In vitro batch cultures of gut microbiota from healthy and ulcerative colitis (UC) subjects suggest that sulphate-reducing bacteria levels are raised in UC and by a protein-rich diet.

Imbalances in gut microbiota composition during ulcerative colitis (UC) indicate a role for the microbiota in propagating the disorder. Such effects were investigated using in vitro batch cultures (with/without mucin, peptone or starch) inoculated with faecal slurries from healthy or UC patients; the growth of five bacterial groups was monitored along with short-chain fatty acid (SCFA) production. Healthy cultures gave two-fold higher growth and SCFA levels with up to ten-fold higher butyrate production. Starch gave the highest growth and SCFA production (particularly butyrate), indicating starch-enhanced saccharolytic activity. Sulphate-reducing bacteria (SRB) were the predominant bacterial group (of five examined) for UC inocula whereas they were the minority group for the healthy inocula. Furthermore, SRB growth was stimulated by peptone presumably due to the presence of sulphur-rich amino acids. The results suggest raised SRB levels in UC, which could contribute to the condition through release of toxic sulphide.

Nephrotic syndrome occurring during tiopronin treatment for cystinuria.

Cystinuria is an autosomal recessive disorder characterized with abnormal tubular reabsorption of cystine and dibasic amino acids leading to cystine urolithiasis. The classical form is caused by mutations in the SLC3A1 gene (OMIM 220100). The cornerstone of the treatment is high hydration and alkalization of the urine to achieve urine pH between 7.0 and 7.5, at which point, cystine solubility in the urine is optimal. These measures very often fail, and thus addition of sulfhydryl agents like penicillamine and tiopronin (mercaptopropionyl glycine) is recommended. Herein, we report a 3-year-old boy with cystinuria resulting in recurrent nephrolithiasis requiring surgery and extracorporeal shock wave lithotripsy. Nine months after introduction of tiopronin, the boy manifested generalized edema, oliguria, and biochemical indices of nephrotic syndrome. Tiopronin was withdrawn, and the boy was given only supportive treatment. Within 10 days, he entered into clinical and biochemical remission. Pediatricians should be aware of this adverse effect of tiopronin, and therefore, testing of the urine with strips or sulfosalicylic acid at least once weekly at home may be very helpful for early detection of proteinuria.

Animal Protein Intake Is Associated with General Adiposity in Adolescents: The Teen Food and Development Study.

Protein plays a crucial role in the growth and development of adolescents. However, being a secondary energy source, protein's role in obesity has been sidelined. We examined whether intake of protein (total, animal, plant), branched-chain (BCAAs), and sulfur-containing (SCAAs) amino acids are associated with general body and central obesity and body composition in a cross-sectional study among healthy adolescents. Students aged 12-18 years old (n = 601) in schools near two major Adventist universities in California and Michigan provided dietary data via a validated web-based food frequency questionnaire (FFQ) and anthropometric data during school visits. Intakes of total, animal, and plant proteins, and BCAAs and SCAAs were derived from FFQ data. We defined general body obesity with body-mass-index-for-age (BMIz) z-scores and central obesity with waist-to-height ratios (WHtR). After full adjustment for covariates, multiple regression analyses showed significant positive associations between intakes of total protein (ß = 0.101, 95% CI: 0.041, 0.161), animal protein (ß = 0.118, 95% CI: 0.057, 0.178), BCAAs (ß = 0.056, 95% CI: 0.025, 0.087), and SCAAs (ß = 0.025, 95% CI: 0.012, 0.038) with general body adiposity. Animal protein (ß = 0.017, 95% CI: 0.001, 0.033) and SCAAs (ß = 0.004, 95% CI: 0.000, 0.008) were also associated with central obesity. Total and animal protein and BCAA and SCAA were also significantly associated with fat mass. Our findings suggest that high protein intake may pose a possible detriment to adolescent health. Longitudinal and safety evaluation studies are recommended.

Primary biliary cirrhosis. A patient with adverse reactions to tiopronin and autoimmune hemolytic anemia with reticulocytopenia.

A 32-year-old woman with asymptomatic primary biliary cirrhosis had autoimmune hemolytic anemia associated with reticulocytopenia and thrombocytopenia despite an intensely erythroid bone marrow. Her anemia was successfully treated with oral prednisolone and intravenous pulse methylprednisolone, with a rapid response of reticulocytosis and sustained erythrocytosis. Tiopronin therapy was later initiated and resulted in fever, rash, exacerbation of the liver disease, and positive direct and indirect antiglobulin tests.

