A global call to action to improve the care of people with fragility fractures.

The ageing of society is driving an enormous increase in fragility fracture incidence and imposing a massive burden on patients, their families, health systems and societies globally. Disrupting the status quo has therefore become an obligation and a necessity. Initiated by the Fragility Fracture Network (FFN) at a "Presidents' Roundtable" during the 5th FFN Global Congress in 2016 several leading organisations agreed that a global multidisciplinary and multiprofessional collaboration, resulting in a Global Call to Action (CtA), would be the right step forward to improve the care of people presenting with fragility fractures. So far global and regional organisations in geriatrics/internal medicine, orthopaedics, osteoporosis/metabolic bone disease, rehabilitation and rheumatology were contacted as well as national organisations in five highly populated countries (Brazil, China, India, Japan and the United States), resulting in 81societies endorsing the CtA. We call for implementation of a systematic approach to fragility fracture care with the goal of restoring function and preventing subsequent fractures without further delay. There is an urgent need to improve: To address this fragility fracture crisis, the undersigned organisations pledge to intensify their efforts to improve the current management of all fragility fractures, prevent subsequent fractures, and strive to restore functional abilities and quality of life.

Pharmacy benefit management companies: dimensions of performance.

Research on pharmacy benefit management companies focuses on descriptive accounts of the organizations and the scope of their services. This review provides a critical analysis of publicly available research on contemporary issues surrounding the operations and effects of pharmacy benefit management companies. There has been very little systematic, empirical research on these issues; major questions concerning the impact of pharmacy benefit management companies on quality, costs, and patient outcomes remain unanswered. We analyze what is known and what needs to be known, and we explore major research challenges that lie ahead in the assessment of the pharmacy benefit management company's role in the health care system and in improving the public's health.

Pruritic urticarial papules and plaques of pregnancy.

We report an intensely pruritic cutaneous eruption that occurs in the third trimester of pregnancy. The clinical manifestations include erythematous urticarial papules and plaques that begin on the abdomen and spread to involve the thighs and occasionally the buttocks and arms. This dermatosis appears to be clinically distinct from previously described pruritic eruptions occurring in pregnancy. Biopsy specimens of the lesions show two histological patterns. We propose that this entity be termed "pruritic urticarial papules and plaques of pregnancy (PUPPP)".

Erythema elevatum diutinum: skin and systemic manifestations, immunologic studies, and successful treatment with dapsone.

Erythema elevatum diutinum is a disease characterized by red, pink, purple and yellow cutaneous papules, nodules, and plaques distributed mainly over extensor surfaces. Histologically, there is leukocytoclastic vasculitis with fibrinoid necrosis of the upper and mid dermal vessel walls. Two of the five patients presented had moderately severe arthralgias and, unlike previously reported cases, three of them had a long history of bacterial infections and one had a coincident IgA monoclonal gammopathy. Each of the four patients treated with dapsone responded dramatically with rapid resolution of existing lesions and marked diminution of systemic symptoms. Skin lesions and systemic complaints recurred within 12 to 48 hours after discontinuing dapsone. Four of the patients had Arthus-like reactions to SKSD skin tests prior to therapy, with a marked decrease in the response after institution of therapy. Neutrophil chemotactic responsiveness of two patients was impaired. The sera of three patients had significant C1q binding activity suggesting that they might have circulating immune complexes.

Autoimmune vitiligo: detection of antibodies to melanin-producing cells.

Vitiligo, a disorder characterized by the destruction of melanocytes, is often associated with diseases in which there are increased frequencies of autoantibodies. For this reason we investigated two patients with vitiligo, alopecia universalis, mucocutaneous candidiasis, and multiple endocrine insufficiencies for antibodies to melanin-producing cells. Using direct immunofluorescence of normal and vitiliginous skin from both patients and indirect immunofluorescence with both patients' serum, we could not detect these antibodies. However, an immunofluorescent complement-fixation test demonstrated a circulating antibody that bound to melanocytes in human skin, nevus cells and melanoma cells. Specificity of cellular fluorescence for nevus and melanoma cells was shown on serial sections stained with hematoxylin and eosin and was inferred for melanocytes from their distribution in human skin and their presence when the normal but not vitiliginous skin of both patients was used as substrate. This antibody was characterized as an IgG that activated complement via the classical pathway.

Juvenile dermatitis herpetiformis: an immunologically proven case.

Subepidermal blistering diseases of childhood have, in the past, been thought to represent cases of juvenile dermatitis herpetiformis, bullous pemphigoid, or benign chronic bullous dermatosis of childhood. While the small-blister variety closely resembles adult-type dermatitis herpetiformis, the large-blister, or bullous, variety has clinical and histologic resemblances to bullous pemphigoid. The patient presented in this report clearly fits previous descriptions of the large-blister type of juvenile dermatitis herpetiformis, bullous pemphigoid, or benign chronic bullous dermatosis of childhood both clinically and histologically, while his therapeutic response to dapsone and the presence of in vivo bound IgA at the basement membrane of normal and perilesional skin are highly characteristic of the adult type of dermatitis herpetiformis. Immunofluorescent studies of similar cases reported in the literature, however, have shown variable results, thus obscuring their classification. Though the proper place of all such cases in the nosology of blistering diseases is not yet clear, at least some of them closely resemble adult-type dermatitis herpetiformis by two important criteria--immunologic and therapeutic.

Herpes gestationis. An update.

Advances in the immunopathology of blistering diseases now provide increased accuracy in the diagnosis of herpes gestationis in pregnancy. Guidelines are presented in this review to determine the presence of the disease. Exogenous corticosteroids will effectively alleviate symptoms and prevent formation of new lesions.

