股骨柄假体表面多孔层孔隙形状改造的动物实验

目的:观察菱形孔隙及方形孔隙两种不同几何形状多孔层设计股骨柄假体的生物学固定效果,分析孔隙几何形状对假体生物学固定的影响。方法:于2003-03/2004-04在中山大学医学部动物中心完成全部实验过程。纳入24只成年杂种犬,雌雄不拘,以随机数字表法均分为2组,即菱形孔隙组及方形孔隙组,各12只。自行设计完成犬骨重建型股骨柄假体,将股骨柄假体近2/3段表层改成两种不同几何形状的粗大多孔层结构,钛丝表面假体,钛丝直径改为1.0mm,孔径加大至5.0mm,孔隙度可达80%。菱形孔隙组钛丝沿股骨假体柄呈螺旋形排列并斜形相交,方形孔隙组钛丝沿股骨假体柄纵横排列并直角相交。均将假体表面孔隙内充填自体股骨头颈骨质制成的骨泥后,行右侧人工股骨头置换术。术后6个月行X射线摄片、组织学检查及生物力学测试,以股骨近端骨吸收情况、新生骨长入深度及孔隙充满度、假体-骨界面最大剪切强度测量为评价指标,了解假体内外成骨和固定情况。结果:菱形孔隙组及方形孔隙组各12只,实验中手术不成功或术后生存不够观察时间的均予实验过程中随时补足,最终每组12只进入结果分析。①组织学观察显示菱形孔隙组多孔层孔隙内最大骨长入深度及孔隙内新生骨平均充盈率均优于方形孔隙组(3000,2450μm;96.2%,71.6%)。②菱形孔隙组假体-骨界面最大剪切强度高于方形孔隙组,差异有显著性意义[(8.57±0.51),(3.15±0.41)N/mm2,P<0.01]。③菱形孔隙组6个月标本肉眼及X射线观察股骨近端无明显骨吸收,优于方形孔隙组;所有实验犬术后伤口缝线任其自行脱落,除1只伤口感染并于术后17d死亡外,余实验犬均伤口愈合良好,未出现不良反应。结论:股骨柄假体表面不同几何形状多孔层设计能影响其生物学固定效果,菱形孔隙设计优于方形孔隙。     

Abnormal pregnancy: early diagnosis by US and serum chorionic gonadotropin levels

Simultaneous sonography and quantitative serum human chorionic gonadotropin (HCG) levels from 126 women with threatened abortion were compared. Of 56 women with normal outcome, 39 (70%) had a gestation sac greater than or equal to 5 mm in mean sac diameter, and in each case the HCG level was 1,800 milli-international units (mIU/ml) or greater. The serum HCG levels strongly correlated with the gestation sac sizes to a mean sac diameter of 25 mm. Of 70 abnormal pregnancies, 31 demonstrated a gestation sac. Of these, 20 women (65%) had disproportionately low HCG levels relative to sac size, including 12 in whom the HCG level was less than 1,800 mIU/ml. One woman with an early molar pregnancy had a disproportionately elevated HCG level. Correlation of sonograms with a simultaneous measurement of serum HCG level is a useful method for evaluating threatened spontaneous abortion. A disproportionately low HCG level relative to gestation sac size is evidence for an abnormal pregnancy.     

BLOOD PLASMA PROTEIN REGENERATION CONTROLLED BY DIET : SYSTEMATIC STANDARDIZATION OF FOOD PROTEINS FOR POTENCY IN PROTEIN REGENERATION. FASTING AND IRON FEEDING

When blood plasma proteins are depleted by bleeding, with return of washed red cells (plasmapheresis) it is possible to bring the dog to a steady state of low plasma protein and uniform plasma protein production on a basal diet. Such dogs are excellent test subjects by which the potency of various diet factors for plasma protein regeneration can be measured. To regenerate plasma proteins in any significant amount the depleted dog requires food protein. Some proteins are very potent for new plasma protein production and others are utilized poorly. Beef serum is very potent and its proteins (2.6 gm.) will produce 1 gm. of new plasma protein in the depleted dog—a potency ratio of 2.6. Kidney protein stands at the bottom of our list and the dog needs 21 gm. of kidney protein to regenerate 1 gm. of plasma protein—a potency ratio of 21.0. Some grain proteins approximate the potency of beef serum and may show potency ratios of 2.7 to 4.6. Some of these grain proteins appear to favor the production of globulin more than albumin in the plasma. Skeletal muscle, gizzard (smooth muscle), lactalbumin and egg white fall into a favorable group with a potency ratio of 5.3 to 6.0. Whole liver, liver fractions, casein, and beef heart are a little less potent and present potency ratios of 6.5 to 8.0. Many of these food substances favor the production of albumin more than globulin. Pancreas and salmon muscle show less favorable potency ratios of 19.0 and 15.0 respectively. Fasting periods indicate that these depleted dogs can produce little if any new plasma protein. Iron feeding in some unexplained manner will influence body metabolism so that an excess of plasma protein will be produced. These observations have a bearing on clinical conditions associated with hypoproteinemia and give suggestions for diet aid or control in some of these abnormal states. The make-up of the diet is obviously of great interest and it is possible that protein combinations may be more potent than a single protein or that food potency ratios may differ in health and disease.     

