Efficacy and safety of elcatonin in postmenopausal women with osteoporosis: a systematic review with network meta-analysis of randomized clinical trials.

The present systematic review aimed to evaluate bone mineral density (BMD) change and complication rates of elcatonin on treating postmenopausal osteoporosis. The result confirmed efficacy of elcatonin and safety in combination therapies of elcatonin (C-E). INTRODUCTION: Postmenopausal osteoporosis is an important issue in global aging trends. One treatment of osteoporosis is elcatonin, a kind of calcitonin. However, it has been challenged for long time because of safety. Many trials investigated on this topic, but they were designed differently. Those designs can be categorized in monotherapy of elcatonin (M-E) and C-E. Unfortunately, no synthesized evidence dealt this topic. METHODS: This study systematically identified target trials from six important databases and only included randomized controlled trial for synthesis. Two investigators assessed quality of eligible trials using the Cochrane Risk of Bias Tool, and they independently extracted data. Network meta-analysis performed Peto odds ratio (POR, used for dealing with zero cell) or weighted mean difference (WMD, for continuous data) with 95% confidence intervals (CI) and consistency H. RESULTS: Sixteen trials recruiting 2754 women with postmenopausal osteoporosis were included in our study. Elcatonin therapies and non-elcatonin medications had comparable fracture rates and bone mineral density change. Yet, C-E (WMD, - 18.93; 95% CI, - 23.97 to - 13.89) and M-E (WMD, - 13.72; 95% CI, - 19.51 to - 7.94) had significantly lower pain score than non-elcatonin medications. However, M-E (POR = 8.413, 95% CI, 2.031 to 34.859) and non-elcatonin medication (Peto OR, 7.450; 95% CI, 1.479 to 37.530) had significantly higher complication rates than placebo. No evidence detected inconsistency and small study effect in this network model. CONCLUSIONS: Based on current evidence, C-E may be considered for treating postmenopausal osteoporosis because it benefits on pain relief and complications. Moreover, it shows comparable fracture rate and bone mineral density change as compared with anti-osteoporosis and calcium supplements. Nevertheless, further trials are needed to investigate formula and dosages of elcatonin.

Keyhole surgery for isolated pituitary stalk metastatic tumors: a case report and review of the literature.

Solitary metastatic pituitary stalk tumors account for approximately less than 1% of all pituitary gland tumors and present difficulties in clinical diagnosis because most of them are clinically silent and usually too small to cause radiological changes. With the advance of microsurgical techniques, keyhole surgery is indicated to obtain a specimen for pathological diagnosis and possible removal of the tumor. Here, we reported a patient who has a history of advanced breast cancer and who complained of polyuria and polydypsia. Magnetic resonance images revealed a solitary tumor over the pituitary stalk. A right supraorbital craniotomy was performed and the pathological report confirmed the diagnosis of metastatic breast cancer. This is the first case report using keyhole surgery to confirm the pathology and improve the clinical symptoms. The relevant literature is also reviewed.

Role of infiltrated leucocytes in tumour growth and spread.

Leucocytes are a major component of the tumour microenvironment. Recent studies have indicated that the infiltration and activity of these host cells are regulated by the tumour to promote its survival and progression. Through the production of an array of growth factors, proteases and angiogenic mediators, leucocytes in the tumour microenvironment promote tumour growth, angiogenesis and metastasis.

Total esophageal reconstruction using a tubed parascapular free flap.

A method for total esophageal reconstruction when intestinal options are no longer available is presented. The technique described utilizes the parascapular microsurgical free flap, which is tubed and interposed between the cervical esophagus and the gastric remnant in the abdomen. The technique involves a well-recognized microsurgical flap and may be added to the armamentarium for total esophageal reconstruction.

Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy.

