Nonpuerperal lactation and normal prolactin regulation.

Prolactin secretion was evaluated in 11 consecutive patients referred with nonpuerperal lactation who did not have clinical evidence of pituitary tumors. Six patients had normal fasting prolactin (PRL) levels, 13.8 plus or minus 1.8 ng per ml (Group I), and the other 5 women had elevated basal serum PRL concentrations, 182 plus or minus 72 ng per ml (Group II). All Group II patients had amenorrhea; however, 5 of 6 Group I patients had menstrual periods. The 24-h mean serum PRL concentrations were 12.8 plus or minus 1.2 (SEM), 13.3 plus or minus 0.7, and 165 plus or minus 62 ng per ml for the controls and Group I and II, respectively. A pattern of intermittent PRL discharge during the day characterized each group; however, a normal sleep related increase in serum PRL concentration was absent in the Group II patients. Chlorpromazine produced greater than two-fold increases in serum PRL concentrations in the controls and Group I patients; however, this response was absent in Group II. L-Dopa produced appropriate suppression of serum PRL concentrations in the normals and both patient groups. Normal serum growth hormone, thyroxine, and plasma cortisol characterized each group. Serum estrogen and/or LH and FSH were decreased in 3 of 5 Group II patients; however, the serum concentrations of these hormones were normal in 5 of 6 Group I patients. Short term L-dopa therapy was effective in suppressing lactation in 3 of 5 Group II patients, and it also decreased lactation in the 4 treated Group I patients without significantly altering 24-h mean serum PRL concentrations in the latter group. Conclusion: hypothalamic-pituitary dysfunction was present in certain patients with nonpuerperal lactation who had elevated 24-h mean PRL concentrations and no PRL release following chlorpromazine and sleep. Frequently, however, nonpuerperal lactation is associated with normal prolactin secretion.     

Recombinant human prolactin promotes human beta cell survival via inhibition of extrinsic and intrinsic apoptosis pathways

Aims/hypothesis

Transplantation of pancreatic islets constitutes a promising alternative treatment for type 1 diabetes. However, it is limited by the shortage of organ donors. Previous results from our laboratory have demonstrated beneficial effects of recombinant human prolactin (rhPRL) treatment on beta cell cultures. We therefore investigated the role of rhPRL action in human beta cell survival, focusing on the molecular mechanisms involved in this process.

Methods

Human pancreatic islets were isolated using an automated method. Islet cultures were pre-treated in the absence or presence of rhPRL and then subjected to serum starvation or cytokine treatment. Beta cells were labelled with Newport green and apoptosis was evaluated using flow cytometry analysis. Levels of BCL2 gene family members were studied by quantitative RT-PCR and western blot. Caspase-8, -9 and -3 activity, as well as nitric oxide production, were evaluated by fluorimetric assays.

Results

The proportion of apoptotic beta cells was significantly lowered in the presence of rhPRL under both cell death-induced conditions. We also demonstrated that cytoprotection may involve an increase of BCL2/BAX ratio, as well as inhibition of caspase-8, -9 and -3.

Conclusions/interpretation

Our study provides relevant evidence for a protective effect of lactogens on human beta cell apoptosis. The results also suggest that the improvement of cell survival may involve, at least in part, inhibition of cell death pathways controlled by the BCL2 gene family members. These findings are highly relevant for improvement of the islet isolation procedure and for clinical islet transplantation.

     

Recombinant human erythropoietin in the treatment of cancer-related anaemia

Abstract: The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000–10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions, was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.     

Recombinant human erythropoietin in the treatment of nonrenal anemia

Recombinant human erythropoietins (rhEPO) reliably increase hemoglobin levels in cancer patients experiencing chemotherapy-associated anemia. However, in patients with “anemia of cancer” not being treated with chemotherapy, rhEPO appears less effective. Recently, two studies have been broadly discussed which have raised concern on the concomitant use of erythropoietin and chemo- or radiation therapy in cancer patients. In addition, use of rhEPO is generally not considered cost-effective. Thus, the application of rhEPO should be limited to indications with proven clinical benefit. This review will provide an overview of the state of the art use of rhEPO in anemic patients and will discuss future developments.     

