Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate osteoclastic bone resorption

As both tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 have been reported to inhibit bone resorption, we examined whether TIMP-1 or TIMP-2 in fetal calf serum (FCS), with which culture media were supplemented, affected osteoclastic bone resorption in vitro. Contrary to our expectation, almost complete suppression of osteoclastic bone resorption was observed when both TIMP-1 and TIMP-2 were removed from the FCS. Bone resorption was, however, almost fully restored by the addition of recombinant TIMPs. TIMPs stimulate bone resorption at significantly lower concentrations (∼ng/ml) than those (∼μg/ml) required to inhibit bone resorption. To understand the mechanism of TIMP-dependent bone resorption, we counted and compared the number of tartrate-resistant acid phosphatase-(TRAP-) positive and multinuclear cells in cultures containing either 10% FCS or TIMP-1-free and/or TIMP-2-free FCS. There was essentially no difference in number among these, suggesting that the TIMP role seems to be related to the functional expression of osteoclasts. Metallo-proteinase inhibitors, either BE16627B[l-N-(N-hydroxy-2-isobutylsuccinynamoyl)-seryl-l-valine] or R94138 {N-methyl-(3S)-2-[(2R)-2-hydroxycarbamoylmethylundecanoyl] hexahydropyridazine-3-carboxamide}, could not replace TIMPs, suggesting that the osteoclast-stimulating activity of TIMPs cannot be ascribed to merely their inhibitory effect on matrix metalloproteinases. Received: Oct. 15, 1998 / Accepted: April 5, 1999     

The Effect of Modifying Dietary Calcium Intake Pattern on the Circadian Rhythm of Bone Resorption

In order to assess day-to-day variations of the circadian rhythm of biochemical bone resorption markers, urinary morning (6–8 a.m.) and evening (7–10 p.m.) samples from 35 individuals were monitored during 3 subsequent days. The bone-specific deoxypyridinoline (DPD) crosslinks of type I collagen followed a circadian rhythm in all individuals. In contrast, no such pattern was observed in the urinary hydroxyproline/creatinine and calcium/creatinine measurements. The DPD crosslink measurements showed a much larger difference between the morning and evening samples collected within 1 day compared with the variation between the samples collected in the morning or evening on subsequent days, indicating the importance of adequate timing of urine sampling for clinical trials aiming to monitor effects on bone resorption. The analysis of DPD crosslinks was then used to evaluate the effects of different patterns of dietary calcium intake on the circadian rhythm of bone resorption in osteoporotic patients. No significant effect on the circadian rhythm of the DPD crosslinks was found after concentrating the normal daily calcium intake to the evening (6–10 p.m.) during 8 days (n = 7). Ingestion of a dietary calcium supplement (600 mg) at 10 p.m. during 8 days (n = 7) resulted in an increased urinary calcium excretion in the morning, and a flattening of the circadian peak and nadir concentrations of urinary DPD/creatinine. The absolute levels of DPD/creatinine in the morning and evening urine samples, respectively, were not significantly altered compared with the control day. We conclude that dietary calcium supplementation in the evening only marginally affects the circadian rhythm of urinary DPD crosslinks in established osteoporosis patients. Received: 23 December 1996 / Accepted: 1 November 1998     

The role of a single free {beta}-human chorionic gonadotrophin measurement in the diagnosis of early pregnancy failure and the prognosis of fetal viability