In human breast carcinomas, overexpression of the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R) correlates with poor prognosis. To establish if there is a causal relationship between CSF-1 and breast cancer progression, we crossed a transgenic mouse susceptible to mammary cancer with mice containing a recessive null mutation in the CSF-1 gene (Csf1(op)) and followed tumor progression in wild-type and null mutant mice. The absence of CSF-1 affects neither the incidence nor the growth of the primary tumors but delayed their development to invasive, metastatic carcinomas. Transgenic expression of CSF-1 in the mammary epithelium of both Csf1(op)/Csf1(op) and wild-type tumor-prone mice led to an acceleration to the late stages of carcinoma and to a significant increase in pulmonary metastasis. This was associated with an enhanced infiltration of macrophages into the primary tumor. These studies demonstrate that the growth of mammary tumors and the development to malignancy are separate processes and that CSF-1 selectively promotes the latter process. CSF-1 may promote metastatic potential by regulating the infiltration and function of tumor-associated macrophages as, at the tumor site, CSF-1R expression was restricted to macrophages. Our data suggest that agents directed at CSF-1/CSF-1R activity could have important therapeutic effects.

Angiogenesis and vascular growth factor receptor expression in malignant melanoma.

The growth and metastases of many solid tumors are dependent on the recruitment of new blood vessels. Tumor angiogenesis is most likely initiated by paracrine release of growth factors that bind to their corresponding endothelial cell surface receptors. To determine whether angiogenesis and growth factor receptor expression are consistent findings in malignant melanoma, primary human melanomas were examined for mRNA expression of receptors for fibroblast growth factors (FGFR-1, FGFR-2), vascular endothelial growth factor (VEGFR-1, VEGFR-2), and the receptors Tiel and Tie2. Charts were reviewed and archival formalin-fixed, paraffin-embedded primary tumors were obtained from patients with thin (<1 mm; n = 10), intermediate (1 to 4 mm; n = 10), or thick malignant melanoma (>4 mm; n = 8). Also examined was whether melanoma cell lines could induce endothelial growth factor receptor synthesis by metabolic labeling. It was found that tumor vascularity did not correlate with clinical stage, melanoma thickness, or clinical outcome. It was also found that melanoma cell lines were not capable of directly regulating endothelial cell synthesis of growth factor receptors. However, expression of Tiel and VEGFR-2 mRNA by the tumor vasculature in select stage IA-IIB patients, and FGFR-1 mRNA expression by the tumor cells in the same clinical stages was found. The expression of these growth factor receptors did not correlate with clinical outcome. These data suggest that angiogenesis is not a prominent characteristic of primary malignant melanoma lesions and that the endothelial cell expression of Tiel and VEGFR-2 in vivo is probably not directly induced by the tumor.

Methemoglobinemia secondary to topical silver nitrate therapy--a case report.

Methemoglobinemia is a rare complication in individuals exposed to nitrates or nitrites. Whereas methemoglobinemia is a recognized potential complication in burn patients treated with topical 0.5% silver nitrate solution, no report of methemoglobinemia in burn patients has been present in the literature for more than 15 years. We raise consciousness about this complication with a case report of a 12-month-old child with necrotizing fasciitis resulting from a cutaneous flank infection. The patient developed cyanosis 20 days after initiation of topical treatment with 0.5% silver nitrate solution. Intravenous injection of methylene blue can restore normal blood oxygenation.

Complexity in uterine macrophage responses to cytokines in mice.

Uterine stromal macrophages change dramatically in density and morphology through the estrous cycle and during early pregnancy, whereas those in the mesometrial triangle do not undergo these changes. The mononuclear phagocytic growth factor, colony-stimulating factor-1 (CSF-1), regulates both the density and morphology of uterine macrophage populations, as shown by the fact that uterine macrophages are depleted and more rounded in the absence of CSF-1 caused by the osteopetrotic (csfm(op)) null mutation, compared to those of normal mice. Restoration of circulating CSF-1 to the nullizygous mice did not affect stromal macrophage density although it restored the population in the mesometrial triangle. This suggests CSF-1 regulation of these macrophage populations by local and humoral routes, respectively. Nevertheless, even in the absence of CSF-1, stromal macrophage population density varies 30-fold through the estrous cycle, suggesting the involvement in their regulation of factors other than CSF-1, such as the chemokines, which are chemoattractive for macrophages. The mRNA for the chemokines JE (MCP-1), C10, RANTES, and MIP1alpha are expressed in the uterus, with elevated levels observed on the first day of pregnancy. Such molecules, together with CSF-1, may play a role in modulating the complexities of uterine macrophage dynamics in response to sex steroid hormones and mating.

A1, a Bcl-2 family member, prolongs cell survival and permits myeloid differentiation.

