Long-term treatment with cimetidine does not essentially affect the hypothalamic-pituitary-gonadal axis in man

The effect of cimetidine maintenance treatment on gonadal function has been assessed by seminal analysis plus prolactin and gonadotropin blood level concentrations. Nine patients, all with duodenal ulcer, 5 of whom had received 400 mg cimetidine at night for 18, 3 for 24 and 1 for 36 months, were studied. All patients were presumably fertile, having fathered a child born not more than 3 years before the start of cimetidine treatment. In all patients two seminal analyses were performed and blood specimens were obtained for radioimmunoassay estimation of FSH, LH and prolactin concentrations both in basal conditions and 20', 30' and 60' after the i.v. injection of Gn-RH (100 micrograms) and TRH (200 micrograms). All but one patient, in whom mild oligoasthenozoospermia was detected, had normal sperm counts and motility; moreover hormonal levels both in basal conditions and after releasing factor stimulation were found to be similar to those observed in a control group. Cimetidine maintenance treatment has no effect on sexual activity, the quality of seminal fluid or the pituitary secretion of gonadotropins or prolactin.     

Metformin does not adversely affect hormonal and symptomatic responses to recurrent hypoglycemia

Body weight gain and severe hypoglycemia are the major adverse effects of insulin therapy in type 2 diabetic patients. Metformin has been shown to prevent insulin therapy-induced body weight gain when used in combination with insulin. However, the effects of metformin on hormonal and symptomatic responses to hypoglycemia mediating hypoglycemia awareness have not been assessed to date. Fifteen young healthy men were treated with 850 mg metformin and placebo twice daily for a 16-d period in a double blind, cross-over design. On the last 2 d of the treatment period, the subjects underwent three hypoglycemic clamp experiments, with the first and the last performed with identical patterns of plasma glucose decrease. Differences between the effects of metformin and placebo (effect of metformin) as well as between first and last hypoglycemic clamps (effect of antecedent hypoglycemia) were assessed. Antecedent hypoglycemia significantly reduced epinephrine, ACTH, cortisol, glucagon, GH, and symptomatic responses to hypoglycemia (P < 0.05 for all variables). There was no detectable effect of metformin on epinephrine, norepinephrine, ACTH, cortisol, glucagon, or autonomic symptomatic response to hypoglycemia (P > 0.05 for all comparisons), except that metformin slightly increased the response of GH to hypoglycemia (P = 0.039). The latter finding may be due to an IGF-I-reducing effect of metformin, as after 14 d of metformin treatment baseline levels of IGF-I were significantly lower than in the placebo condition (236.9 +/- 13.9 vs. 263.2 +/- 14.4 microg/liter; P = 0.015). The data indicate that metformin does not adversely affect hormonal and symptomatic responses to hypoglycemia. This finding appears to be relevant with regard to the safety of the combination of metformin with insulin therapy.     

Prior treatment with alpha interferon does not adversely affect the outcome of allogeneic transplantation for chronic myeloid leukaemia

Summary. The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Société Française de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft‐versus‐host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHD ≥ 2 at 3 months which was higher in group I (65 ± 10%) than in group II (38 ± 5%; P = 0·01). Moreover, disease‐free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 ± 10% vs. 41 ± 6%; P = 0·005)(95% CI) and (41 ± 10% vs. 55 ± 6%; P = 0·002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.     