Nociceptive effects of intrathecal administration of sulphur-containing amino acids.

This study examined the nociceptive effects of the intrathecal administration of various doses of the following endogenous excitatory sulphur-containing amino acids (SAAs): L-cysteic acid (L-CA), L-cysteine sulfinic acid (L-CSA), L-homocysteic acid (L-HCA) and L-homocysteic sulfinic acid (L-HCSA). For a period of 10min, rats were observed for spontaneous nociceptive behaviours (SNBs), including: tail elevation, twitching or licking; hindpaw elevation, licking or shaking; and caudally directed biting or scratching. The amount of time each rat spent eliciting these individual behaviours was recorded and a total time (in seconds) spent exhibiting SNBs was then calculated. To determine which glutamate receptors are primarily responsible for these nociceptive behaviours, we pretreated additional groups of rats with selective antagonists for N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid/kainate (AMPA/KA) and group I metabotropic glutamate receptors (mGluR1 and 5). Results indicate that SAAs dose-dependently produce SNBs that are attenuated by NMDA receptor and group I mGluR antagonists.

Tiopronin-nephropathy: clinical, pathological, immunological and immunogenetic characteristics.

Nine patients who developed proteinuria while on Tiopronin (a D-Penicillamine-like drug) have been studied. Nephrotic syndrome was observed in six cases. Immunologic analysis revealed a high frequency of ANA positivity and RF seronegativity by the time nephropathy appeared. Six patients were biopsied. Immunofluorescence, electron and light microscopy studies showed: glomerulonephritis with segmental deposits in the mesangium and along the capillary walls in one patient, mesangioprolipherative glomerulonephritis in one case and stage 1 membranous glomerulonephritis in four cases. Immunogenetic typing disclosed a strong association with B35-Cw4 class I antigens.

Serum IgA levels and ANA behaviour in rheumatoid patients with and without toxicity to remission-inducing drugs.

IgA levels and ANA behaviour were studied in twenty-five patients suffering from toxicity to remission-inducing drugs (Tiopronin or Gold thiosulphate) and in thirty-two without any evidence of toxicity. A comparable number of patients with low IgA levels were found in the two groups. ANA test positivity correlated better with the appearance of toxicity, but the low specificity and predictivity hinder its application as a screening parameter.

Association between DR3 and thrombocytopenia due to gold or tiopronin. Case reports and review of the literature.

Two patients who developed thrombocytopenia while on Tiopronin and gold salts respectively were HLA typed. Their common haplotype was A25(10), B8, DR3. A survey of the literature showed that the association between DR3 and the sudden onset form of thrombocytopenia is striking. A genetic predisposition, besides other unknown factors, seems to play a crucial role.

Sulfhydryl drug-induced eruption: a clinical and histological study.

Sulfhydryl drug-induced skin eruptions were studied clinically and histologically in 23 patients. In this study, tiopronin, D-penicillamine, captopril and gold sodium thiomalate were considered to be sulfhydryl drugs, because they have a thiol group or release sulfhydryl compounds. The clinical features included skin eruptions that were maculopapular, erythema multiforme-like, eczematous, psoriasis-like, seborrheic dermatitis-like, Gibert-like, lichen planus-like, and pemphigus-like. These clinical findings were reminiscent of the wide variety of eruptions seen in cutaneous graft-versus-host reactions (GVHR). Histologically, areas of vacuolation and eosinophilic necrosis with a satellite infiltrate of lymphoid cells were seen in the epidermis, and perivascular infiltrates were noted in the dermis. These findings were similar to the histological picture of cutaneous GVHR. In skin tests with sulfhydryl compounds, 19 out of 20 subjects showed positive reactions, and autoantibodies were found in 8 out of 12 subjects tested. Sulfhydryl drugs seem likely to induce immunologic changes in the host and to produce a distinctive reaction similar to that of cutaneous GVHR.

Dissociated taste disorder.

Dissociated taste disorder is a special symptom occurring when only one or two taste qualities of the four primary taste are disturbed. Eleven % of all cases of taste disorders complain of this symptom. The subjects of this investigation were 46 patients due to be examined. We used our filter-paper disc method invented for clinical qualitative and quantitative gustometry by taste examination. True dissociated taste disorder was confirmed in 12 patients only with respect to sweetness. No dissociated taste disorder was found for the other types of taste. Sweetness differs from the other three primary tastes in that it is brought about by a protein acting as a receptor. In patients suffering from true dissociated taste disorders, the predominant cause of the condition is zinc deficiency. When zinc is not available in adequate quantities, the synthesis of the protein at the sweet-sensitive receptor site can no longer be achieved smoothly, and this may lead to the development of the complaint.

