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Extract: In iliac crest biopsies from 11 patients (ages from 4 to 22 years) with osteogenesis imperfecta, cortical thickness, osteoid width, and number of osteons were less than normal at all ages. Bone surface activity (formation and resorption), measured by quantitative microradiography, was lower than normal in younger patients; the normal pubertal decrease in surface activity was not evident in patients with osteogenesis imperfecta and, consequently, bone surface activity in the older patients was higher than in age-matched normal subjects. The ultrastructure of osteocytes, bone collagen, and scleral collagen did not differ from normal; corneal collagen fibers, however, were approximately half the diameter of normal. Total urinary hydroxyl-proline excretion, measured in 11 patients, was below normal in all except 2 infants (less than 12 months old). Serum parathyroid hormone levels, measured in nine patients, were normal. Long term treatment with sodium fluoride (two patients) and treatment with magnesium oxide (three patients) did not alter bone morphology or bone surface activity. Speculation: The supposition that in osteogenesis imperfecta the connective tissue is characterized by an immature form of collagen was not substantiated by this study. The abnormal fibrillar pattern and paucity of collagen in various connective tissues suggest a qualitative defect, related to collagen maturation, as well as a quantitative deficit in the amount of collagen produced.

SummaryA significant increase was induced by lathyrism in the small fraction of collagen-like material solubilized from rat glomeruli. An increased affinity and staining by PTA of fibrils within the GBM of lathyritic rats was found by electron microscopy, and also probably reflects an alteration in the collagen-like moiety of the GBM by APN, a material known to affect the cross-linking of collagens. No change in total proteinuria was found in lathyritic rats, nor other major changes in renal structure by conventional microscopy, electron microscopy, or specialized stains of the sialoprotein layer of the glomerulus. Further study of physicochemical alterations induced in the GBM combined with methods to evaluate glomerular permeability, may reveal the location and nature of the filtration barrier.

A case of acquired hypothyroidism with precocious puberty and galactorrhea is presented. Qualitative and quantitative abnormalities in the composition of the mammary secretions are given in detail and compared with the composition of normal human milk. The total fat content of the milk was increased without qualitative alterations of fat composition although the quantity of lactose was decreased. The serum albumin component of the milk was increased. The lactalbumin and characteristic casein components were diminished and absent, respectively. The role of the thyroid gland in controlling lactation is discussed although no conclusions can be drawn regarding hormonal influences on specific mammary secretions.

Four children with acute lymphoblastic leukemia received a controlled dietary intake of protein, calcium and phosphorus to study prospectively the changes in the serum and urinary calcium and phosphorus values, which occur during therapy of the disease. Two 12-hour urine collections were obtained daily for determinations of phosphorus, calcium, uric acid and creatinine. Serum creatinine, urea nitrogen, calcium, phosphorus and uric acid were measured midway through each collection. Hyperphosphatemia (values of 5.7 to 9.4 mg per 100 ml), hypocalcemia (values of 6.6 to 8.3 mg per 100 ml) and marked hyperphosphaturia were observed within 24 to 48 hours of the initiation of chemotherapy. The tubular reabsorption of phosphorus decreased to levels that were 20 to 70 per cent of pretreatment base-line values. Symptomatic hypocalcemia is most common in patients with exceptionally high peripheral lymphoblast counts and some degree of renal insufficiency. These events may be caused by the increased endogeno...

The isolated short circuited frog skin has been employed in an attempt to elucidate the mechanism of action of human growth hormone (HGH) on salt and water metabolism. 100 mU per ml clinical grade HGH (CHGH) in the solution bathing the inner membrane surface increased short circuit current (SCC) 3.5 μeq Na+ per cm2 hr (P < 0.01). SCC was unchanged at 0.1 mU per ml but increased 1.2 μeq Na+ per cm2 hr at 1.0 mU per ml. In contrast, purified HGH (PHGH) at 100 mU per ml increased SCC only 0.7 μeq Na+ per cm2 hr (P < 0.01). No pressor or uterine contractile activity could be demonstrated in the PHGH preparation. CHGH, however, contained 180 mU pressor and 250 mU uterine activity per unit CHGH. Further, the CHGH preparation had a marked antidiuretic effect when administered to patients with diabetes insipidus. Several other CHGH preparations contained widely differing amounts of rat pressor activity. It is concluded that: 1) HGH has an intrinsic ability to stimulate net sodium transport in the isolate...