A1, a bcl-2 family member, has been identified as a hematopoietic-specific, early inducible gene. In this study it is shown that stable transfection of A1 into an interleukin-3 (IL-3)-dependent myeloid precursor cell line, 32D c13, leads to a retardation of IL-3 withdrawal-induced cell death similar to that observed with transfection of bcl-2. However, unlike bcl-2. A1 expression permits the accumulation of differentiated myeloid cells both before and after IL-3 withdrawal. Total cell accumulation, on the other hand, is considerably greater after IL-3 deprivation in the bcl-2 transfectant than in A1-expressing cells. Cells cotransfected with the two genes behave similarly to cells singly transfected with bcl-2, except that viability following IL-3 withdrawal is somewhat further enhanced. These results suggest that these two proteins have distinct roles that may be related to the divergent regulation of their expression during myeloid differentiation.

HIV infection and surgeons.

The human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome, which remains uniformly fatal in affected individuals. A common route of HIV transmission is via inoculation of contaminated blood, which may occur during surgical procedures. Surgeons may estimate their risk of HIV infection over a 30-year surgical career based on HIV prevalence among surgical patients, percutaneous injury rate per operation, and seroconversion rate. Surgeons can reduce their risk by various means, but the most pragmatic is by reducing the rate of percutaneous injury through optimal surgical technique and proper precautions.

Selective induction of the beta chemokine C10 by IL-4 in mouse macrophages.

The beta chemokines are a family of 8- to 12-kDa leukocyte chemoattractants that are typically produced by activated macrophages or lymphocytes. We examined the expression in primary macrophages of a recently described, and as yet functionally uncharacterized, murine beta chemokine, C10, and contrasted its regulation with that of several other beta chemokines. Although three other beta chemokines, macrophage inflammatory protein-1 alpha (MIP-1 alpha), JE, and RANTES, were all induced by LPS treatment of bone marrow-derived macrophages (BMM) and/or resident peritoneal macrophages (RPM), LPS stimulation of C10 was never observed. Conversely, IL-3 and granulocyte macrophage-CSF (GM-CSF) strongly induced C10 in both macrophage populations, whereas MIP-1 alpha and RANTES showed a weaker induction restricted to BMM. JE was strongly induced but only in BMM. Finally, IL-4 strongly induced C10 in a dose-dependent manner in both BMM and RPM but failed to stimulate any of the other three beta chemokines. The accumulation of C10 protein in culture supernatants paralleled the induction of mRNA, and the combination of IL-4 and GM-CSF led to enhanced protein levels. The expression of the C10 message in response to cytokines was completely blocked by cycloheximide, whereas the other three chemokines were all overexpressed in the presence of this inhibitor. These results demonstrate a sharp divergence between the regulation of C10 expression and that of other chemokines and suggest that this molecule may have distinct functions in host defense.

Increased expression of Fc gamma RI on isolated PMN from individuals of African descent.

Fc gamma R plays an important role in host defense, triggering and/or facilitating many immunologic responses. Of the three defined Fc gamma Rs, Fc gamma RI (CD64) is not known to be constitutively expressed on normal PMN. We report here that there is markedly increased expression of Fc gamma RI on the PMN of normal, healthy blacks, detected by binding of monoclonal antibody to this receptor. This may have significant implications when multiracial data are pooled in studies of receptor expression as markers of response to various chemotherapeutic agents.

Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates hemopoietic cell proliferation, differentiation, and functional activation by inducing the expression of specific genes. As part of an investigation of the regulation of gene expression by GM-CSF, we have previously identified a novel murine GM-CSF-inducible gene, A1. In this report, we present the complete nucleotide sequence of the A1 mRNA as well as a portion of the 5' flanking region, and describe the expression pattern of the gene. The results demonstrate that A1 is a hemopoietic tissue-specific gene that is expressed in several hemopoietic cell lineages, including T-helper lymphocytes, macrophages, and neutrophils. In murine bone marrow-derived macrophages, A1 gene expression is rapidly and transiently induced by GM-CSF, and the induction was independent of de novo protein synthesis. In addition to GM-CSF, a transient induction of A1 mRNA accumulation was observed in response to LPS in macrophages. This induction is not mediated by IL-1 alpha or IL-6, neither of which stimulate A1. In the myeloid precursor cell line, 32D cl3, A1 gene expression is stably induced during granulocyte colony-stimulating factor-stimulated myeloid cell differentiation. The A1 message encodes a predicted polypeptide with an M(r) of 20,024 and no signal peptide. The peptide sequence contains a region of 80 amino acids that shows similarity to bcl-2 and to the recently described bcl-2-related gene, MCL1. These data demonstrate that A1 is a novel early-response gene whose expression is associated with a variety of stimuli and occurs in several hemopoietic cell types.

