Molecular and Cell Endocrinology: 7 (Principles of Medical Biology)

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Each participant, or a parent in the case of children younger than 16 yr, provided written informed consent, and all studies were conducted in accordance with the principles of the Declaration of Helsinki. The normal range for each assay was established in house by measuring EDTA plasma samples from 30 healthy donors; the upper limit of this range is used to identify pathological activation. The CP hemolytic complement titer CP-CH50 was measured in the fluid phase using antibody sensitized sheep erythrocytes as target.

The alternative pathway AP hemolytic complement titer AP-CH50 was measured in the fluid phase using unsensitized rabbit erythrocytes as target. Hemolytic activity in hemolytic units HUs is calculated relative to a standard serum sample. C3 nephritic factors were identified based upon their capacity to stabilize the AP C3 convertase in vitro , as described in Ref.

C4 nephritic factors were identified based upon CP C3 convertase stabilizing activity using a modified version of a published assay The first patient underwent a surgical biopsy of residual anterior abdominal wall sc fat, which was processed as described previously A yr-old Indian woman with a 2-yr history of oral lichen planus developed jaundice. Laboratory investigation revealed an elevated prothrombin time Liver histology showed active cirrhosis; the periportal infiltrate was characterized by lymphocytes, plasma cells, and polymorphonuclear neutrophils, and the features were consistent with autoimmune hepatitis.

She was treated with corticosteroids with rapid recovery of liver function.

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There was no evidence of steatosis. Three months later hemolytic anemia with a positive direct antiglobulin test developed, followed by diabetes mellitus after initiation of oral corticosteroids. At this point, fat loss was also noted on her limbs and, to a lesser extent, her abdomen. Her course was complicated by poor glycemic control despite large doses of insulin , and increasing axillary, nuchal, and flexural skin pigmentation.

Physical examination revealed scleral icterus, extensive acanthosis nigricans, and predominantly limb lipodystrophy in this manuscript we consider femorogluteal fat as part of limb fat Fig. Abdominal sc fat loss was patchy with some apparently preserved areas. Hyperinsulinemia, hyperglycemia, and dyslipidemia were found, with serum leptin levels toward the lower end of the reference range and undetectable plasma adiponectin Table 1.

Severe polyclonal hypergammaglobulinemia and weakly positive antinuclear antibody persisted with selective suppression of complement factor C4 Table 1 and supplemental Fig. No anti-insulin receptor antibodies were detected. Fat mass by DXA in patient 1. Sequential data points stars represent scans before first star and after 6, 12, and 24 months the initiation of immunosuppressive therapy.

Reference ranges for leptin and adiponectin are dependent upon gender and body weight. Six months later, severe hemolytic anemia recurred in association with rapidly progressive sensorimotor polyneuropathy, proteinuria, continuing hypergammaglobulinemia, and very low C4.

Renal histology showed no evidence of immune complex-mediated nephritis, amyloid deposition, or diabetic nephropathy. Immunohistochemistry confirmed the residual nature of these lipid droplets because they stained negatively for perilipin only viable adipocytes are immunoreactive to perilipin Electron microscopy EM revealed the presence of adipocyte remnants near the residual lipid droplets and numerous macrophages laden with lipid droplets Fig. Together, these light microscopy, immunohistochemistry, and EM findings suggest that the dead adipocytes surrounded by lipid reabsorbing macrophages some in the form of giant multinucleated cells represent crown-like structures CLSs previously described by Cinti and colleagues 19 , 20 in adipose tissue samples from obese mice and humans.

Representative white adipose tissue histology from patient 1. A, Hematoxylin and eosin stain showing very large adipocytes and many CLSs arrows. B, Perilipin immunohistochemistry—viable adipocytes are perilipin positive arrows , whereas cells surrounded by macrophages CLS lack perilipin staining. C, CD 79 B cell marker immunohistochemistry showing perivascular B-cell infiltrates.

D, CD plasma cell marker immunohistochemistry showing plasma cell infiltration. E, Electron micrograph EM showing lipid-filled macrophages solid arrows , residual adipocyte material dotted arrow , and the lipid droplet dashed arrow. She received aggressive immunosuppressive therapy in an effort to reduce Ig levels, and ameliorate the hemolytic anemia and polyneuropathy.

This included plasma exchange, corticosteroids, rituximab, mycophenolate mofetil, and azathioprine. Treatment successfully ameliorated the anemia and polyneuropathy, although anemia has been a recurring problem.

MCQs on Enzymes - Biochemistry MCQs

C4 complement levels, whereas always low, varied over time and tended to fluctuate together with IgG levels supplemental Fig. Her lipodystrophy appears to have stabilized, but fat has not returned in those areas where it was clearly lost Fig. Complement component levels were otherwise normal data not shown , and there was no evidence of either C3 or C4 nephritic factor activity. A yr-old woman was referred with acne, hirsutism, and oligomenorrhea. At 10 yr old, she had been noted to have reduced adipose tissue on her arms and legs.