Background Copper oxide nanomaterials (CuO NMs) are exploited in many products including inks, cosmetics, textiles, wood preservatives and food contact materials. Their incorporation into these products may enhance oral exposure in consumer, environmental and occupational settings. Undifferentiated and differentiated monocultures of Caco-2 cells are commonly used to assess NM toxicity to the intestine in vitro. However, the integration of other cell types into Caco-2 in vitro models increases their physiological relevance. Therefore, the aim of this study is to evaluate the toxicity of CuO NMs and copper sulphate (CuSO4) to intestinal microfold (M) cell (Caco-2/Raji B) and mucus secreting (Caco-2/HT29-MTX) co-culture in vitro models via assessment of their impact on barrier integrity, viability and interleukin (IL)-8 secretion. The translocation of CuO NMs and CuSO4 across the intestinal barrier was also investigated in vitro. Results CuO NMs and CuSO4 impaired the function of the intestinal barrier in the co-culture models [as indicated by a reduction in transepithelial electrical resistance (TEER) and Zonular occludens (ZO-1) staining intensity]. Cu translocation was observed in both models but was greatest in the Caco-2/Raji B co-culture. CuO NMs and CuSO4 stimulated an increase in IL-8 secretion, which was greatest in the Caco-2/HT29-MTX co-culture model. CuO NMs and CuSO4 did not stimulate a loss of cell viability, when assessed using light microscopy, nuclei counts and scanning electron microscopy. CuO NMs demonstrated a relatively similar level of toxicity to CuO4 in both Caco-2/Raji B and Caco-2/HT29-MTX co- culture models. Conclusions The Caco-2/Raji B co-culture model was more sensitive to CuO NM and CuSO4 toxicity than the Caco-2/HT29-MTX co-culture model. However, both co-culture models were less sensitive to CuO NM and CuSO4 toxicity than simple monocultures of undifferentiated and differentiated Caco-2 cells, which are more routinely used to investigate NM toxicity to the intestine. Obtained data can therefore feed into the design of future studies which assess the toxicity of substances (e.g. NMs) and pathogens to the intestine (e.g. by informing model and endpoint selection). However, more testing with a wider panel of NMs would be beneficial in order to help select which in vitro models and endpoints to prioritise when screening the safety of ingested NMs. Comparisons with in vivo findings will also be essential to identify the most suitable in vitro model to screen the safety of ingested NMs. Electronic supplementary material The online version of this article (10.1186/s12951-019-0503-1) contains supplementary material, which is available to authorized users.

MANY investigators have shown that catecholamines are unusually stable in whole blood1,2. The persistence of catecholamines in blood has variously been attributed to non-specific absorption by erythrocytes3, platelets4, phospholipids5 and albumin (Cohen-Fraction V)6. Bovine adrenal glands perfused with acetylcholine containing Locke's solution have been shown to release catecholamines and a specific protein into the perfusate7, and recent work utilizing tritiated noradrenaline has demonstrated that intravenously administered catecholamines are removed from the circulation in at least two stages: an initial rapid phase causing disappearance of 60–70 per cent of a given dose within 2 min and a slow phase lasting several hours8. These data suggest that under physiological conditions circulating catecholamines may bind to formed blood elements and thereby become temporarily unavailable for biotransformation. The present investigation was undertaken to determine whether circulating catecholamines were bound to a specific protein component of plasma (catecholamine binding protein) in a manner analogous to corticosteroid binding globulin9 or thyroxine binding globulin10.