Biphasic effects of moderate drinking on prolactin during lactation

Background: Contrary to the popular lore that encourages women to drink alcohol as an aid to lactation, we previously showed that alcohol consumption disrupted lactational performance and the hormonal milieu of the lactating mother in the short term. Methods: Thirteen lactating women participated in a 4‐session, double‐blind, 2 × 2 within‐subject study to test several hypotheses related to the effects of alcohol on prolactin (PRL) responses and milk yield over time. The two within‐subject factors were beverage condition (control or 0.4 g/kg dose of alcohol) and pumping condition (pumping occurred at fixed intervals once or twice during the 5.3‐hour session). Plasma PRL, blood alcohol concentrations (BAC), and milk yield were measured. Results: Alcohol consumption increased basal PRL levels (p < 0.0001) and modified the PRL response to pumping (p < 0.0001) but the directionality of the response depended on when pumping occurred along the BAC curve. Pumping enhanced PRL response when it occurred during the ascending BAC limb but blunted the response when it occurred during the descending limb, providing evidence that the effects were transient and of a biphasic nature. The slower the alcohol was metabolized, the greater the relative PRL response to breast pumping (p < 0.05). The dynamics of the PRL response between pumping sessions was also altered if women drank. If women pumped within the hour after drinking alcohol, the PRL response during the next pumping some 1.5 hours later, was delayed by a few minutes. Milk yield was significantly lower after drinking alcohol but such deficits were not significantly related to PRL or the speed at which alcohol was eliminated. Conclusions: Effects of alcohol on suckling‐induced PRL were biphasic in nature, but could not explain the deficits in lactational performance. Such findings provide further evidence that the dynamic changes in neuroendocrine state are integrally involved in alcohol’s effects over time and underscore the complexity of lactation.     

Inhibition of prolactin and lactation by methylergometrine hydrogenmaleate.

Reports on the effect of methylergometrine hydrogenmaleate (MEM) on prolactin (PRL) secretion and lactation are still controversial. Therefore a prospective study was designed to follow the influence of MEM on post-partum PRL levels and milk production. MEM was given orally to 30 post-partum women from day 1 to day 7 in a daily dose of 0.6 mg. Thirty untreated women served as control. PRL plasma levels and milk yield were compared at day 1, 3 and 7. PRL levels were significantly lower in the treated group at day 7 (P less than 0.01), while the difference at day 3 was statistically not significant. Milk yield was significantly reduced at day 3 (P less than 0.05) and day 7 (P less than 0.01). These results indicate PRL inhibiting properties of MEM resulting consequently in reduced lactation.     

Recombinant human erythropoietin for the treatment of anemia in myelofibrosis with myeloid metaplasia

The high incidence of opportunistic pulmonary infections in fludarabine-treated patients at Walter Reed Army Medical Center (WRAMC) and in the literature are described. A CancerLlt search of fludarabine from June 1983-April 1994 with subsequent cross referencing and a retrospective review of all patients receiving fludarabine at WRAMC was performed. A total of 2,269 patients with low-grade lymphoid malignancies who received 7,547 + cycles of fludarabine were identified from the literature. Seventy-three (3.2%) of these patients developed opportunistic infections. Seventy-one (97%) of these infections occurred in patients who were pretreated with alkylator regimens or corticosteroids. Forty-five (2%) of these were of respiratory origin and associated with a 56% mortality rate. In contrast, 6 of the 21 patients (29%) treated with fludarabine at WRAMC developed opportunistic pulmonary infections which included three Pneumocystis carinii (PCP), one PCP/disseminated Candidiasis, one Mycobacterium avium intracellulare, and one Aspergillus niger pneumonia. These infections developed during and after treatment with fludarabine in alkylator-resistant patients who had received corticosteroids before (n = 6), during (n = 1), or after (n = 4) fludarabine therapy. Lack of PCP prophylaxis was the only significant (P = .018) variable that differentiated patients who developed opportunistic pulmonary infections. Corticosteroid treatment before, during, or after fludarabine treatment in patients with alkylator-resistant, low-grade lymphoid malignancies who have not received PCP prophylaxis is associated with an increased risk of opportunistic pulmonary infections. Aggressive work-up of pulmonary syndromes and PCP prophylaxis in these patients should be considered during and after treatment with fludarabine. © 1995 Wiley-Liss, Inc.     