Dietary sulfur amino acid effects on fasting plasma cysteine/cystine redox potential in humans.

OBJECTIVE: Oxidation of plasma cysteine/cystine (Cys/CySS) redox potential (E(h)CySS) has been associated with risk factors for cardiovascular disease in humans. Cys and CySS are derived from dietary sulfur amino acids (SAA), but the specific effects of SAA depletion and repletion on Cys/CySS redox indices are unknown. The present study examined the effect of dietary SAA intake level on free Cys, free CySS, and E(h)CySS in human plasma under fasting conditions. METHODS: Healthy individuals aged 18-36 y (n = 13) were equilibrated to foods providing the RDA for SAA and then fed chemically defined diets without SAA (0 mg · kg(-1) · d(-1); n = 13) followed by SAA at levels approximating the mean (56 mg · kg(-1) · d(-1); n = 8) or 99th percentile (117 mg · kg(-1) · d(-1); n = 5) intake levels of Americans. Fasting plasma samples were collected daily during 4-d study periods and analyzed for free Cys, free CySS, and the E(h)CySS. RESULTS: The SAA-free diet significantly (P < 0.05) decreased plasma-free Cys concentrations and oxidized E(h)CySS values after 4 d of SAA depletion. With SAA repletion at 56 mg · kg(-1) · d(-1), plasma-free Cys increased significantly and values for E(h)CySS became more reduced. Administration of a diet providing a higher dose of SAA (117 mg · kg(-1) · d(-1)) resulted in a significantly higher level of free Cys and a more reduced E(h)CySS. CONCLUSIONS: These results show that free Cys and Cys/CySS redox potential (E(h)CySS) in fasting plasma are affected by dietary SAA intake level in humans. Significant changes occur slowly over 4 d with insufficient SAA intake, but rapidly (after 1 d) with repletion.

Thiopronine-induced pemphigus vulgaris in rheumatoid arthritis.

Thiopronine, a D-penicillamine-like agent, is being prescribed increasingly for RA. Among side effects, only benign skin reactions have been mentioned to date. A single case of pemphigus erythematosus induced by this drug was recently reported. We describe here 3 other patients who developed pemphigus vulgaris during long-term thiopronine therapy and who improved after the drug was stopped.

Pemphigus foliaceus and proteinuria induced by alpha-mercaptopropionylglycine.

Pemphigus foliaceus and proteinuria occurred in a patient with cystinuria treated with alpha-mercaptopropionylglycine. This drug is similar to D-penicillamine in structure and function, and it is being used in patients who are unable to tolerate D-penicillamine. Although side effects of D-penicillamine are common, no major adverse reactions have been reported previously with alpha-mercaptopropionylglycine. Pemphigus foliaceus and proteinuria occurring during therapy with alpha-mercaptopropionylglycine and D-penicillamine are discussed.

In vitro acantholysis by captopril and thiopronine.

The possible acantholytic property of captopril and thiopronine has been investigated using in vitro tissue cultures. Normal human breast skin explants have been cultured in Hanks' balanced salt solution containing 40% normal inactivated human serum with the addition of L-cysteine, or reduced glutathione (GSH), or captopril, or thiopronine, at four different concentrations (1, 5, 10, 15 mM). Patterns of diffuse, mainly suprabasal acantholysis, with formation of bullae, were observed in the skin explants cultured with captopril or thiopronine at a 15-mM concentration after 5 days of culture; intraepidermal splits were present also at a 10-mM concentration. Focal acantholysis was seen in specimens cultured with L-cysteine or GSH at a 15-mM concentration. No lesions occurred in the samples treated with lower concentrations of the above substances, nor in controls. The results show a biochemical acantholytic potential of both captopril and thiopronine, resembling that of penicillamine in similar experimental conditions, and consonant with clinical observations of pemphigus induced by drugs containing thiol groups in their molecule (SH drugs).

Toxicity due to remission inducing drugs in rheumatoid arthritis. Association with HLA-B35 and Cw4 antigens.

Twenty-five patients with rheumatoid arthritis (RA) who developed toxicity while taking remission inducing drugs and 30 without toxicity were studied for possible associations with class I and II HLA antigens. A strong association has been found between nephritis and dermatitis due to Tiopronin (a D-Penicillamine like compound) and class I antigens B35-Cw4, and between dermatitis due to gold thiosulphate and B35. Compared to healthy controls a lower DR5 frequency was observed in patients with RA except for the Tiopronin related nephritis group.