Hemisynthesis of antineoplastic conjugates with nitrogen-mustard proteins

The synthesis of new conjugates with inhibitory action on tumour growth is investigated by linking amino functions of proteins compounds (lysozyme and alpha s-casein) through an amide linkage at the carboxylic function of nitrogen mustards (chlorambucil and melphalan). The polychlorambucil amides of lysozyme and alpha s-casein derivatives prepared showed experimental antitumour activity when these conjugates were screened against the experimental P388 leukemia. In the case of the conjugates lysozyme-melphalan, an antitumour activity is observed when the amino function of the drug is combined with the carboxylic functions of the protein contrary to the situation of the free amino function of the drug described into the literature.     

Plasma concentrations of epidural bupivacaine in mother and newborn: 0.125% versus 0.375%

Central venous plasma concentrations of bupivacaine were determined in two groups of 15 parturients each who were given epidural analgesia for labor and vaginal delivery. One group received 10 ml of 0.125% bupivacaine plus epinephrine 1:800,000, the other group received 7 ml of 0.375% bupivacaine plus epinephrine 1:800,000. Plasma concentrations of bupivacaine in the umbilical venous (UV) and the umbilical arterial (UA) blood of their babies were also determined. The mean UA, UV, and maternal central venous (MV) plasma concentrations of bupivacaine differed significantly between the two groups: in patients given 0.375% bupivacaine UA values were 63% higher (P less than 0.01), UV values were 57% higher (P less than 0.01), and the MV values were 34% higher (P less than 0.05) than in patients given 0.125% bupivacaine. The measured plasma concentrations speak in favor of the less concentrated solution of bupivacaine in epidural analgesia for obstetrics. Seven milliliters of bupivacaine 0.375% is suitable for epidural analgesia in obstetrics but a low concentration-low dose technique, using 10 ml of bupivacaine 0.125% plus epinephrine 1:800,000 is safer. It provides good analgesia with minimal or no motor block and is associated with low maternal and neonatal plasma concentrations of bupivacaine, well below toxic levels and, to our knowledge, lower than in any other study.     

NK cells developing in vitro from fetal mouse progenitors express at least one member of the Ly49 family that is acquired in a time-dependent and stochastic manner independently of CD94 and NKG2

NK cells developing in vitro from fetal progenitors in the presence of IL-2 are phenotypically and functionally indistinguishable from mature adult NK cells, with the exception that they generally lack surface expression of any of the Ly49 molecules that have previously been examined. Using two recently developed anti-Ly49 mAb, we show here that most of these NK cells in fact express high levels of at least one previously uncharacterized member of the Ly49 family, most likely Ly49E. Detailed kinetic and clonal analysis revealed that these Ly49 molecules were acquired in a progressive and stochastic manner independently of CD94 and NKG2. CD94 and NKG2 were both expressed early in NK cell development, sometimes in the absence of NK1.1, with CD94 invariably being expressed at two different levels. IL-4 differentially inhibited the expression of CD94 and Ly49 receptors, but had little or no effect on the expression of NKRP1 molecules.     

Artificial Circulation of the Liver: Machine Perfusion as a Preservation Method in Liver Transplantation

Due to the sharp increase in liver transplant candidates and the subsequent shortage of suitable donor livers, an extension of the current donor criteria is necessary. Simple cold storage, the current standard in organ preservation has proven to be insufficient to preserve extended criteria donor livers. Therefore a renewed interest grew toward alternative methods for liver preservation, such as hypothermic machine perfusion and normothermic machine perfusion. These “new” preservation methods were primarily assessed in rat models, and only a few clinically relevant large animal models have been described so far. This review will elaborate on these alternative preservation methods. Anat Rec, 291:735–740, 2008. © 2008 Wiley‐Liss, Inc.     