Recombinant human erythropoietin for the treatment of the anaemia associated with autologous bone marrow transplantation

Summary. Patients with solid tumours undergoing highdose chemotherapy with autologous bone marrow transplantation use an average of 10 units of packed red blood cells (PRBC) while awaiting haemopoietic reconstitution. They are also known to have inappropriately low endogenous erythropoietin levels for their degree of anaemia. This pilot study was designed to determine the effects of recombinant human erythropoietin (rHuEPO) on erythroid recovery and PRBC transfusion requirements. Ten patients received high-dose chemotherapy (days - 7 to -3), bone marrow reinfusion (day 0), and then rHuEPO (day 1 onward). RHuEPO (200 units/kg intravenous bolus daily), along with iron supplementation, was administered for 28 d or until a haematocrit (Hct) of 35% (independent of transfusions) was reached, whichever occurred first. PRBCs were routinely given for Hct 25% and platelets for counts < 20000/μl. Eight (80%) patients developed a brisk reticulocytosis (median peak reticulocyte count 0.32 × 10⁹/l) and a haematocrit 30% independent of red blood cell transfusions within 32 d of receiving marrow, as compared to 20/37 (54%) similarly treated controls. An unexpected finding was the more rapid engraftment in myeloid and platelet lineages in a subset of rHuEPO-treated patients. Quick return of red blood cells (17 v 33d) (P = 0.0001), platelets (14 v 19d) (P = 0.04), and neutrophils (13 v 25d) (P = 0.01) (with circulating myeloblasts and early myeloid forms) characterized recovery from an ifosfamide-based intensification with rHuEPO support. Similar trilineage enhancement of haemopoiesis did not occur with the possibly more myeloablative cyclophosphamide-based regimens. Despite the enhancement by rHuEPO on reticulocytosis, there was no significant decrease in PRBC transfusion requirements. RHuEPO proved to be a well-tolerated agent in enhancing reticulocytosis following high-dose chemotherapy. further study to elucidate the activity of erythropoietin on both erythroid and non-erythroid growth and maturation appears warranted.     

重组人脑利钠肽治疗心力衰竭

大量对照临床试验表明,对急性失代偿性心力衰竭患者,外源性给予一种基因重组人脑利钠肽(nesiritide)可以改善临床症状和血流动力学状况,还能够有效抑制神经内分泌的激活。     

Endovascular treatment for vertebrobasilar insufficiency

Opinion statement Endovascular management of supra-aortic atherosclerotic vascular disease is becoming relatively common in the innominate, subclavian, and carotid arteries. However, revascularization of vertebral artery disease is an infrequently used treatment option due to several reasons: 1) stroke etiology and prevention is generally considered with respect to carotid disease as posterior circulation ischemia is poorly defined; 2) the limited success and excessive morbidity have made surgery an unattractive option for vertebral artery revascularization; 3) routine screening for posterior circulation disease as an etiology for stroke is rarely performed; and 4) endovascular treatment of vertebrobasilar insufficiency is not routinely performed in peripheral interventional programs. Randomized data comparing medical therapy, endovascular treatment, or surgical treatment do not exist. Due to infrequent identification of vertebral artery disease as the etiology of posterior circulation symptomatology, randomized comparisons will be difficult to obtain. Balloon angioplasty alone, provisional stenting, or primary stent placement for the treatment of vertebral artery stenosis is associated with low restenosis rates and high success rates. The available literature demonstrates angioplasty with stent placement of posterior circulation, symptomatic, vertebrobasilar atherosclerotic disease is a safe and effective approach that avoids the morbidity associated with major surgery. We believe primary stent placement is the treatment of choice for vertebral artery revascularization due to the high technical success rate, low incidence of morbidity and mortality, and long-term durability.     

Erratum to: Recombinant human prolactin promotes human beta cell survival via inhibition of extrinsic and intrinsic apoptosis pathways

Aims/hypothesis  

Transplantation of pancreatic islets constitutes a promising alternative treatment for type 1 diabetes. However, it is limited by the shortage of organ donors. Previous results from our laboratory have demonstrated beneficial effects of recombinant human prolactin (rhPRL) treatment on beta cell cultures. We therefore investigated the role of rhPRL action in human beta cell survival, focusing on the molecular mechanisms involved in this process.     