HLA-B8 and dermatitis herpetiformis in patients with IgA deposits in skin.

The association between antigens of the HLA system and dermatitis herpetiformis (DH) using in vivo-bound IgA as an added criteria for diagnosis is reexamined. Twenty-eight of 33 (85%) immunologically proven patients with DH were HLA-B8 positive, whereas only 17 of 92 (18%) controls were HLA-B8 positive.

Immunofluorescent localization of basement membrane in lesions of dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is a blistering disease with a characteristic histology that includes papillary edema, neutrophilic papillary microabscesses, and development of subepidermal blisters. In spite of this pathologic sequence occurring entirely beneath the basement membrane zone, prior studies have indicated that the basement membrane, as defined by period acid-Schiff (PAS) or silver stains, lies at the floor of fully formed blisters or is destroyed by the disease process. To more accurately assess its location in primary lesions of DH, the basement membrane was stained using immunofluorescent techniques. Lesional skin from 5 patients with DH was used as substrate for indirect immunofluorescence with sera from patients with bullous pemphigoid (BP) and fluoresceinated antihuman IgG. The BP-stained basement membrane was attached to the roofs of early blisters, where it would be expected from the pathologic sequence of blister formation. PAS stains of the same or serial sections show the basement membrane to be in the roof or at the floor of the blisters. PAS stains of sections from formalin-fixed lesional skin, on the other hand, show the basement membrane to routinely lie at the blister floor, when not destroyed. The BP-stained epidermal basement membrane has greater anatomic and functional significance than either the PAS-or silver-stained basement membrane for two reasons: (1) it corresponds to a specific morphologic structure, the lamina lucida, a part of the epidermis, and remains attached to the rest of the epidermis unless destroyed; and (2) it is antigenic, capable of binding with BP antibodies.

Dermatitis herpetiformis: immunoelectronmicroscopic and ultrastructural studies of a patient with linear deposition of IgA.

Using immunoelectronmicroscopic techniques, we have demonstrated three distincet patterns of IgA deposition in the skin of patients with dermatitis herpetiforms. The least common of these patterns is the localization of reaction products to the lamina lucida. As this is the location of the immunoreactants in bullous pemphigoid and herpes gestationis and because the ultrastructural findings in our patient's early lesional skin differ from those usually seen in patients with dermatitis herpetiformis, we herein detail this patient's clinical, histologic, immunologic, and ultrastructural findings. The most prominent findings are (1) IgA deposition in the lamina lucida, (2) vesicle formation between basal lamina and the basal cells, and (3) fibrin-like material in the epidermis with showering into the dermis.

Effect of sulfones on complement deposition in dermatitis herpetiformis and on complement-mediated guinea-pig reactions.

The role of complement and the mechanism of sulfone action in dermatitis herpetiformis (DH) have not yet been established; prior studies have presented conflicting data regarding the effect of sulfones on complement activation and deposition. Thirty-eight DH patients were studied. Twenty-four of 25 perilesional skin biopsies and 50 of 67 normal-appearing skin biopsies showed the third component of complement (C3) deposited in areas corresponding to those of IgA deposition. Nine of 10 patients with bound C3 in normal-appearing and perilesional skin during periods of active disease continued to have C3 in normal-appearing skin when treatment with sulfones kept them completely free of lesions for 2 to 8 weeks. When either Hartley-strain or C4-deficient guinea pigs were given up to 150 mg/kg sulfoxone (a water-soluble sulfone) intraperitoneally for 8 days before elicitation of active Arthus, reverse passive Arthrus reactions, or Forssman shock, there was no difference in time course, character, or intensity of reactions when compared to saline-treated control animals. We were therefore unable to demonstrate any effect of sulfones on complement deposition in DH skin or on complement activation in classical or alternate complement pathway-mediated guinea-pig reactions.

Herpes gestationis. A clinicopathologic study.

Herpes gestationis is a pruritic, blistering eruption of pregnancy and the puerperium. In three patients with immunologically verified disease, the clinical presentation consisted of widespread erythematous, edematous papules and plaques, grouped vesicles on erythematous bases, and tense bullae. Histologically, these lesions showed a moderately dense, mixed-inflammatory cell infiltrate around superficial and deep dermal blood vessels, and focal necrosis of epidermal basal cells. Papillary dermal edema, subepidermal bullae, and spongiosis were prominent. Eosinophils were frequently present in the subepidermal and intrepidermal vesicles. Differentiation of herpes gestationis from other blistering diseases and other dermatitides of pregnancy may be difficult.

Herpes gestationis. Immunopathology and characterization of the HG factor.

Five patients with herpes gestationis, a blistering disease of pregnancy, were studied immunologically. All had in vivo deposition of C3 in a linear band along the basement membrane zone of lesional and normal-appearing skin, the location of early blister formation. Immunoglobulin deposition was more variable, though four patients had evidence of in vivo bound IgG at the same site. A circulating, complement binding herpes gestationis factor was demonstrated in the sera of four of the patients, its concentration unrelated to the activity of clinical disease. Characterization of this factor by sucrose gradient ultracentrifugation, specific absorption studies, and papain digestion indicates that it is an IgG. Evidence exists for involvement of both the classical and alternate complement pathways in vivo, though in vitro studies implicate the classical pathway as the primary route of complement activation. Three offspring were studied, none with clinical involvement; one showed in vivo deposition of C3 at the basement membrane zone of normal skin and a second showed the herpes gestationis factor in cord blood.