At that time her C3 level was normal, but C4 was low at 0. Examination confirmed moderate hirsutism without virilization, flexural acanthosis nigricans, and limb lipodystrophy. At this stage abdominal sc fat was preserved. Laboratory investigation revealed severe insulin resistance. Serum leptin was lower than body mass index BMI and sex-matched controls, whereas adiponectin was undetectable Table 1. Rosiglitazone was introduced, but over the subsequent month, there was progressive weight loss, worsening liver function and dyslipidemia, and no improvement in her lipodystrophy.

Although serum alanine aminotransferase improved after withdrawal of the thiazolidinedione, severe hemolytic anemia developed with a strongly positive direct antiglobulin test hemoglobin nadir 3. Further investigation revealed end-stage liver disease and portal hypertension. Shortly afterwards, diabetes mellitus was diagnosed and insulin started.

Sensitivity or Response to Stimuli

Complement C3 was persistently normal, whereas C4 remained undetectable Table 1. Despite iv Ig and plasmapheresis, severe hemolysis persisted.

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A detailed autoantibody screen, including antinuclear antibody, antineutrophil cytoplasmic antibody, and anti-C1q, was negative, but IgG was elevated at Despite the introduction of rituximab and further plasmapheresis, her condition deteriorated, and she died while awaiting a liver transplant. A 5-yr-old boy presented with a history of recurrent infections and failure to thrive.


His parents had also noted that he had become very thin with minimal sc fat. His birth weight was 3. Generalized lipodystrophy was formally recognized at age 7 yr. At this time IgG was elevated, and C4 barely detectable, whereas C3 levels were within the normal range Table 1. Antinuclear factor, antidouble-stranded DNA, and antimitochondrial antibodies were undetectable. At this time he was also noted to have acanthosis nigricans, impaired glucose tolerance, and very high insulin levels Table 1. He subsequently remained lipodystrophic and insulin resistant, but no further evidence of hepatitis or other autoimmune disease was found.

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Between 5 and 18 yr old, immunological assessment revealed persistently nearly undetectable C4 with normal C3, high levels of Igs, and elevated C1q binding of serum, evidence for the presence of circulating immune complexes. CH50 assay of classical and terminal complement pathways was also persistently low, consistent with high complement turnover.

Reevaluated at the age of 32 yr old, he had normal C3 and C4 levels 1. However, his lipodystrophy was unchanged, and leptin and adiponectin were both nearly undetectable Table 1. Gorden and colleagues 21 , 22 have assembled a large cohort of patients with lipodystrophy. Within this cohort, 13 patients were classified as having AGL. Interestingly, three of these patients also had autoimmune hepatitis, and none of them had autoimmune glomerulonephritis.

The pathogenesis of acquired forms of lipodystrophy remains incompletely understood. AVT is involved in the regulation of ion transport in the intestine of the sea bream Sparus aurata. Triclosan interferes with the thyroid axis in the zebrafish Danio rerio. PTHrP-induced modifications of the sea bream Sparus auratus vertebral bone proteome. Identification of androgen receptor variants in testis from humans and other vertebrates. Cartilage Acidic Protein 2 a hyperthermostable, high affinity calcium-binding protein.

Biochim Biophys Acta. Mol Hum Reprod. Olfactory transduction pathways in the Senegalese sole Solea senegalensis. J Fish Biol.

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Thyroid disruption in the lizard Podarcis bocagei exposed to a mixture of herbicides: a field study. Cancela L. Development of an in vitro cell system from zebrafish suitable to study bone cell differentiation and extracellular matrix mineralization. DAX1 regulatory networks unveil conserved and potentially new functions. Comparative analysis of a teleost skeleton transcriptome provides insight into its regulation. Waterborne exposure of zebrafish embryos to micromole concentrations of ioxynil and diethylstilbestrol disrupts thyrocyte development. Aquat Toxicol. Identification of molecular and physiological responses to chronic environmental challenge in an invasive species: the Pacific oyster, Crassostrea gigas.

Reference genes to quantify gene expression during oogenesis in a teleost fish. Four stanniocalcin genes in teleost fish: structure, phylogenetic analysis, tissue distribution and expression during hypercalcemic challenge. Frontiers in Endocrinology. Chemically-mediated sexual display postures in pre-ovulatory female topmouth gudgeon, Pseudorasbora parva. Sample richness and genetic diversity as drivers of chimera formation in nSSU metagenetic analyses.

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Nucleic Acids Res. Prolactin regulates luminal bicarbonate secretion in the intestine of the sea bream Sparus aurata L. CpG-containing oligodeoxynucleotides increases resistance of Anopheles mosquitoes to Plasmodium infection.