重组人促甲状腺素介导分化型甲状腺癌的131I治疗

目的 研究重组人促甲状腺素(rhTSH)介导分化型甲状腺癌131I治疗对内源性TSH、甲状腺球蛋白、FT3、FT4的影响及其清甲成功率.方法 31例(年龄14～70岁,其中女性23例)接受rhTSH介导的131I治疗(甲状腺功能正常组),31例(年龄23～72岁,其中女性22例)停用甲状腺素后的行131I治疗[甲状腺功能减退组(甲减组)]观察注射rhTSH前后血清TSH、FT3、FT4以及甲状腺球蛋白抗体(TGAb)、甲状腺球蛋白浓度变化,以及131I治疗后6～12个月131I全身诊断显像评价其疗效.结果 使用rhTSH前后,血清TSH、甲状腺球蛋白、FT3、FT4的平均浓度分别是(1.08±4.01)和(140.26±27.20)mIU/L(P＜0.05)、(23.75±132.92)和(169.58±178.49)μg/L(P＜0.05)、(4.52±1.16)和(4.42±1.11)pmol/L(P＞0.05)、(15.09±5.83)和(13.66±5.85)pmol/L(P＞0.05).诊断剂量131I-全身显像显示甲状腺功能正常组24/31(77.4%)及甲减组22/31(71.0%)被考虑成功清甲(P＞0.05).以甲状腺球蛋白评价两组131I治疗疗效统计学无显著差异(P＞0.05),甲状腺功能正常组20/31(64.50%)及甲减组18/31(58.06%)被考虑成功清甲.结论 使用rhTSH能有效刺激内源性TSH增高,提高生活质量,获得较高的清甲成功率.使用rhTSH能有效刺激血清甲状腺球蛋白,有利于监测肿瘤残存、复发与转移.

Abstract：

Objective To observe the influence of recombinant human thyrotropin(rhTSH)on serum concentration of endogenous thyrotropin(TSH), free triiodothyronine(FT3), free thyroxine(FT4), thyroglobulin antibody(TGAb), and thyroglobulin(Tg). To evaluate the efficacy of rhTSH-aided radioiodine treatment in patients with differentiated thyroid carcinoma(DTC). Methods The study recruitment took place between November 2007 and March 2009. 62 patients(including 45 females)with biopsy confirmed DTC had undergone total or nearly total thyroidectomy, and received 131I treatment. 31 patients(including 22 females), median age of 45 years(23-72), received radioiodine treatment 4 weeks after L-thyroxine(T4)withdrawal. The other 31 patients(including 23 females), median age of 44 years(14-70), underwent rhTSH-aided radioiodine treatment. Before and after rhTSH injection, serum TSH, FT3, FT4, TGAb, and thyroglobulin were tested. Post-radiotherapy whole body scan was performed 5 to 7 days after radioiodine treatment and qualitatively and blindly evaluated by two nuclear medicine physicians. Follow-up took place 6 to 12 months after radioiodine treatment. The efficacy of rhTSH-aided radioiodine treatment was evaluated by whole body scan with diagnostic dose radioiodine. SPSS 13.0 statistical software was applied. Results (1)Before and after rhTSH-aided radioiodine treatment, the serum TSH was(1.08±4.01)vs(140.26±27.20)mIU/L(P＜0.05), thyroglobulin(23.75±132.92)vs(169.58±178.49)μg/L(P＜0.05), FT3(4.52±1.16)vs(4.42±1.11)pmol/L(P＞0.05), and FT4(15.09±5.83)vs(13.66±5.85)pmol/L(P＞0.05),respectively.(2)rhTSH-aided radioiodine ablation treatment had the same effect as L-T4withdrawal aided. The complete response ratio was 77.4% vs 71.0%(P＞0.05)by radioiodine whole body scan of diagnostic dose. Conclusion rhTSH-aided radioiodine treatment of DTC was effective and safe, and did at least at equivalent degree as did L-T4withdrawal. Furthermore, Serum thyroglobulin level could be effectively stimulated by rhTSH with tumor relapse or metastasis.     