This prospective controlled study investigated the concentrationsof free -human chorionic gonadotrophin (HCG) subunit in 554women with a singleton intrauterine or tubal pregnancy. Theypresented with vaginal bleeding and/or abdominal pain in thefirst 18 weeks of pregnancy. The control group comprised 156women with musculo-skeletal pain and no vaginal bleeding. Theirpregnancies continued to term. The study group comprised 398women (141 threatened-continuing pregnancies, 37 threatened-miscarriages,185 non-continuing pregnancies and 35 tubal pregnancies). Free-HCG concentrations were significantly lower in the non-continuing,threatened-miscarriage and tubal pregnancy groups [mean 4.62,6.50 and 4.27 ng/ml respectively; 95% confidence interval (CI)3.75–-5.69, 4.46–9.48 and 2.92–6.2 respectively]than in the control and threatened-continuing groups (mean 41.61and 48.22 ng/ml respectively; 95% CI 34.53–50.13 and 42.03–55.32respectively) (P < 0.001 in all cases). A cut-off value at20 ng/ml was found to differentiate between the ‘viable’(control and threatened-continuing) and the ‘abnormal’(non-continuing, threatened-miscarriage and tubal) pregnancies,with 88.3% sensitivity and 82.6% positive predictive value.An excellent diagnostic and prognostic usability of free HCGwas confirmed by a receiver operating characteristic curve plotIn conclusion, a single serum free -HCG measurement taken inearly pregnancy is valuable in the immediate diagnosis of earlypregnancy failure and the long-term prognosis of viability.     

Randomized trial of two beta-mimetic drugs (ritodrine and fenoterol) in acute intra-partum tocolysis

Summary The uterine inhibitory effect and potential maternal and fetal side effects of two -mimetic compounds, ritodrine hydrochloride and fenoterol hydrobromide, were compared in a randomized trial. The drugs were administered by intravenous infusion to 24 healthy term nulliparous women during effective first-stage labour; each of them received fenoterol (1, 2, or 4 µg/min) or ritodrine (100, 200, or 400 µg/min). There was no difference between the drugs in the intensity of the uterine inhibition. However, for a similar inhibitory effect, the duration of tocolysis was longer after ritodrine. During the intrapartum and neonatal periods, neither compound induced any change in the fetal parameters investigated, and their effects on maternal parameters were comparable.     

Role of prenatal echocardiography in the study of hypertrophic cardiomyopathy in the fetus

The increased incidence of hypertrophic cardiomyopathy in children of diabetic mothers has already been demonstrated, but its prenatal diagnosis has not yet been extensively studied. The purpose of this prospective study was to evaluate the frequency, severity, and echocardiographic features of fetal hypertrophic cardiomyopathy in a population with several indications for prenatal echocardiography. From March 1987 to April 1991, 283 fetuses were submitted to comprehensive prenatal echocardiography, including M-mode measurements, cross-sectional imaging, Doppler studies, and color flow mapping. One hundred seventy-six were pregnancies complicated by previous or gestational diabetes. The diagnosis of disproportionate septal hypertrophy was made in 39 fetuses (mean septal thickness 7.12 +/- 1.6 mm), at a mean gestational age of 32 weeks. Diabetes mellitus was present in 36 of these pregnancies (92.3%). In four cases, nonimmune hydrops was detected. A systolic anterior motion of the mitral valve was present in three fetuses, but only one showed a gradient across the left ventricular outflow tract. Postnatal echocardiographic examination in 27 babies did not show false positivity. In ten cases, spontaneous regression of the septal hypertrophy was shown. There were three neonatal deaths, unrelated to the myocardial disease. We concluded that transient hypertrophic cardiomyopathy is a frequent entity, especially when associated with diabetes during gestation, being a potential cause for nonimmune hydrops. Fetal echocardiography is the method of choice for its prenatal diagnosis and should always be indicated in diabetic mothers.     

Iodine-125 labeled phenylphosphonic acid: A new radiopharmaceutical for long-term investigations of the skeleton

A skeletal seeking radiopharmaceutical labeled with a long-lived radionuclide was developed to evaluate regional bone formation and its subsequent resorption. The agent is [phosphonate (phenylmethylene hydroxy) bis]-I-125 or I-125 PA. Tissue distribution studies in mice (N=16) showed approximately 40% of the administered dose to be retained by the skeleton up to 336 hours post IV injection. The percentage of the dose accumulated by the thyroid gland remained at less than 0.5%, indicating minimal deiodination of the I-125 PA. Whole body retention studies in the same species revealed a triexponential release pattern with the longest component comprising 33% of the dose with a biologic half-life of 962 days. A fractured rat tibia model was studied with I-125 PA and Tc-99^m MDP. Chronic loss of the I-125 PA relative to normal tibia was quantitated: five days (62.8%); 30 days (47.4%). Concomitant increased uptake of the Tc-99^m MDP was observed at the fracture site relative to normal: five days (186%); 30 days (1,041%). The above data suggest that I-125 PA can be utilized to measure acute bone formation and chronic resorption.     