The effects of IL-1, IL-2, and tumor necrosis factor on polymorphonuclear leukocyte Fc gamma receptor-mediated phagocytosis. IL-2 down-regulates the effect of tumor necrosis factor.

It has been reported that the Fc gamma R-mediated phagocytic activity of polymorphonuclear leukocytes (PMN) from patients with acute bacterial infections is markedly enhanced when compared with healthy controls. Inasmuch as several potent cytokines are known to be involved in inflammatory and infectious processes, we studied the effects of three such cytokines (IL-1 beta, IL-2, and TNF-alpha) on normal PMN Fc gamma R-mediated phagocytosis. IL-1 beta and TNF alpha both caused a significant increase in the ingestion of EIgG by adherent PMN. In combination, IL-1 beta and TNF-alpha had an additive effect, even when each was used at its optimal concentration. In contrast to the enhancing effects mediated by IL-1 beta and TNF-alpha, IL-2 alone had no significant effect on PMN phagocytosis. Notably, however, IL-2 at a concentration of 10(4) U/ml partially inhibited TNF-alpha-mediated enhancement of phagocytosis by decreasing TNF binding to the PMN cell surface. This inhibitory effect of IL-2 on TNF was reversed by anti-IL-2 antibody and mAb directed against the low affinity IL-2R (anti-Tac), whereas mAb directed against the intermediate affinity receptor (mik-beta 1) had no such effect. These findings may have important physiologic implications, because patients receiving IL-2 therapy have been shown to have increased susceptibility to infection.

Effects of ethanol on CRF release in vitro.

Acute ethanol exposure produces activation of the brain-pituitary-adrenal (BPA) axis, resulting in the release of ACTH, beta-endorphin, and glucocorticoids. While elevated levels of plasma glucocorticoids are also found after chronic ethanol administration, plasma ACTH and beta-endorphin are normal or reduced. It is also unclear whether chronic ethanol exposure results in tolerance to the stimulatory effect of ethanol on BPA activity. To determine the site and mechanism of ethanol action on the BPA axis we studied the CRF secretory profile in a superfused rat hypothalamic preparation after chronic ethanol administration in vivo and the CRF responses after acute ethanol exposure in vitro. Superfused hypothalami from normal and pair-fed control rats released CRF-like immunoreactive material (CRF-LI) in a pulsatile manner, with a mean (+/- SE) frequency of 5.1 +/- 0.7 pulses/h. In contrast, the pulse frequency of CRF-LI release from hypothalami of rats receiving chronic ethanol treatment (fed an alcohol-containing liquid diet for 2 weeks) increased dramatically; the basal mean CRF level, pulse amplitude, and pulse duration remained unchanged. Hypothalamic CRF content was decreased. This chronic ethanol exposure also altered the dose-response characteristics of CRF release when ethanol was introduced acutely, as a pulse, into the in vitro preparation. Acute exposure to 20 mg/100 ml ethanol produced greater release of CRF-LI from control hypothalami than from chronic ethanol-exposed hypothalami. A further elevation above basal levels was produced by 200 mg/100 ml ethanol in control, but not ethanol-exposed, hypothalami. Secretion of CRF from ethanol-exposed hypothalami in response to depolarizing concentrations of potassium chloride was suppressed. Chronic ethanol treatment had no effect on CRF-LI and CRF bioactivity responses to stimulation with acetylcholine. These findings suggest the presence of a high frequency pulse-generating mechanism for CRF release in the hypothalamus. This pulsatile secretory mechanism is altered by chronic ethanol exposure of the animals in vivo. Chronic intoxication resulted in tolerance to the stimulatory effect of ethanol on CRF release in vitro.