Neuroendocrine mechanisms regulating growth hormone and prolactin secretion during lactation

The maternal plasma concentrations of GH and PRL increase dramatically upon the initiation of lactation in the rat. In light of the fact that these two hormones have evolved from one common precursor, we sought to determine if the neuroendocrine mechanisms regulating their concomitant increase during lactation are common or if they are functionally distinct. To evaluate this, lactating rats were passively immunized with antiserum raised against GHRH and then monitored for changes in GH and PRL secretion in response to suckling. On day 9 or 10 postpartum, pups were removed from their mothers at 0800 h. At 1100 h mothers were injected with normal rabbit serum (NRS) or GHRH antiserum (GHRH-ab). At 1400 h a control blood sample was drawn. Pups were then returned to their mothers, with subsequent blood samples drawn over the next 60 min. Plasma concentrations of GH significantly increased to 12.3 +/- 1.0 ng/ml (mean +/- SEM) in NRS-treated females after the return of the pups. In contrast, there was no change in GH concentrations in the females treated with the GHRH-ab. Plasma PRL concentrations rose approximately 200 ng/ml in both the NRS-treated animals and the GHRH-ab-treated ones. Body weight gains of the pups during the 60-min period of lactation were similar in both groups. These results suggest that the neuroendocrine mechanisms regulating the increases in GH and PRL during lactation are distinct and that GHRH is the hypothalamic factor responsible for the increase in GH. Furthermore, these results suggest that acutely interrupting the increase in GH secretion that occurs during lactation does not compromise nursing behavior and performance.     

Recombinant human thrombopoietin is an effective treatment for thrombocytopenia in hemophagocytic lymphohistiocytosis

The aim of this study was to investigate the effectiveness and safety in the treatment of thrombocytopenia in hemophagocytic lymphohistiocytosis (HLH) by recombinant human thrombopoietin (rhTPO). A prospective randomized study was conducted between March 2010 and December 2011 in 40 patients with adult HLH whose blood platelet counts (BPC) were lower than 40?×?10⁹/L. The 40 patients were randomly assigned into the rhTPO group or control group based on sex, age, primary disease, and BPC (20 in each group). All patients were given conventional systemic therapy for HLH. The rhTPO group was administered by subcutaneous injection of rhTPO at a dose of 300 IU/kg Qd. The BPC, platelet transfusion, bleeding, and survival rate in the two groups were monitored and compared. There was no significant difference in BPC between the two groups before the treatment. Two weeks after the treatment, the BPC of the rhTPO group was significantly higher than that of the control group at every time point (P?<?0.05). Although there was no significant difference in skin and mucous membrane bleeding between the rhTPO group and control group, however, the number of patients presented with gastrointestinal bleeding, urinary tract bleeding, and pulmonary bleeding in the control group were higher than that in the rhTPO group (P?=?0.013). The frequency of platelet transfusion in the control group (7.25 per patient, 145 in 19 patients) was significantly higher than that in the rhTPO group (2.25 per patient, 45 in 14 patients) (P?<?0.01). There was no significant difference in the survival rate between the two groups. The average recovery time of platelets to normal levels in the rhTPO groups was shorter than that in the control group (the rhTPO group vs the control group: 13.43?±?4.62 D vs 18.00?±?3.98 D, P?=?0.013). In the early stage of HLH treatment, rhTPO combined with conventional systemic therapy can restore the BPC to normal level within a shorter period of time, reduce the frequency of platelet transfusion and severe bleeding.     

Glycosylated human prolactin

A glycosylated form of human PRL (G-hPRL) was isolated from pituitary glands. The glycoprotein was separated from the major form of PRL on columns of lentil lectin-Sepharose 4B. The major form of PRL did not bind to the lentil lectin, whereas the glycosylated modification did and could be eluted with methyl-alpha-D-mannopyranoside. By gel electrophoresis in sodium dodecyl sulfate, a mol wt of 25,000 was estimated for the glycosylated PRL. The mol wt of hPRL is 23,000. In a RIA for hPRL, the glycosylated hormone was about one third as reactive as the principal form. Since there is only one Asn-X-Ser(Thr) sequence in hPRL, the asparagine at position 31 is the likely point of N-linked glycosylation.