Comparative patterns of i-antigen expression, F-cell frequency and Hb A2 level in acute myeloid leukemia and in acute lymphoid leukemia

Hb F, Hb A₂ and i-antigen expression were investigated in adulthood acute leukemias. The study of i-antigen expression by immuno-agglutination and immunofluorescence showed that it is preferentially increased among AML patients. A similar result was obtained for F-cell frequency which was often increased in AML, while it was normal in ALL. Hb A₂ level was significantly lower in AML than in ALL. These differences between AML and ALL red cell patterns further suggest that the leukemic clone involves the erythroid lineage in AML but not in ALL.     

重度妊高征血清尿酸及β_2-MG监测对评价围产期结局的临床意义

目的 :探讨尿酸 (UA)、β2-微球蛋白(β2-MG)对重度妊高征围产期结局的影响。方法 :测定51例重度妊高征患者血清UA、β2-MG、尿素氮 (BUN)、肌酐(Cr)水平和尿蛋白定量 ,统计孕期及新生儿情况 ,按围产儿存活与否分为死亡组与存活组进行分析。结果 :(1)死亡组前3个指标明显高于存活组 ,尿蛋白定量2组差异无统计学意义。(2)血清UA水平与BUN、β2-MG水平呈正相关 ,与新生儿体重呈负相关。结论 :监测重度妊高征患者血压、尿蛋白、尿素氮、肌酐的同时更应密切监测尿酸和β2-MG的变化 ,以指导临床诊治     

高频振荡通气及联合硫酸镁治疗新生猪重症胎粪吸入综合征的实验研究

目的　探讨高频振荡通气 (HFOV)及联合硫酸镁 (Mg SO4 )治疗合并持续肺动脉高压(PPH)的重症胎粪吸入综合征 (MAS)模型氧合、循环功能 ,血镁浓度及肺组织病理改变。　方法　以2 0 %胎粪混悬液制备重症 MAS模型 ,健康新生猪随机分为 3组 ,即模型 HFOV治疗组 (HFOV组 ,n= 6 ) ,HFOV+Mg SO4 治疗组 (HFOV+Mg SO4 组 ,n=7) ,HFOV对照组 (对照组 ,n=5 ) ,HFOV+Mg SO4 组同时静脉持续泵入 Mg SO4 。监测生命体征、血气、血镁浓度。　结果　 (1) HFOV和 HFOV+Mg SO4 治疗均使 MAS模型动脉血氧分压 (Pa O2 )、动脉血氧 /肺泡血氧分压比 (a/ APO2 )增加 ,肺泡-动脉血氧分压差 (A- a DO2 )、肺内分流 (Qs/ Qt)降低 ,治疗 30 min与治疗前比差异有非常显著性 (P<0 .0 1)。HFOV组各时间点 Pa O2 、a/ APO2 低于对照组 ,A- a DO2 、Qs/ Qt高于对照组 (P<0 .0 5 )。HFOV+Mg SO4 组治疗 12 0 m in后上述指标与对照组差异无显著性 (P>0 .0 5 )。 (2 )尽管氧合功能改善 ,单独 HFOV对重症 MAS的 PPH无降低作用 ,联合 Mg SO4 治疗 30 min即可有效降低 PPH(P<0 .0 5 ) ,并保持疗效。(3) HFOV组较 HFOV+Mg SO4 组有明显肺出血 ,出血沿肺段、小叶分布 ,两组病理评分差异有显著性 (P<0 .0 5 )。 (4) HFOV+Mg SO4 组血镁浓度较治疗