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Proper deposition of the extracellular matrix and its major components, the collagens, is essential for endochondral ossification and bone mass accrual. Collagen prolyl 4-hydroxylases (C-P4Hs) hydroxylate proline residues in the -X-Pro-Gly- repeats of all known collagen types. Their product, 4-hydroxyproline, is essential for correct folding and thermal stability of the triple-helical collagen molecules in physiological body temperatures. We have previously shown that inactivation of the mouse P4ha1 gene, which codes for the catalytic α subunit of the major C-P4H isoform, is embryonic lethal, whereas inactivation of the P4ha2 gene produced only a minor phenotype. Instead, mice with a haploinsufficiency of the P4ha1 gene combined with a homozygous deletion of the P4ha2 gene present with a moderate chondrodysplasia due to transient cell death of the growth plate chondrocytes. Here, to further characterize the bone phenotype of the P4ha1+/−; P4ha2−/− mice, we have carried out gene expression analyses at whole-tissue and single-cell levels, biochemical analyses, microcomputed tomography, histomorphometric analyses, and second harmonic generation microscopy to show that C-P4H α subunit expression peaks early and that the C-P4H deficiency leads to reduced collagen amount, a reduced rate of bone formation, and a loss of trabecular and cortical bone volume in the long bones. The total osteoblast number in the proximal P4ha1+/−; P4ha2−/− tibia and the C-P4H activity in primary P4ha1+/−; P4ha2−/− osteoblasts were reduced, whereas the population of osteoprogenitor colony-forming unit fibroblasts was increased in the P4ha1+/−; P4ha2−/− marrow. Thus, the P4ha1+/−; P4ha2−/− mouse model recapitulates key aspects of a recently recognized congenital connective tissue disorder with short stature and bone dysplasia caused by biallelic variants of the human P4HA1 gene. Altogether, the data demonstrate the allele dose-dependent importance of the C-P4Hs to the developing organism and a threshold effect of C-P4H activity in the proper production of bone matrix.

Background. Drug-induced hyperthyroidism is a rare condition linked to dietary supplements, iodine-con-taining medications and intentional or unintentional over ingestion of levothyroxine; its detection is important since, if left untreated, thyroid storm can develop, carrying a mortality rate of 20-50%. Case presentation. Here we describe the case of an oldest old (84 years) woman, with severe cognitive impairment and immobilization syndrome attending our geriatric ward for aspiration pneumonia. During the fifth day of hospitalization, while pneumonia and respiratory symptoms were improving, tachycardia persisted (heart rate 130 bpm), associated with tremors and lack of sleep. The patient was affected by multinodular goiter and, a diagnosis of thyrotoxicosis was documented by elevated serum free thyroxine and free triiodothy-ronine levels (4.7 ng/dL and 6.6 ng/L, respectively), associated with undetectable thyroid-stimulating hormone (TSH 0.04 mIU/L), elevated urinary iodine excretion (849 µg/L) and normal serum thyroglobulin levels (10 ng/ mL).131I thyroid scan showed diffuse low uptake, suggesting iatrogenic thyrotoxicosis. The patient suffered from immobilization syndrome with bedsores that had been medicated twice a week with iodoform gauzes for one year. Prior to starting the use of iodoform dressings the patient was documented euthyroid. Conclusions. Over the past century, few cases have been described regarding possible severe toxicity caused by the use of iodoform gauzes, all of them presenting with neurovegetative symptoms as vomiting, altered sensor, which disappeared after withdrawn of the medication, but iatrogenic thyrotoxicosis was never demonstrated. Thus, to our knowledge, this is the first report documenting the onset of thyrotoxicosis induced by lasting use of iodoform gauzes.

The relationship between abnormal cell proliferation and aberrant control of hormonal secretion is a fundamental and poorly understood issue in endocrine cell neoplasia. Transgenic mice with parathyroid-targeted overexpression of the cyclin D1 oncogene, modeling a gene rearrangement found in human tumors, were created to determine whether a primary defect in this cell-cycle regulator can cause an abnormal relationship between serum calcium and parathyroid hormone response, as is typical of human primary hyperparathyroidism. We also sought to develop an animal model of hyperparathyroidism and to examine directly cyclin D1’s role in parathyroid tumorigenesis. Parathyroid hormone gene regulatory region–cyclin D1 (PTH–cyclin D1) mice not only developed abnormal parathyroid cell proliferation, but also developed chronic biochemical hyperparathyroidism with characteristic abnormalities in bone and, notably, a shift in the relationship between serum calcium and PTH. Thus, this animal model of human primary hyperparathyroidism provides direct experimental evidence that overexpression of the cyclin D1 oncogene can drive excessive parathyroid cell proliferation and that this proliferative defect need not occur solely as a downstream consequence of a defect in parathyroid hormone secretory control by serum calcium, as had been hypothesized. Instead, primary deregulation of cell-growth pathways can cause both the hypercellularity and abnormal control of hormonal secretion that are almost inevitably linked together in this common disorder.