The Application of Science- and Risk-Based Concepts to Drug Substance Stability Strategies

The International Conference on Harmonization (ICH) has provided practical guidance on the amount and type of drug substance stability data needed to support marketing applications (International Conference on Harmonization 2001, 2002, 2003a, b). Additional guidance has been issued by the World Health Organization (WHO 2009). Recent scientific advances and practices have resulted in improved scientific understanding of the chemical and physical attributes that contribute directly or indirectly to drug substance stability. Combining this improved understanding with the science- and risk-based approaches detailed in ICH Q8, Q9, and Q10 allows for alternative and more scientifically driven approaches to meet the scientific and regulatory objectives for drug substance stability (International Conference on Harmonization 2005, 2008, 2009). In this paper, proposals are presented to more fully leverage enhanced product knowledge to design improved stability strategies. The chemical and physical attributes that potentially impact drug substance stability are discussed, and strategies that leverage accelerated stability studies are presented.     

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants

Objectives: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 ± 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow‐up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow‐up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow‐up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.     

RAIDING OF BODY TISSUE PROTEIN TO FORM PLASMA PROTEIN AND HEMOGLOBIN : WHAT IS PREMORTAL RISE OF URINARY NITROGEN?

Dogs with sustained anemia and hypoproteinemia due to bleeding and a continuing low protein or protein-free diet with abundant iron will continue to produce much new hemoglobin and plasma protein for many weeks. The stimulus of double depletion (anemia and hypoproteinemia) leads to raiding of body and tissue protein to fill the demand for new hemoglobin and plasma protein. The blood proteins in these experiments take priority over the organ and tissue proteins. This is another illustration of the "ebb and flow" or dynamic equilibrium between organ or tissue protein and blood proteins. The average dog cannot tolerate this drain of double depletion for more than 7 to 11 weeks and during this time may lose 30 to 40 per cent of body weight. Some dogs are much more resistant to this raiding than others. Some dogs show a high blood protein output during every week up to the danger point. With the largest blood protein output one usually observes the most rapid weight loss. For every kilogram of weight loss we observe 50 to 140 gm. blood protein output. The weekly blood protein production ranges from 40 to 66 gm. These experiments make heavy demands on the body protein and we expected to record a "premortal rise" in urinary nitrogen. No such observations are noted, rather a most frugal use of all protein and minimum figures for urinary nitrogen. We suspect that "premortal rise" in many experiments means a terminal infection with the related catabolism of tissue protein and high urinary nitrogen.     

Exogenous lung surfactant: effect on radiographic appearance in premature infants

At birth, premature infants of 25-29 weeks gestation, at high risk for development of neonatal respiratory distress syndrome (RDS), were given a single dose (90 mg) of calf lung surfactant extract (CLSE) by intratracheal instillation. The frequency and severity of RDS were assessed with use of a simple radiographic scoring system in which pulmonary parenchymal densities and the prominence of the air-bronchogram effect were used as indicators of widespread atelectasis. Radiographs were obtained in surfactant-treated and control infants within the first 90 minutes of life as part of an initial evaluation of their pulmonary status. Subsequent examinations were performed at less than 24 hours and less than 48 hours of age. Radiographic assessment of lung disease compared consistently with coordinated data on oxygen and mean airway pressure requirements of the infants. Both indicated a significantly decreased frequency and severity of RDS in the infants treated with surfactant. The results provide supporting evidence of the effectiveness of exogenous lung surfactant replacement in mitigating RDS in very premature infants.     

Thrombosis at venous insertion sites after inferior vena caval filter placement

Color Doppler flow imaging or compression ultrasound (US) was used to prospectively determine frequency of thrombosis at 54 venous insertion sites (47 in common femoral veins, seven in right internal jugular veins) after percutaneous placement of Greenfield filters for interruption of the inferior vena cava. Fifty-one filters were successfully placed in 51 patients with a dilator set or a balloon angioplasty catheter. Nine focal thrombi were detected in the common femoral vein (19%) and one in the right internal jugular vein (14%). Use of dilators induced eight thrombi (24%), compared with two (10%) from balloon catheters. The left common femoral vein had a high frequency of thrombosis, regardless of dilation technique (five of nine). Of nine patients with acute common femoral vein thrombosis, four became symptomatic within 10 days after the procedure. Patients may remain asymptomatic or have delayed symptoms; thus, US is valuable for determining patients at risk of thrombosis of the common femoral vein.