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Bovine testicular beta-galactosidase (beta-D-galactoside galactohydrolase, EC 3.2.1.23) is rapidly and selectively assimilated by human skin fibroblasts. The assimilation of the enzyme is strongly inhibited by mannose 6-phosphate and by a glycoprotein fraction isolated from bovine testes (glycoprotein inhibitors). These results suggest that beta-galactosidase and the glycoprotein inhibitors have a common recognition marker that contains mannose 6-phosphate. The presence of mannose phosphate in the glycoprotein inhibitors was demonstrated by acid hydrolysis of the glycoproteins to liberate mannose phosphate followed by reduction with NaB(3)H(4) to give [(3)H]mannitol phosphate. The (3)H-labeled compound was identified by paper electrophoresis and by the release of [(3)H]mannitol on treatment with phosphatase. The [(3)H]mannitol phosphate was oxidized with periodate and the resulting phosphorylated fragment, on reduction with NaB(3)H(4), yielded [(3)H]ethylene glycol phosphate, indicating substitution of phosphate on carbon 6 of mannitol. Mannose 6-phosphate was also found in a major carbohydrate-containing fraction of peptides produced from the glycoprotein inhibitors by tryspin digestion. It was estimated that about 2% of the mannose residues were present as mannose 6-phosphate. Phosphorylated oligosaccharides were also identified in hydrolysates of the glycoprotein inhibitors. One, a disaccharide, was identified as alpha-(mannosyl-6-phosphate)-(1 --> 2)-mannose. These observations suggest that the recognition marker of beta-galactosidase contains alpha1,2-linked mannose 6-phosphate; terminal alpha1,2-linked mannose residues are known to occur in the high-mannose type oligosaccharides present on beta-galactosidase.

To clarify further the etiology of the carbohydrate intolerance in idiopathic hemochromatosis, we investigated the glucose, insulin, C-peptide, and glucagon responses to arginine (0.5 g/kg) infused during 30 min in lean normal subjects; in insulin-requiring subjects with hemochromatosis, genetic diabetes, and total pancreatectomy; and in nondiabetic cirrhotic subjects without portosystemic shunting. Serum insulin, C-peptide, and glucagon responses (30K antibody) were determined by RIA, and glucose level was determined by a glucose oxidase technique. Hemochromatotic and genetic diabetic subjects had similar basal glucose (157 +/- 25 vs. 168 +/- 40 mg/dl) and C-peptide (0.73 +/- 0.42 vs. 0.65 +/- 0.22 ng/ml) values, with subnormal C-peptide peak responses to stimulation (1.05 +/- 0.38 and 1.40 +/- 0.83 vs. 3.95 +/- 0.4 ng/ml in normals; P less than 0.05). No glucagon or C-peptide response to arginine was seen in any pancreatectomized subject. Similar but excessive glucagon levels were present in hemochromatosis, diabetes, and cirrhosis under basal conditions (166 +/- 24, 232 +/- 111, and 263 +/- 116 vs. 76 +/- 15 pg/ml; P less than 0.05) and after arginine stimulation (782 +/- 80, 834 +/- 123, and 902 +/- 275 vs. 489 +/- 81 pg/ml; P less than 0.05) when compared with normals. The excessive glucagon levels found in hemochromatosis, diabetes mellitus, and cirrhosis contrast to the absent response in pancreatectomized subjects and indicate that generalized islet cell destruction is not the major factor in diabetic hemochromatotic subjects.

Urinary stones form as a consequence of urinary supersaturation. Supersaturation occurs as a result of elevated concentrations of urinary solutes. Dietary, metabolic, endocrine, hereditary, and infectious processes alter urinary solute concentrations. Struvite (MgNH4PO. 6H2O) and carbonate-apatite [Ca10(PO4)6CO3] stones form in urine that becomes supersaturated as a by-product of the hydrolysis of urea by the bacterial enzyme urease. Urease-induced stones manifest primarily as branched renal calculi and as bladder calculi. Conventional therapy has usually consisted of surgical removal of the stone combined with a short course of antimicrobial therapy. Such treatment is curative in about 50% of cases. Recurrent stone formation and progressive pyelonephritis occur in those who are not cured. Adjunctive medical treatment with acetohydroxamic acid or hydroxyurea lessens the risk of calculogenesis and decreases growth of residual stones in patients who are not cured by conventional therapy. Patients with urea-splitting urinary infection and renal stones have a major life-threatening disease. The morbidity and expense that result from this disease are great. Long-term (perhaps lifetime) chemotherapy with antimicrobial agents and/or urease-inhibiting drugs combined with judicious and expert surgical intervention can be expected to significantly improve the plight of these unfortunate patients.

A large Mormon pedigree of a proband with hemochromatosis was studied, using transferrin saturation as the quantitative phenotypic trait. The analysis indicated that the inheritance of hemochromatosis was recessive, with partial expression in some heterozygotes. The lod score of 6.88 (theta = .0) was strongly indicative of linkage between the hemochromatosis locus and the human major histocompatibility (HLA) loci.

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