Cytogenetic clonal evolution alone in CML relapse post-transplantation does not adversely affect response to imatinib mesylate treatment

Good prognosis after imatinib mesylate treatment has been reported if cytogenetic clonal evolution (CE) is the only criterion of accelerated phase (AP) chronic myelogenous leukemia (CML). To evaluate the impact of CE upon imatinib treatment in post-transplant settings, responses and toxicities in the relapsed AP-CE were analyzed in comparison with those in the relapsed chronic phase (CP). Both CP (n=7) and AP-CE patients (n=6) received imatinib mesylate in an oral dose of 400 mg/day. Complete cytogenetic responses were obtained in six patients of each group, CP (86%) and AC-CE (100%), while molecular remission was seen in 43 and 50%, respectively. Granulocytopenia or thrombocytopenia of grade III or more occurred in four (57%) and two (33%) patients with CP and AP-CE, respectively. Nonhematological adverse events were mild and tolerable in both groups and only one (7%) of the 13 patients experienced recurrent graft-versus-host disease after imatinib treatment. Although this is a relatively small group of patients, we suggest that imatinib mesylate should be considered as a front-line treatment for relapsed CML as it showed the high response rate and low toxicity. We also suggest that CE alone is not an important factor in the induction of cytogenetic and molecular remissions in post-transplant relapse.     

Selective treatment of rectal cancer with single-stage coloanal or ultralow colorectal anastomosis does not adversely affect morbidity and mortality

Background and aims The surgical treatment of low rectal cancer commonly includes low pelvic anastomoses with coloanal or ultralow colorectal anastomoses. Anastomotic leak rates in low pelvic anastomoses range from 4 to 26%. Many surgeons opt to routinely create a diverting ostomy to reduce the extent of morbidity should an anastomotic leak occur. The intent of our study was to determine if our policy of selected diversion is safe. Materials and methods A retrospective chart review of 66 rectal cancer patients who underwent proctectomy and low pelvic anastomoses—less than 6 cm from anal verge, with or without a diverting ostomy—was undertaken. Temporary diverting stomas were utilized at the discretion of the attending surgeon primarily based on subjective criteria. The main outcome was postoperative complications. Results/findings Forty-nine patients (78% preoperatively irradiated) were treated with a one-stage operation, whereas 17 (53% preoperatively irradiated) underwent reconstruction with proximal diversion. The mean anastomotic height for patients with a single stage procedure was 3.8 cm above the anal verge versus 2.6 for patients with a two-stage procedure (p = 0.076). Complication rates were lower in patients who did not undergo diversion (29% vs 47%, p = 16). With regard to anastomotic-associated complications for single stage versus two stage, complication rates were 8% versus 18%, respectively (p = 0.27). Interpretation/conclusion Low pelvic anastomoses in rectal cancer patients can be safely performed as a single-stage procedure, reserving the use of diversion for select cases.     

Isoflavone consumption does not increase the bone mass in osteopenic obese female zucker rats

Some controversy exists in the literature concerning the effects of leptin on bone metabolism. Thus we have compared femoral bone density and biochemical markers of bone metabolism in male and female fatty (leptin-resistant) Zucker rats and their lean homozygous controls at 3 and 6 months of age. At 3 months, no differences concerning total, diaphyseal (cortical bone), and distal metaphyseal (trabecular bone) femoral bone densities, plasma osteocalcin concentrations, and urinary deoxypyridinoline excretion were observed between fatty and lean rats. On the opposite, at 6 months of age, in both males and females, total, diaphyseal, and distal metaphyseal femoral bone densities and plasma osteocalcin concentrations were lower in Zucker than in lean rats. Soybean isoflavone consumption (40 microg/g body weight/day for 90 days, a dose which prevents osteopenia following ovariectomy both in lean Zucker homozygous controls and in Wistar rats) by obese female Zucker rats had no significant effect upon their bone mass.     

Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans

Objective: In this study we examined the effect of rapamycin (RAPA), a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function in vivo.

