Mild iron deficiency does not ameliorate the phenotype of a murine erythropoietic protoporphyria model

Reduced ferrochelatase activity in erythropoietic protoporphyria (EPP) causes the accumulation of protoporphyrin IX (PPIX) leading to acute cutaneous photosensitivity and liver injury. Many EPP patients also have a mild hypochromic, microcytic anemia and iron deficiency. Iron deficiency can lead to decreased PPIX accumulation in another erythropoietic porphyria, congenital erythropoietic porphyria (CEP). Expression of the iron regulatory peptide hepcidin is negatively regulated by the serine protease TMPRSS6. Hepcidin induction by siRNA-mediated inhibition of TMPRSS6 expression reduces iron availability and induces iron deficiency. To interrogate the therapeutic potential of iron deficiency to modify EPP, we treated an ethylnitrosourea-induced mouse model of EPP, Fech ^m1Pas, with a GalNAc-conjugated Tmprss6 siRNA and PPIX levels, anemia and iron parameters were monitored. The GalNAc-RNAi therapeutic reduces Tmprss6 expression and induces mild iron deficiency in Fech ^m1Pas animals. However, decreases in erythrocyte PPIX levels and liver PPIX accumulation were not seen. These results indicate short-term induction of iron deficiency, at least in a murine model of EPP, does not lead to decreased PPIX production.     

Plasminogen activator inhibitor type-1 deficiency does not influence the outcome of murine pneumococcal pneumonia

Urokinase-type plasminogen activator (uPA) and its receptor uPAR are components of the fibrinolytic system and are important for an adequate immune response to respiratory tract infection, in part through their role in the migration of inflammatory cells. PA inhibitor-1 (PAI-1) is the predominant inhibitor of soluble and receptor-bound uPA. To determine the role of PAI-1 in host defense against pneumococcal pneumonia, the following studies were performed: (1) Patients with unilateral community-acquired pneumonia demonstrated elevated PAI-1 concentrations together with decreased PA activity in bronchoalveolar lavage fluid (BALF) obtained from the infected, but not from the contralateral, site. (2) Mice with Streptococcus pneumoniae pneumonia displayed elevated PAI-1 protein and mRNA levels in their lungs. (3) PAI-1 gene-deficient mice, however, had an unaltered immune response to pneumococcal pneumonia, as measured by cell recruitment into lungs, bacterial outgrowth, and survival. Furthermore, plasminogen-gene-deficient mice also had an unremarkable defense against pneumococcal pneumonia. These data indicate that pneumonia is associated with inhibition of the fibrinolytic system at the site of the infection secondary to increased production of PAI-1; an intact fibrinolytic response is not required for an adequate host response to respiratory tract infection, however, suggesting that the previously described role of uPA and uPAR are restricted to their function in cell migration.     

Cholecystectomy does not significantly increase the risk of fatty liver disease

AIM: To investigate the relationship between cholecystectomy and fatty liver disease(FLD) in a Chinese population.METHODS: A total of 32428 subjects who had voluntarily undergone annual health checkups in the Second Affiliated Hospital of Nanjing Medical University from January 2011 to May 2013 were included in this study. Basic data collection, physical examination, laboratory examination, and abdominal ultrasound examination were performed.RESULTS: Subjects undergoing cholecystectomy were associated with greater age, female sex, higher body mass index, and higher levels of systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol, and triglycerides. However, no significant differences were found in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transpeptidase, albumin, and serum uric acid. The overall prevalence of FLD diagnosed by ultrasonography was high at 38.4%. The prevalence of FLD was significantly higher for subjects who had undergone cholecystectomy(46.9%) than those who had not undergone cholecystectomy(38.1%; χ2 test, P < 0.001). Cholecystectomy was positively associated with FLD(OR = 1.433, 95%CI: 1.259-1.631). However, after adjusting for possible factors associated withFLD, multivariate regression analysis showed that the association between cholecystectomy and FLD was not statistically significant(OR = 1.096; 95%CI: 0.939-1.279). CONCLUSION: According to our study results, cholecystectomy may not be a significant risk factor for FLD.     

Administration of recombinant erythropoietin alone does not improve the phenotype in iron refractory iron deficiency anemia patients

Mutations in transmembrane protease, serine 6 (TMPRSS6) cause iron refractory iron deficiency anemia (IRIDA). Parenteral iron administration may slightly improve hemoglobin level but is troublesome for patients. Optimal treatment has yet to be determined. We identified five patients from four independent families displaying the IRIDA picture with truncating biallelic mutations in TMPRSS6, one of which is novel. Liver iron determined by superconducting quantum interference device biosusceptometry ranged from 390 to 720 µg Fe/g wet weight (normal range 100–500; n?=?3). Intestinal iron absorption (12 and 32 %, normal range 10–50; n?=?2) and 59Fe erythrocyte incorporation after ingestion of 59Fe (57 and 38 %, normal range 70–90; n?=?2) were inadequately low for iron-deficient anemic individuals. Baseline serum erythropoietin was elevated or borderline high in four patients. Administration of recombinant human erythropoietin (rhEPO) at up to 273 and 188 U/kg body weight/week alone did not improve anemia or result in a decrease of urinary hepcidin in two individuals. In conclusion, the ability of exogenous rhEPO to increase hemoglobin level appears to be impaired in IRIDA.     

