Vitamin D receptor genotype and risk of osteoporotic hip fracture in elderly women of Utah: an effect modified by parity

Introduction The associations between vitamin D receptor (VDR) Bsm I and Fok I genotypes, parity, and risk of osteoporotic hip fracture were evaluated in a statewide population-based case-control study in Utah.Methods Women age 50–89 years with hip fracture (n=882) were ascertained via surveillance of 18 Utah hospitals from 1997 to 2001. Age-matched controls were randomly selected (n=897). Participants were interviewed in their homes, and blood samples were collected for genotyping.Results In logistic regression analyses that controlled for multiple confounders, Bsm I VDR genotype but not Fok I genotype was associated with risk of osteoporotic hip fracture (OR bb vs. BB genotype: 0.68; 95% CI: 0.50, 0.95). In similar analyses, no overall association was observed between parity status and risk of osteoporotic hip fracture. However, the effect of VDR genotype was modified by parity status. Among nulliparous women (n=140), Bsm I genotype was not associated with risk of hip fracture (OR bb vs. BB: 0.82; 95% CI: 0.28, 2.4); among primiparous women (n=133), bb genotype was associated with increased risk of hip fracture (OR bb vs. BB: 3.30; 95% CI: 0.96, 11.29); among multiparous women (n=1,400), bb genotype was associated with decreased risk of hip fracture (OR bb vs. BB: 0.59; 95% CI: 0.42, 0.84).Conclusion VDR Bsm I genotype was associated with risk of hip fracture in Utah women, and this effect was modified by parity status. Hormonal or lifestyle factors related to parity may underlie this interaction.     

An experimental painful peripheral neuropathy due to nerve constriction. I. Axonal pathology in the sciatic nerve.

A constriction injury to the sciatic nerve of the rat produces a painful peripheral neuropathy that is similar to the conditions seen in man. The pathology of the sciatic nerve in these animals was examined at 10 days postinjury, when the abnormal pain sensations are near maximal severity. The nerves were examined with (1) complete series of silver-stained longitudinal sections of pieces of the nerve (3 cm or more) that contained the constriction injury in the center, (2) toluidine blue-stained semithin sections taken at least 1 cm proximal and 1 cm distal to the constriction, and (3) EM sections taken adjacent to those stained with toluidine blue. One centimeter or more proximal to the constriction, both myelinated and unmyelinated axons were all normal. Nearer to the constriction, extensive degeneration of myelinated axons became increasingly common, as did signs of endoneurial edema. Distal to the constriction, the nerve was uniformly edematous and full of myelinic degeneration. There was a profound loss of large myelinated axons and a distinctly less severe loss of small myelinated and unmyelinated axons. These observations show that at 10 days postinjury the constriction produces a partial and differential deafferentation of the sciatic nerve's territory. The absence of degeneration in the nerve 1 cm proximal to the constriction indicates the survival of the primary afferent neurons whose axons are interrupted.     

The sensory innervation of the rat rhinarium

The present study documents the characteristics of innervation of the rhinarium or hairless rat snout skin by light and electron microscopy. The outer glabrous surface is covered with a stratified squamous epithelium that forms both rete pegs and rete ridges, the latter on the inferior border near the philtrum. The glabrous skin contains numerous presumptive epidermal and dermal free nerve endings (FNE's), Merkel terminals at the base of the rete ridges and pegs, and simple, nonencapsulated corpuscles. A second region of dense innervation, found on an elevation of the inner wall of the vestibule, contains similar components of innervation, with the exception that no Merkel terminals were identified. Since no Merkel terminals were present in this area of the vestibule, intraepidermal as well as dermal FNE's could be identified with certainty. This skin is covered by a thin squamous epithelium overlying dense connective tissue. The simple corpuscles are similar to those in the rhinarium, as well as resembling those described in other species. FNE's were frequently observed intimately associated with simple corpuscles. Several examples of large FNE's with two to three layers of cytoplasmic lamellae were found, suggestive of transitional forms between FNE's and simple corpuscles. Thus, the pattern of sensory innervation in the glabrous rat snout skin is similar to that found in other furred species described to date, but in addition, the sensory innervation of ridged skin in the rat also resembles that of epidermis organized into rete pegs. This dense sensory innervation may be correlated with whisking behavior of the predominantly nocturnal rat.     

The differentiation of the skin and its appendages. I. Normal development of papillary ridges.

In the present study, the normal development of papillary ridges was studied in the volar pads of both fore and hindpaws of the opossum, Monodelphis domesticus. At birth, the developmental state of the opossum's paws is equivalent to that of a six-week human embryo. The development of papillary ridges in the opossum occurs entirely postnatally and the hindpaw lags behind the forepaw by at least four days in most developmental parameters. Papillary ridge formation is preceded by four events: skin innervation, Merkel cell differentiation, mesenchymal condensation, and epidermal proliferation. The apical pads at the tips of the digits and the interdigital pads between the heads of the metacarpals (or metatarsals) have a unique pattern of innervation and mesenchymal content as compared to the non-pad skin. Each pad is innervated by a prominent nerve trunk and axons ascend towards the epidermis providing a density of innervation that exceeds that in the non-pad epidermis. Merkel cells are absent in non-pad epidermis but present in the pads prior to the onset of formation of papillary ridges. A loose aggregation of mesenchyme forms the core of the pads and the superficial dermis is more cellular in the pads as compared to the equivalent dermis in surrounding non-pad skin. Developing papillary ridges always contained Merkel cell-axon complexes. Merkel cell axon complexes serve as the anatomical substrate of slowly adapting (SA) mechanoreceptors. The presence of these complexes during early skin differentiation is consistent with the use of the opossum's forepaw in climbing to the nipple, but also suggests other possible functions. We hypothesize that the nervous system might play a role in the timing or patterning of the formation of papillary ridges.     

Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity During Fracture Healing in Different Murine Strains

Smokers are at a higher risk of delayed union or nonunion after fracture repair. Few specific interventions are available for prevention because the molecular mechanisms that result in these negative sequelae are poorly understood. Murine models that mimic fracture healing in smokers are crucial in further understanding the local cellular and molecular alterations during fracture healing caused by smoking. We exposed three murine strains, C57BL/6J, 129X1/SvJ, and BALB/cJ, to cigarette smoke for 3 months before the induction of a midshaft transverse femoral osteotomy. We evaluated fracture healing 4 weeks after the osteotomy using radiography, micro-computed tomography (μCT), and biomechanical testing. Radiographic analysis demonstrated a significant decrease in the fracture healing capacity of smoking 129X1/SvJ mice. μCT results showed delayed remodeling of fracture calluses in all three strains after cigarette smoke exposure. Biomechanical testing indicated the most significant impairment in the functional properties of 129X1/SvJ in comparison with C57BL/6J and BALB/cJ mice after cigarette smoke exposure. Thus, the 129X1/SvJ strain is most suitable in simulating smoking-induced impaired fracture healing. Furthermore, in smoking 129X1/SvJ murine models, we investigated the molecular and cellular alterations in fracture healing caused by cigarette smoking using histology, flow cytometry, and multiplex cytokine/chemokine analysis. Histological analysis showed impaired chondrogenesis in cigarette smoking. In addition, the important reparative cell populations, including skeletal stem cells and their downstream progenitors, demonstrated decreased expansion after injury as a result of cigarette smoking. Moreover, significantly increased pro-inflammatory mediators and the recruitment of immune cells in fracture hematomas were demonstrated in smoking mice. Collectively, our findings demonstrate the significant cellular and molecular alterations during fracture healing impaired by smoking, including disrupted chondrogenesis, aberrant skeletal stem and progenitor cell activity, and a pronounced initial inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR).     

F(2)-isoprostanes mediate high glucose-induced TGF-beta synthesis and glomerular proteinuria in experimental type I diabetes

BACKGROUND: The recently discovered arachidonic acid derivatives, isoprostanes, are increased in pathological conditions associated with oxidative stress, such as diabetes. No role has yet been described for isoprostanes during the development of diabetic nephropathy. Cell culture in high ambient glucose has been used as a model in elucidating cellular mechanisms underlying diabetic nephropathy. Among the growth factors involved in the effect of high glucose, transforming growth factor-beta (TGF-beta) has been described as playing a key role in the development of nephropathy. METHODS: Streptozotocin-induced diabetic rats were supplemented in their diet with the antioxidant vitamin E (1000 U/kg diet). Blood and urine samples were taken to determine renal function and isoprostane concentration, as determined by gas chromatography/mass spectrometry. Glomerular mesangial and endothelial cells were cultured in high ambient glucose to determine the synthesis of isoprostanes and the role of isoprostanes in high glucose-induced synthesis of TGF-beta. RESULTS: Streptozotocin-induced diabetic rats had marked increases in plasma levels and urinary excretion rates of F(2)-isoprostanes. Dietary supplementation with vitamin E normalized (plasma) and reduced (urine) isoprostane levels and, surprisingly, improved proteinuria and blood urea nitrogen (BUN) levels. High ambient glucose increased F(2)-isoprostane synthesis in glomerular endothelial and mesangial cells in culture. Incubation of glomerular cells with F(2)-isoprostanes stimulated the production of TGF-beta. CONCLUSIONS: Increased F(2)-isoprostane synthesis during diabetes appears to be responsible in part for the increase in renal TGF-beta, a well-known mediator of diabetic nephropathy.     

IMRT for breast. a planning study.

BACKGROUND AND PURPOSE: To evaluate the performance of ten different treatment-planning systems when intensity modulated (IMRT) plans are designed for breast treatments that include the irradiation of the internal mammary chain. PATIENTS AND METHODS: A dataset of five patients (CT images and volumes of interest) was distributed to design IMRT plans on the ten systems. To minimise biases, the same geometry and clinical planning aims were imposed on the individual plans. Results were analysed in terms of dose distributions and dose volume histograms. RESULTS AND CONCLUSIONS: For target coverage, the volume receiving more than 95% of the prescribed dose ranged from 77% (OTP) to 91% (Eclipse and Pinnacle), the volume receiving more than 107% ranged from 3.3% (Hyperion) to 23.2% (OTP). The mean dose to ipsilateral lung ranged from 13 Gy (Eclipse) to 18 Gy (OTP). The volume of the contralateral breast receiving more than 10 Gy ranged from 3% (Pinnacle) to 26% (Precise). The volume of heart receiving more than 20 Gy ranged from 7% (Eclipse) to 47% (Precise), the maximum significant dose to heart ranged from approximately 27 Gy (XiO) to approximately 49 Gy (Precise). The maximum significant dose to healthy tissue ranged from approximately 51 Gy (Eclipse) to approximately 62 Gy (OTP). It was also possible to show that the treatment geometry proposed here enables to minimise contralateral breast irradiation while keeping minimal ipsilateral lung (or heart) involvement and satisfactory target coverage.