Methods and results: Diabetic C57BL/6 or BALB/C recipient mice were transplanted with 350 syngeneic islets through the portal vein (PV-Tx; C57BL/6 n = 60; BALB/C n = 22) and treated with once-daily oral RAPA (1 mg/kg) or vehicle. No differences in post-transplant blood glucose concentrations and glucose tolerance were observed between RAPA- and vehicle-treated mice. The impact of RAPA on human islet engraftment was assessed in 10 patients with type 1 diabetes treated with

0.1 mg/kg/day rapamycin before islet transplantation. Compared to non pre-treated islet transplant recipents (n = 12), RAPA pre-treated patients had increased blood RAPA concentrations (p = 0.006) and fasting C-peptide concentrations (p = 0.005) in the two weeks post-transplant. RAPA pre-treatment was associated with a reduction in chemokines CCL2 and CCL3 concentrations pre-transplant (p < 0.01), and a dampened chemokine response (p = 0.005) post-transplant. Concordantly, in vitro RAPA inhibited the secretion of CCL2 and CCL3 by monocytes.

Conclusion: Rapamycin does not adversely affect intrahepatic islet engraftment in the mouse, and potentially improves islet engraftment in humans by an anti-inflammatory mechanism.     

Omeprazole treatment does not affect the metabolism of caffeine

This study was performed to investigate the possible influence of repeated omeprazole dosing on the metabolism of caffeine, which has been shown to reflect the activity of one specific enzyme within the hepatic cytochrome P450 family, P450IA2. Ten healthy, nonsmoking young men participated in this placebo-controlled double-blind trial. Each subject was given omeprazole, 20 mg, every morning for 1 week and placebo every morning for 1 week in random order and separated by a 2-3 week washout period. On the sixth and seventh days of each period urine was collected twice daily, and urinary metabolites of caffeine were determined by high-performance liquid chromatography. The urinary metabolite ratio of three paraxanthine 7-demethylation products relative to a paraxanthine-hydroxylation product corresponds to caffeine clearance and, therefore, to P450IA2 activity. This calculated ratio was 4.8 (95% confidence interval, 3.9-5.6) in the placebo and 4.6 (95% confidence interval, 3.6-5.5) in the omeprazole period. These results show that the metabolism of caffeine was unaltered following omeprazole treatment, indicating that omeprazole treatment has no influence on cytochrome P450IA2 activity in the clinical situation.     

尼尔雌醇皮埋剂保护去卵巢大鼠的骨量

目的：探讨尼尔雌醇（NYL）皮埋剂对卵巢切除（OVX）大鼠骨量的影响。为长期雌激素替代治疗提供一种新的选择。方法：用DEXA分别测定假手术（Sham）组、卵巢切除（OVX）组、卵巢切除加左炔诺孕酮皮埋剂（LNG）组、卵巢切除加LNG皮埋剂和NYL皮埋剂（LNG＋NYL）组及OVX加NYL皮埋剂（NYL）组大鼠的活体和离体骨密度（BMD），并对血清碱性磷酸酶（ALP）和尿吡啶啉／肌酐（Pyr/Cr)进行检测。结果：与Shasm组比较，OVX组和LNG组大鼠全身，腰椎活性BMD和腰椎，股骨整体及各兴趣区（除第3兴趣区）、胫骨整体及干骺端第1兴趣区离体BMD均显著下降（P＜0．05－P＜0．01），而血清ALP和尿Pyr/Cr增高，后者差异有显著性（P＜0．05）。LNG＋NYL皮埋剂组和NYL皮埋剂组BMD较OVX组增加，在许多部位差异有显著性（P＜0．05－P＜0．01），BMD与Sham组接近，而它们的血清ALP和尿Pyr/Cr较OVX组下降（P＜0．05－P＜0．01）。结论：LNG皮埋剂不能阻止OVX导致的骨丢失，NYL皮埋剂有保护OVX大鼠骨量的作用。     

Sevelamer restores bone volume and improves bone microarchitecture and strength in aged ovariectomized rats