Leukocyte-depletion of blood components does not significantly reduce the risk of infectious complications

Allogeneic blood transfusions are claimed to be an independent risk factor for postoperative infections in open colorectal surgery due to immunomodulation. Leukocyte-depletion of erythrocyte suspensions has been shown in some open randomized studies to reduce the rate of postoperative infection to levels observed in nontransfused patients. Using a double-blinded, randomized design, we studied the postoperative infection rate in patients undergoing open colorectal surgery transfused with either leukocyte-depleted erythrocyte suspensions (LD-SAGM) or non-leukocyte-depleted erythrocyte suspensions (SAGM). Unselected patients (n 279) were allocated to receive LD-SAGM (n 139) or SAGM (n 140) if transfusion was indicated. Forty-five percent were transfused, yielding 48 patients in the LD-SAGM group and 64 in the SAGM group. Thirteen patients were excluded because they received one type of transfusion in spite of randomization to the other type. No significant differences in the rates of postoperative infections (P=0.5250) or postoperative complications (P=0.1779) were seen between the two transfused groups. Infection rates were 45% and 38% in the transfused groups and 21% and 23% in the nontransfused groups. No significant difference between the transfused groups was seen on any single infectious event, mortality rate, or duration of hospitalization. Leukocyte-depletion of erythrocyte suspensions transfused to patients undergoing open colorectal surgery does not reduce postoperative infection rates.     

Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome.

The recent discovery of the contribution of proopiomelanocortin (POMC)-derived peptides to the regulation of energy homeostasis and exocrine gland secretion in mice aroused new interest in the complex function of the endocrine POMC network. In addition, the first mutations in the gene encoding POMC have been identified in two patients affected by adrenal insufficiency, early onset severe obesity and red hair pigmentation. Therefore, the focus of this brief review will be the detailed discussion of the implications of these new findings in the physiology of the human POMC ligand-receptor system.     

The phenotype of the aromatase knockout mouse reveals dietary phytoestrogens impact significantly on testis function

Estrogen is synthesized in the testis, both in Leydig cells and seminiferous epithelium, and its importance in spermatogenesis is highlighted by the phenotype of the aromatase knockout (ArKO) mouse. These mice are unable to synthesize endogenous estrogens. The males develop postmeiotic defects by 18 wk of age. We hypothesized that maintenance of spermatogenesis in younger animals may be mediated by exogenous estrogenic substances. Dietary soy meal, contained in almost all commercial rodent diets, provides a source of estrogenic isoflavones. We thus investigated spermatogenesis in wild-type and ArKO mice raised on a diet containing soy, compared with a soy-free diet, to elucidate the biological action of phytoestrogens on the testis. In ArKO mice, dietary phytoestrogens could partially prevent disruptions to spermatogenesis, in that they prevented the decline in germ cell numbers. They also seemed to maintain Sertoli cell function, and they blocked elevations in FSH. The impairment of spermatogenesis seen in soy-free ArKOs occurred in the absence of a decreased gonadotropic stimulus, suggesting that the effects of dietary phytoestrogens are independent of changes to the pituitary-gonadal axis. Our study highlights the importance of estrogen in spermatogenesis and shows that relatively low levels of dietary phytoestrogens have a biological effect in the testis.     

Variation in barometric pressure in Melbourne does not significantly affect the BTPS correction factor

The conventional BTPS (body temperature and pressure, saturated with water vapour) correction factor varies with ambient barometric pressure (P(B)) and many lung function laboratories measure P(B) daily. The aim was to investigate whether a fixed value for P(B) could replace daily measurements. P(B) was measured daily over a 12-month period. The highest and lowest values in Melbourne in the last century were also recorded from data published by the Bureau of Meteorology. Using these P(B) values, the BTPS factor was determined for a range of spirometer temperatures and compared to the BTPS factors obtained using a fixed ambient pressure of 101.3 kPa. The mean (SD) P(B) measured over the 12-month period was 102.2 kPa (0.64) with a range of 99.9-103.6 kPa. The level of disagreement between the BTPS factor calculated using a P(B) of 101.3 kPa instead of the measured value was greater at lower temperatures. Over the extremes of P(B) during the last century (98.0-104.3 kPa) the use of a standard pressure (101.3 kPa) produced an error in the BTPS factor of 相似文献   

KATP channel opening does not contribute significantly to the vasodilatory effect of SH-group-containing ACE inhibitors