Association between bone mineral density (DXA), body structure,and body composition in middle‐aged men

The association between bone mass, body structure, and body composition was explored in 156 men, 40 years of AGE . Bone mineral density (total body, lumbar spine, left arm, and left leg) was obtained by dual‐energy X‐ray absorptiometry (DXA; Hologic QDR 4500A). Body structure was determined from a battery of anthropometric dimensions with a principal components analysis. Body composition was estimated with DXA. From the 24 anthropometric dimensions, three components were extracted and identified as muscle, fat, and skeletal length. Significant correlations between the muscle component and all BMD measurements (r = 0.28–0.44) were obtained. Except for BMD of the left arm, which correlated significantly, but negatively, with the fat component (r = ?0.16), no significant relations were found between the fat component and BMD. There were significant correlations between lean mass, fat mass, and BMD measurements. The correlations were higher between lean mass and BMD (r = 0.22–0.44) than between fat mass and BMD (r = 0.08–0.24). The multiple regression analysis revealed that except for BMD of the left arm only lean mass or the muscle component, and not fat mass or the fat component, were independent predictors of BMD. It is concluded that the principal anthropometric determinant of BMD in middle‐aged men is lean mass or muscle. Am. J. Hum. Biol. 14:735–742, 2002. © 2002 Wiley‐Liss, Inc.     

A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine

OBJECTIVES: Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). METHODS: In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. RESULTS: The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05). CONCLUSIONS: Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.     

Ovarian Sertoli-Leydig cell tumour with raised serum alpha fetoprotein

Summary A case of ovarian Sertoli-Leydig cell tumour with a raised serum alpha fetoprotein in reported. The patient first presented at the age of 27 years with a history of 6 years' amenorrhoea followed by 3 months irregular vaginal bleeding. A ovarian tumour was found and excised and shown microscopically to be a spindle cell malignant tumour. The patient was treated with chemotherapy and had a complete response. Thirty months after first presentation there was a recurrence in the pelvis which microscopically showed the typical features of a Sertoli-Leydig cell tumour. Six months later a second recurrence had the microscopic appearance of a lipid cell tumour. A raised serum alpha fetoprotein was found at the time of the second recurrence and immunohistochemistry showed this protein in the Leydig and luteinized cells of the recurrent tumours but not in the spindle cells of the original ovarian neoplasm.     

Ly49E expression points toward overlapping,but distinct,natural killer (NK) cell differentiation kinetics and potential of fetal versus adult lymphoid progenitors

Using a new antibody, we found previously that contrary to adult natural killer (NK) cells, fetal NK cells have a unique phenotype, as they exclusively express Ly49E. This can be explained by an intrinsic different NK differentiation potential of fetal versus adult lymphoid progenitors, by immaturity of fetal NK cells or by instability of Ly49E expression. Here, we show that adult progenitor cells were still capable of differentiating into Ly49E-expressing NK cells but at a much lower frequency. Surprisingly, Ly49E expression in vitro did not require stromal cells. Kinetic analysis in vivo showed that Ly49E was expressed early, together with CD94/NKG2 and Ly49G2, followed by Ly49C, and finally Ly49D. Transfer of sorted Ly49E-positive fetal NK cells showed stable Ly49E expression, and later, part of these cells up-regulated other Ly49 members. These data indicate that although there are intrinsic differences, there is no strict fetal and adult wave of NK cell differentiation.     

Dampened Muscle mTORC1 Response Following Ingestion of High-Quality Plant-Based Protein and Insect Protein Compared to Whey

Increased amino acid availability acutely stimulates protein synthesis partially via activation of mechanistic target of rapamycin complex 1 (mTORC1). Plant-and insect-based protein sources matched for total protein and/or leucine to animal proteins induce a lower postprandial rise in amino acids, but their effects on mTOR activation in muscle are unknown. C57BL/6J mice were gavaged with different protein solutions: whey, a pea–rice protein mix matched for total protein or leucine content to whey, worm protein matched for total protein, or saline. Blood was drawn 30, 60, 105 and 150 min after gavage and muscle samples were harvested 60 min and 150 min after gavage to measure key components of the mTORC1 pathway. Ingestion of plant-based proteins induced a lower rise in blood leucine compared to whey, which coincided with a dampened mTORC1 activation, both acutely and 150 min after administration. Matching total leucine content to whey did not rescue the reduced rise in plasma amino acids, nor the lower increase in mTORC1 compared to whey. Insect protein elicits a similar activation of downstream mTORC1 kinases as plant-based proteins, despite lower postprandial aminoacidemia. The mTORC1 response following ingestion of high-quality plant-based and insect proteins is dampened compared to whey in mouse skeletal muscle.