Sevelamer hydrochloride, a noncalcium phosphate binder, has been shown to reduce coronary artery and aortic calcification, and to improve trabecular bone mineral density in hemodialysis patients with chronic kidney disease. Here, we examined whether sevelamer given orally for 12 wk with normal food could restore bone volume (BV) and strength in aged ovariectomized (OVX) rats starting at 4 wk after OVX. Dual-energy x-ray absorptiometry, microcomputerized tomography, and bone histomorphometry analyses showed that OVX animals receiving sevelamer had increased trabecular BV (51%), trabecular number (43%), trabecular thickness (9%), cortical thickness (16%), mineral apposition rate (103%), bone formation rate (25%), and enhanced cortical and trabecular bone mechanical strength as compared with OVX rats. Sevelamer decreased collagen C telopeptide, increased osteocalcin levels, and decreased phosphate and magnesium levels without affecting calcium levels in the blood. Although sevelamer was not absorbed systemically, it stimulated osteoblast differentiation in BM-derived mesenchymal stem cell cultures, as evaluated by alkaline phosphatase positive colony-forming units, and inhibited recombinant human soluble receptor activator of nuclear factor-kappaB ligand-induced osteoclast differentiation, as evaluated by tartrate-resistant acid phosphatase positive cells in bone mineral-hematopoietic stem cell cultures. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis revealed that 69 proteins were differently expressed after OVX, of which 30% (20 of 69) were reversed to sham activity after sevelamer intake. PTH, fibroblast growth factor-23, and cytokine profile in serum were not significantly changed. Together, these results suggest that sevelamer in food increases the BV and improves biomechanical properties of bone in OVX rats.     

Long-term excess of endogenous calcitonin in patients with medullary thyroid carcinoma does not affect bone mineral density.

In a cross-sectional study of 39 patients with medullary thyroid carcinoma (MTC), we have investigated the effects of long-term calcitonin excess on bone mineral density. Bone mineral density was measured by dual X-ray absorptiometry at the lumbar spine between the second and fourth vertebra and by single photon absorptiometry at the distal forearm. The mean observation time of each patient between diagnosis of tumour and measurement of bone mineral density was 62.4 months (range 1-158 months). The mean calcitonin serum level was 14.4 micrograms/l at the time of measurement of bone mineral density. All patients were substituted with 150-200 micrograms L-thyroxine daily. At both sites, the mean bone mineral densities of all patients with MTC were not significantly different from controls. Patients with normal calcitonin levels (below 0.2 micrograms/l) after treatment had a normal bone mineral density of the spine but significantly (P less than 0.05) reduced bone mineral density values of the forearm. This was due to the decreased body surface areas of patients in this subgroup. Patients with multiple endocrine neoplasia type IIa had significantly higher bone mineral densities. Other bone-influencing factors, such as postoperative hypoparathyroidism, calcium intake, diarrhoea, menopause, tumour stage, previous anti-tumour treatment, or thyroxine substitution dose, did not affect bone mineral density. We thus conclude that long-term excess of endogenous calcitonin in patients with MTC has no positive effect on bone mineral density.     

Prolonged low-dose infusion of human parathyroid hormone does not increase femoral cancellous bone volume in ovariectomized rats.

OBJECTIVE: Daily injections of human parathyroid hormone (hPTH) increase bone volume in various animal species and in osteoporotic women. For hPTH to be widely accepted as an anabolic therapy for treating postmenopausal osteoporosis alternative delivery options need to be explored to replace the need for daily patient subcutaneous self-injection. Among these are inhalation, oral delivery and the use of programmable implanted minipumps to deliver the peptide. While infusion of high doses of PTH causes bone loss and hypercalcemia, no studies have assessed the effects of prolonged infusion of low doses of PTH on bone growth. DESIGN AND METHODS: [Leu(27)]-cyclo(Glu(22)-Lys(26))-hPTH-(1--31)NH(2) was delivered by Alzet minipumps to ovariectomized rats for 6 weeks after which histomorphometric indices (cancellous bone volume, trabecular thickness, mean trabecular number) of bone formation were measured in distal femurs. RESULTS: Infusing low doses (0.05 and 0.1 nmole/100g body weight/day) of the hPTH analog, [Leu(27)]-cyclo(Glu(22)-Lys(26))-hPTH-(1--31)NH(2), for 6 weeks does not prevent the ovariectomy-induced loss of rat femoral cancellous bone volume, trabecular thickness or trabecular number. CONCLUSION: These results support the absolute requirement of daily injections for the osteogenic action of hPTH on bone.     