Summary Angiotensin-converting enzyme (ACE) inhibitors are widely used in the management of hypertension, heart failure, and nephropathy. It has been suggested that ACE inhibitors containing the sulfhydryl group (SH) have an additional effect on K_ATP channels. To prove this hypothesis, we studied the effects of the SH-containing ACE inhibitors, captopril and zofenopril, on K_ATP channel opening of bovine coronary arteries and guinea pig thoracic aortas. Bovine coronary arteries were precontracted with the thromboxane A2 analogue, U46619, and guinea pig thoracic aortas were precontracted with phenylephrine and then relaxed with either captopril or zofenopril (n=8). Inhibition of K_ATP channel opening with glibenclamide moderately attenuated the zofenopril-induced relaxation of guinea pig thoracic aorta. However, in the bovine coronary arteries, the relaxing effect of both captopril and zofenopril remained uneffected by glibenclamide. In experiments with enalapril (a non SH-containing ACE inhibitor:n=6) on guinea pig thoracic aortas, no effect on K_ATP channels could be seen. From our experiments, we conclude that the postulated opening of K_ATP channels by SH-group-containing ACE inhibitors contributes little to the vasodilation of guinea pig thoracic aortas caused by ACE inhibitors, and that SH groups have no influence upon K_ATP channels of bovine coronary arteries.     

Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency

Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency.     

A marked deficiency in circulating and renal IGF-I peptide does not inhibit compensatory renal enlargement in uninephrectomized mice

Objective

Increase in kidney IGF-I levels due to its increased trapping from the circulation was hypothesized to be a key mediator of compensatory renal enlargement. We tested this hypothesis using genetically engineered mice with extremely low circulating IGF-I levels.

Design

Both IGF-I deficient (ID) and normal (N) mice underwent a uninephrectomy (UNx) and sacrificed 2 or 9 days later.

Results

Initial body weight (BW) and kidney weight (KW) were significantly reduced in ID vs. N mice, while KW/BW ratios were similar. KW increased post-UNx to a comparable extent in ID and N mice (125 ± 4 and 118 ± 6% of pre-UNx KW, p < 0.05 vs. C). Kidney IGF-I mRNA levels were similar in the ID and N mice and did not change post-UNx. Kidney IGF-I peptide levels pre-UNx were significantly lower in ID vs. N mice (25 ± 5 vs. 305 ± 39 ng/g) and increased in both groups after UNx, remaining low in ID mice (45 ± 4 in ID vs 561 ± 64 ng/g in N). IGF type 1 receptor phosphorylation was unchanged.

Conclusion

While a severe deficiency of circulating IGF-I impairs body growth, UNx induces a significant and proportional increase in renal mass in ID mice despite markedly decreased kidney IGF-I levels (> 90% reduction) and no significant change in receptor phosphorylation. This all suggests that factors other than circulating and locally produced IGF-I are responsible for compensatory renal enlargement.     

Protein Z-dependent protease inhibitor deficiency produces a more severe murine phenotype than protein Z deficiency

Protein Z (PZ) is a plasma vitamin K–dependent protein that functions as a cofactor to dramatically enhance the inhibition of coagulation factor Xa by the serpin, protein Z–dependent protease inhibitor (ZPI). In vitro, ZPI not only inhibits factor Xa in a calcium ion–, phospholipid-, and PZ-dependent fashion, but also directly inhibits coagulation factor XIa. In murine gene-deletion models, PZ and ZPI deficiency enhances thrombosis following arterial injury and increases mortality from pulmonary thromboembolism following collagen/epinephrine infusion. On a factor V_Leiden genetic background, ZPI deficiency produces a significantly more severe phenotype than PZ deficiency, implying that factor XIa inhibition by ZPI is physiologically relevant. The studies in mice suggest that human PZ and ZPI deficiency would be associated with a modest thrombotic risk with ZPI deficiency producing a more severe phenotype.      

rhG-CSF does not affect the phenotype of adult donor peripheral blood NK cells

Considerable evidence in preclinical models as well as in human transplantation now suggests that donor-derived natural killer (NK) cells can contribute to alloimmune recognition of recipient residual tumour cells. This makes the NK cell population an attractive target for in vitro or in vivo manipulations, in order to improve the antitumour effect of allogeneic transplantation. However, conditions in which allogeneic donor cells are collected vary; several reports have emphasised the different phenotypic and functional properties of T cells derived from marrow, cord blood or mobilised peripheral blood grafts; others have demonstrated different clinical outcomes following blood or marrow transplantation after myeloablative conditioning regimens. NK cells have been examined in this setting; the availability of new tools to study the expression of a variety of surface antigens that are involved in the control of NK cell activity offered us an opportunity to extensively characterise the phenotypic properties of NK cells from donors, before and after administration of pharmacological doses of rhG-CSF used for haematopoietic progenitor mobilisation. Our study suggests that rhG-CSF does not reproducibly alter blood NK cell phenotype in normal individuals, and thus that donor-derived cells are fully equipped to exert their potential antitumour effect.