnish population with over 200 patients. The carrier frequency in Finland has been estimated to be in the range of 2.5-3% of the population. So far there are 20 other rare family AGU alleles that have been characterized at the molecular level in the world's population. Recently, two knockout mouse models for AGU have been developed. In addition, the crystal structure of human leukocyte glycosylasparaginase has been determined and the protein has a unique alphabetabetaalpha sandwich fold shared by a newly recognized family of important enzymes called N-terminal nucleophile (Ntn) hydrolases. The nascent single-chain precursor of glycosylase araginase self-cleaves into its mature alpha- and beta-subunits, a reaction required to activate the enzyme. This interesting biochemical feature is also shared by most of the Ntn-hydrolase family of proteins. Many of the disease-causing mutations prevent proper folding and subsequent activation of the glycosylasparaginase.     

Gonadal dysfunction in the spontaneously diabetic BB rat: alterations of testes morphology, serum testosterone and LH

Serum testosterone, luteinizing hormone (LH), testicular histology and ultrastructure were examined in 91 spontaneously diabetic BB, semi-starved, and control Wistar rats. Between 80-120 days of age serum testosterone was decreased (1.67 +/- .25 vs. 2.95 +/- .48 ng/ml; P less than .05) in the BB rats compared to controls but not different from semi-starved rats. LH values were similar in control and BB rats (49.4 +/- 10.9 vs. 46.8 +/- 6.2 ng/ml). Abnormal lipid droplets were noted within Leydig cells at this period. From 121-150 days of age serum testosterone was lower in BB (1.38 +/- .23 vs. 3.42 +/- .45 vs. 2.94 +/- .81 ng/ml; P less than .05) than controls or semi-starved rats. Serum LH was not significantly higher in controls than in BB rats (63.2 +/- 7.4 vs. 36.6 +/- 12 ng/ml; P = NS). Between 151-200 days of age, there was further lipid accumulation in Leydig cells in the BB rat and occasional epithelial disorganization. After 200 days, serum testosterone decreased (P less than .05) to similar levels in both control and BB rats (1.42 +/- .87 vs. 1.22 +/- .25; P = NS) and was similar in BB rats after 250 days (1.02 +/- .2 ng/ml). After 250 days of age Leydig cell morphology appeared relatively normal but marked alterations were apparent in Sertoli cells, germ cells and morphology of the tubule wall.(ABSTRACT TRUNCATED AT 250 WORDS)