7 patients (pts) with OP (4 infants ages 0.3-0.6 yrs and 3 children ages 2.0-3.8 yrs) were studied biochemically and by bone biopsy to correlate laboratory parameters with disease outcome. All pts presented in the first 6 mo of life with optic atrophy, cranial n. dysfunction, respiratory abnormalities, and pallor. Distinguishing features are summarized below: Two infants (with advanced fibrosis) received massive doses (24 ug/d) of 1,25-(OH)2D3 for 3 weeks without bone biopsy improvement despite hydroxyprolinuria. Three infants and 1 child underwent bone marrow transplantation. Bony remodeling occurred in 1 infant and 1 child. Of the 2 infants with advanced fibrosis, 1 was evaluable and had engraftment in the nonfibrotic, membranous bone but not in the fibrotic endochondral bone. We conclude that the above parameters may correlate with bone biopsies and that advanced fibrosis may be predictive of resistence to therapies.

Osteogenesis imperfecta is likely to be caused by primary disorders of synthesis of organic components of connective tissues accounting for clinical and laboratory observations in several affected tissues. Defects in the structure of collagen is well documented in several instances. There is no evidence of a primary disorder in the synthesis of glycosaminoglycans. Several studies of pyrophosphate metabolism and the hormonal control or the overall metabolic activity of isolated cells do not implicate a pathogenic mechanism for this disorder. Detailed biochemical and further clinical correlations are necessary in order to elucidate the pathogenesis of osteogenesis imperfecta.

A high frequency of abnormalities were noted in radiographic measurements of bone density, microradiography of the iliac crest, serum alkaline phosphatase, urinary hydroxyproline and dietary calcium intake in 12 patients with Scheuermann's juvenile kyphosis. Scheuermann's kyphosis may be a manifestation of generalized skeletal disease which becomes symptomatic during the growth spurt of puberty.

Cell-mediated immunity in 15 patients with chronic mucocutaneous or systemic candidiasis has been studied by measuring the proliferative response of patients' peripheral mononuclear cells to mitogen and specific antigen in vitro. Cells from all patients responded within normal limits to mitogen, but consistently failed to proliferate in response to antigen, including Candida antigen. Positive responses to Candida antigen were obtained, however, by increasing the density at which the cells were cultured and by addition of monocytes from normal donors. Patient's monocytes failed to reconstitute the response of monocyte-free lymphocytes from normal, Candida-sensitive donors to antigen. These results demonstrate that candidiasis patients have circulating Candida-sensitive lymphocytes and suggest that failure of these cells to proliferate in response to antigen is due to defective monocytes. Further experiments suggest that this defect may be acquired due to factors present in patients' sera. Work supported by NIH, Minnesota Heart Association, Minnesota Medical Foundation and the University of Minnesota Graduate School.

Aspects of phosphate biochemistry pertinent to therapy, the distribution of phosphorus in body compartments, therapeutic phosphorus preparations, prevention of hypophosphatemia, therapeutic guidelines, and side-effects of phosphorus therapy are reviewed. Severe hypophosphatemia (less than 0.32 mmol/litre or less than 1 mg/dl) can occur with normal or depleted body stores. Because a large amount of phosphorus may shift rapidly between the extracellular and intracellular or bone compartments, the size of a possible total body deficit cannot be estimated from the serum phosphorus level. Similar shifts may occur unpredictably during repair of hypophosphatemia. Therefore, correction of hypophosphatemia in any patient must be empiric and the response of serum levels to therapy should be followed closely. We discuss a method likely to correct hypophosphatemia while minimizing side-effects.

Previous examinations of skin biopsies suggested that connective tissue may be abnormal in patients with idiopathic scoliosis. The fibroblast culture system has proven a powerful technique for approaching many diseases of known connective origin, and therefore, seemed an appropriate method with which to study scoliosis. Present observations on collagen synthesis, skin collagen extractability, and glycosaminoglycan (GAG) synthesis and degradation appear normal. Idiopathic scoliosis does not prove to be a generalized connective tissue disorder. While factors other than collagen and GAG metabolism seem not to be at fault, other possibilities seem not to be taken into consideration by basic research on the spinal column: genetics, biochemistry, and physiology.

A case of severe hypophosphatemia was due to prolonged antacid therapy and chronic hemodialysis. The primary manifestation was severe muscle weakness which was apparently corrected by phosphorus infusion and addition of phosphorus to the dialysis bath. The pathogenesis of the symptoms of hypophosphatemia may be due to depletion of energy substrate for muscle contraction.