Body mass index does not affect the survival of pancreatic cancer patients

AIM to evaluate the association of body mass index(b MI) with the overall survival of pancreatic ductal adenocarcinoma(PDAC) patients.METHODS A retrospective analysis of PDAC patients diagnosed in the National Cancer Center of China between January 1999 and December 2014 was performed. these patients were categorized into four b MI groups( 18.5, 18.5-22.9, 23-27.4 and ≥ 27.5 kg/m2). χ2 tests for comparison of the proportions of categorical variables, and Student's t-test or Mann-Whitney test for continuous variables were employed. Survival analysis was performed with the Kaplan-Meyer method. their HRs of mortality and 95%CIs were estimated using the Cox proportional hazards model.RESULTS With a median age of 59.6 years(range: 22.5-84.6 years), in total 1783 PDAC patients were enrolled in this study. their mean usual b MI was 24.19 ± 3.53 for the whole cohort. More than half of the patients(59.3%) experienced weight loss during the disease onset and progression. Compared with healthy-weight individuals, newly diagnosed patients who were overweight or obese had more severe weight loss during their disease onset and progression(P 0.001). Individuals who were overweight or obese were associated with positive smoking history(P 0.001). A significant difference in comorbidity of diabetes(P = 0.044) and coronary artery disease(P 0.001) was identified between high b MI and normal-weight patients. After a median follow-up of 8 mo, the survival analysis showed no association between b MI and the overall survival(P = 0.90, n = 1783). When we stratified the whole cohort by pancreatic cancer stage, no statistically significant association between b MI and overall survival was found for resectable(P = 0.99, n = 217), unresectable locally advanced(P = 0.90, n = 316) and metastatic patients(P = 0.88, n = 1250), respectively. the results did not change when we used the b MI at diagnosis.CONCLUSION Our results showed no significance of b MI for the overall survival of PDAC patients.     

Effects of chronic prednisolone treatment on bone resorption and bone composition in intact and ovariectomized rats and in ovariectomized rats receiving beta-estradiol

To examine the interactions between estrogen deficiency and glucocorticoid excess on bone metabolism the osteopenic effects of a standard dose of prednisolone (2 mg/kg BW.day) were studied in sham-ovariectomized (Sham-OVX), ovariectomized (OVX), and OVX rats given replacement beta-estradiol (OVX + E2). For 12 weeks six groups of female albino rats aged 4 months which had their skeletons labeled with 45Ca were fed matched amounts of low-calcium (0.1% Ca) hydroxyproline-free diet. The six treatment groups were: group 1, Sham-OVX; group 2, Sham-OVX + prednisolone; group 3, OVX; group 4, OVX + prednisolone; group 5, OVX + E2; group 6, OVX + E2 + prednisolone. Bone resorption was estimated by studying the urinary excretion of hydroxyproline and 45Ca. Parathyroid function was assessed indirectly from urinary cAMP excretion. Treatments did not influence parathyroid activity or serum levels of calcium or 1,25-dihydroxyvitamin D. However, ovariectomy increased bone resorption and induced osteopenia whereas prednisolone decreased bone resorption and formation and caused osteopenia. Ovariectomy increased the rate of bone resorption in prednisolone-treated rats; prednisolone lowered the rates of bone resorption and formation in OVX rats. The osteopenic effects of prednisolone and ovariectomy were additive and independent. E2 protected bone from the osteopenic effects of ovariectomy but did not affect bone loss induced by prednisolone. These results suggest prophylactic estrogen should help to avoid bone loss from estrogen deficiency in patients requiring chronic high dose glucocorticoid treatment.