Monocytes and γδ T cells control the acute‐phase response to intravenous zoledronate: Insights from a phase IV safety trial

Aminobisphosphonates (NBPs) are used widely against excessive bone resorption in osteoporosis and Paget's disease as well as in metastatic bone disease and multiple myeloma. Intravenous NBP administration often causes mild to severe acute‐phase responses (APRs) that may require intervention with analgesics and antipyretics and lead to treatment noncompliance and nonadherence. We here undertook a phase IV safety trial in patients with osteoporosis to investigate the APR of otherwise healthy individuals to first‐time intravenous treatment with the NBP zoledronate. This study provides unique insight into sterile acute inflammatory responses in vivo, in the absence of confounding factors such as infection or cancer. Our data show that both peripheral γδ T cells and monocytes become rapidly activated after treatment with zoledronate, which ultimately determines the clinical severity of the APR. Our study highlights a key role for IFN‐γ in the zoledronate‐induced APR and identifies pretreatment levels of monocytes and central/memory Vγ9/Vδ2 T cells as well as their responsiveness to zoledronate in vitro as predictive risk factors for the occurrence of subclinical and clinical symptoms. These findings have diagnostic and prognostic implications for patients with and without malignancy and are relevant for Vγ9/Vδ2 T‐cell–based immunotherapy approaches. © 2012 American Society for Bone and Mineral Research. © 2013 American Society for Bone and Mineral Research.     

Influence of antithymocyte globulin treatment of brain‐dead organ donor on inflammatory response in cardiac grafts: an experimental study in mice

The expression of proinflammatory cytokines in donor hearts after antithymocyte globulin (ATG) treatment given prior to organ removal was evaluated to analyze changes in inflammatory response. Adult female OF‐1 mice were randomized into brain death (BD) groups (BD Control, BD ATG) with or without treatment, and Controls (Control, ATG). BD induction was performed through gradual inflation of an intracranial positioned balloon catheter. At the end of a 6‐h observation period, ATG (1 mg/kg BW) was given intravenously. After 45 min, the donor hearts were removed. Proinflammatory markers IL‐2 and IL‐6 were examined using ELISA and immunohistochemistry staining. After single administration of ATG, the inflammatory reaction in the myocardium showed a significant reduction in IL‐2 expression (BD Control vs. BD ATG, P = 0.033). Our investigation showed expected increase in proinflammatory mediators after BD. This increase was abolished by single infusion of ATG, indicated by significant reduction in IL‐2 levels in the myocardium. We observed a reduction of IL‐6 deposition in media cells in ATG‐treated specimens. Further research is necessary to evaluate the role of ATG in donor management considering a potentially positive effect of ATG on IL‐2‐directed inflammatory response and possible reduction of IL‐6‐mediated vascular changes.     

Multiple granulomas in three squirrel monkeys (Saimiri sciureus) caused by Mycobacterium microti

Mycobacterium microti, a member of the Mycobacterium tuberculosis complex, causes tuberculosis in small rodents and occasionally in other mammals including man. Three adult male squirrel monkeys, two with a history of lethargy, weakness and stridor and one with paralysis of the hind legs, were presented for necropsy. One of the two lethargic animals showed multiple granulomas in the mesentery, mesenteric lymph nodes, lung, liver, kidneys and spleen, while the other showed granulomas only in the lung. The animal with paralysis of the legs had an abscess-like lesion in the skeletal muscle of the neck, granulomas in the mesenteric and mediastinal lymph nodes, and a fracture of the thirteenth thoracic vertebra with severe lesions of the spinal cord. Histologically the granulomas showed typical features of tuberculous granulomas, i.e., central necrosis surrounded by epithelioid cells, multinucleated giant cells, inflammatory cells and a border of connective tissue. Ziehl-Neelsen stain demonstrated sporadic acid-fast bacilli within the granulomas, these organisms being identified as M. microti by microbiological and molecular methods.     

Surgical therapy of breast cancer: to operate radically or to preserve the breast?

Surgical treatment, i.e. partial resection (R) versus modified radical mastectomy (M) in lymph node negative T1/2 patients and M versus the classical Halsted procedure (RM) in lymph node positive cases, as well as adjuvant treatment forms, namely chemotherapy (B) and chemoimmunotherapy (C) versus a control group treated by surgery only (A) have been evaluated in 241 patients with breast cancer follow up over a median observation time of 48 months. Whereas M showed significantly better results than R, no difference was detected between M and RM. The incidence of recurrence in the R group did not appear to be markedly reduced by cytotoxic treatment. In the same way, the data from a retrospective study on non-randomized patients treated by breast resection, showed a relatively high local recurrence rate (23.6%) at a median observation level of 10 years. Considering the various forms of surgical treatment for operable breast cancer by analysing the data from retrospective studies and prospective randomized trials from the literature as well as our own results, the only recommendation for the standard treatment of patients with primary operable breast cancer should be nothing less than modified radical mastectomy. Breast-conserving treatment forms should be tested only within the framework of controlled clinical trials.     

Increased Trabecular Volumetric Bone Mass Density in Familial Hypocalciuric Hypercalcemia (FHH) Type 1: A Cross-Sectional Study

Familial Hypocalciuric Hypercalcaemia (FHH) Type 1 is caused by an inactivating mutation in the calcium-sensing receptor (CASR) gene resulting in elevated plasma calcium levels. We investigated whether FHH is associated with change in bone density and structure. We compared 50 FHH patients with age- and gender-matched population-based controls (mean age 56 years, 69 % females). We assessed areal BMD (aBMD) by DXA-scans and total, cortical, and trabecular volumetric BMD (vBMD) as well as bone geometry by quantitative computed tomography (QCT) and High-Resolution peripheral-QCT (HR-pQCT). Compared with controls, FHH females had a higher total and trabecular hip vBMD and a lower cortical vBMD and hip bone volume. Areal BMD and HRpQCT indices did not differ except an increased trabecular thickness and an increased vBMD at the transition zone between cancellous and cortical bone in of the tibia in FHH. Finite element analyses showed no differences in bone strength. Multiple regression analyses revealed correlations between vBMD and P-Ca²⁺ levels but not with P-PTH. Overall, bone health does not seem to be impaired in patients with FHH. In FHH females, bone volume is decreased, with a lower trabecular volume but a higher vBMD, whereas cortical vBMD is decreased in the hip. This may be due to either an impaired endosteal resorption or corticalization of trabecular bone. The smaller total bone volume suggests an impaired periosteal accrual, but bone strength is not impaired. The findings of more pronounced changes in females may suggest an interaction between sex hormones and the activity of the CaSR on bone.     

The effect of social health insurance on prenatal care: the case of Ghana

Many developing countries have introduced social health insurance programs to help address two of the United Nations’ millennium development goals—reducing infant mortality and improving maternal health outcomes. By making modern health care more accessible and affordable, policymakers hope that more women will seek prenatal care and thereby improve health outcomes. This paper studies how Ghana’s social health insurance program affects prenatal care use and out-of-pocket expenditures, using the two-part model to model prenatal care expenditures. We test whether Ghana’s social health insurance improved prenatal care use, reduced out-of-pocket expenditures, and increased the number of prenatal care visits. District-level differences in the timing of implementation provide exogenous variation in access to health insurance, and therefore strong identification. Those with access to social health insurance have a higher probability of receiving care, a higher number of prenatal care visits, and lower out-of-pocket expenditures conditional on spending on care.