CALLA-positive myeloma: an aggressive subtype with poor survival

Detailed immunotyping was carried out on 21 direct myeloma bone marrow aspirates and eight human myeloma cell lines. Four previously untreated common acute lymphoblastic leukemia antigen (CALLA)-positive myeloma patients were identified and six of eight cell lines (75%) were also positive. CALLA positivity, as part of an immature B phenotype, was found to correlate with very aggressive clinical disease: median survival six months v 56 months for the CALLA-negative group.     

Activity of 3 beta-hydroxysteroid dehydrogenase-5,4-en isomerase in chorioallantois and amnion from pregnant sheep

Activity of 3 beta-hydroxysteroid dehydrogenase-5,4-en isomerase (3 beta-HSD; pregnenolone to progesterone) was investigated in homogenates of chorioallantois and amnion obtained from sheep at three gestational ages (day 50, day 100 and term) using an isotope assay. Chorioallantois and, to a lesser extent, amnion possessed 3 beta-HSD at each gestational age studied. Activity in the chorioallantoic membrane was greater at term than at days 50 and 100, and was similar to that in the placenta at day 100 and term. Activity in the placenta was considerably greater at day 50 than at day 100 and term. The subcellular distribution of 3 beta-HSD in chorioallantoic membrane was particulate in nature. The mean Km values (+/- S.E.M.) were 56.8 +/- 5.5 and 39.0 +/- 8.7 nmol/l at day 50 and term respectively. The mean Vmax values were 14.1 +/- 3.1 and 62.7 +/- 11.4 pmol/min per mg protein at day 50 and term respectively. Several steroids inhibited the conversion of pregnenolone to progesterone, particularly dehydroepiandrosterone (DHEA), oestrone and oestradiol. Oestrone and DHEA were competitive inhibitors. The Ki values were 19.6 +/- 5.9 and 40.2 +/- 14.7 nmol/l for oestrone and DHEA inhibition respectively. The results show that ovine fetal membranes have the capacity to convert pregnenolone to progesterone and demonstrate the possibility of inhibition by other steroids. Progesterone produced by the fetal membranes might influence the local intra-uterine steroid milieu during pregnancy and before parturition.     

Characterization and quantitation of the circulating forms of serum transferrin receptor using domain-specific antibodies

To characterize the nature of the immunoreactive transferrin receptor in human serum, antisera were developed to peptide sequences of the extracellular domain of human transferrin receptor between amino acids 107 and 120 and the intracellular domain between amino acids 40 and 54. Antisera against the extracellular domain exhibited reactivity against both purified intact receptor and immunopurified circulating receptor, whereas antisera against the intracellular domain reacted only with intact receptor. Using competitive binding enzyme-linked immunosorbent assays, transferrin receptor in ultracentrifuged sera from normal subjects and patients with sickle cell anemia could be detected with antisera against the extracellular but not the intracellular domain. When the pellet obtained by ultracentrifugation of these sera was assayed after solubilization in 1% teric (polyoxyethylene-9-lauryl ether), only 0.6% of total serum receptor was detected in normal subjects and 3.8% in subjects with sickle cell disease. Roughly equal amounts of this pelleted immunoactivity were detected with antibodies against the extracellular and intracellular domains. These results indicate that less than 1% of transferrin receptor in normal human sera is intact receptor consistent with an exosomal origin and that virtually all circulating transferrin receptor is in the form of a truncated extracellular domain.     

Architectural properties of the first dorsal interosseous muscle

Muscle architecture is considered to reflect the function of muscle in vivo, and is important for example to clinicians in designing tendon‐transfer and tendon‐lengthening surgeries. The purpose of this study was to quantify the architectural properties of the FDI muscle. It is hypothesized that there will be consistency, that is low variability, in the architectural parameters used to describe the first dorsal interosseous muscle because of its clear functional role in index finger motion. The important architectural parameters identified were those required to characterize a muscle adequately by modeling. Specifically the mass, cross‐sectional area, and length of the tendon and muscle were measured in cadavers along with the muscle fiber optimum length and pennation angle, and the moment arm of the first dorsal interosseous at the metacarpophalangeal joint. These parameters provide a characterization of the architecture of the first dorsal interosseous, and were used to indicate the inherent variability between samples. The results demonstrated a large amount of variability for all architectural parameters measured; leading to a rejection of the hypothesis. Ratios designed to describe the functioning of the muscles in vivo, for example the ratio of tendon to fiber optimum lengths, also demonstrated a large variability. The results suggest that function cannot be deduced from form for the first dorsal interosseous, and that subject‐specific architectural parameters may be necessary for the formulation of accurate musculoskeletal models or making clinical decisions.     

Nutrition and the early origins of adult disease

There is now overwhelming evidence that much of our predisposition to adult illness is determined by the time of birth. These diseases appear to result from interactions between our genes, our intrauterine environment and our postnatal lifestyle. Those at greatest risk are individuals in communities making a rapid transition from lives of 'thrift' to a lives of 'plenty'. From a global perspective, such origins of diabetes, coronary heart disease and stroke, should render research in these fields as one of the highest priorities in human health care. Prevention will be enhanced by elucidation of the mechanisms by which the fetus is programmed by the mother for the life she expects it to live. At the present time, there is evidence that fetal nutrition and premature exposure to cortisol are effective intrauterine triggers, but a multitude of alternative pathways require investigation. It is also likely that programming extends across generations, and may involve the embryo and perhaps the oocyte. An oocyte that becomes an adult human develops in the uterus of its grandmother, so further research is required to describe the role of environments of grandmothers and mothers in predisposing offspring to health or illness in adult life.     

Linking assessment to learning: a new route to quality assurance in medical practice

BACKGROUND: If continuing professional development is to work and be sensible, an understanding of clinical practice is needed, based on the daily experiences of doctors within the multiple factors that determine the nature and quality of practice. Moreover, there must be a way to link performance and assessment to ensure that ongoing learning and continuing competence are, in reality, connected. Current understanding of learning no longer holds that a doctor enters practice thoroughly trained with a lifetime's storehouse of knowledge. Rather a doctor's ongoing learning is a 'journey' across a practice lifetime, which involves the doctor as a person, interacting with their patients, other health professionals and the larger societal and community issues. OBJECTIVES: In this paper, we describe a model of learning and practice that proposes how change occurs, and how assessment links practice performance and learning. We describe how doctors define desired performance, compare actual with desired performance, define educational need and initiate educational action. METHOD: To illustrate the model, we describe how doctor performance varies over time for any one condition, and across conditions. We discuss how doctors perceive and respond to these variations in their performance. The model is also used to illustrate different formative and summative approaches to assessment, and to highlight the aspects of performance these can assess. CONCLUSIONS: We conclude by exploring the implications of this model for integrated medical services, highlighting the actions and directions that would be required of doctors, medical and professional organisations, universities and other continuing education providers, credentialling bodies and governments.     

Activation of the hypothalamic-pituitary-adrenal axis with repetitive umbilical cord occlusion in the preterm ovine fetus

OBJECTIVE:To determine whether repeated hypoxic insults with umbilical cord occlusion over 4 days will lead to activation of the hypothalamic-pituitary-adrenal (HPA) axis altered adrenocortical responsiveness in the preterm ovine fetus. METHODS: Umbilical cord occlusions of 90 seconds duration were performed every 30 minutes for 3 to 5 hours each day (experimental group n = 7, control group n = 7; at 112-116 days' gestation, term = 147 days). Arterial blood was sampled at predetermined times for blood gases and pH, plasma ACTH, and cortisol. Pituitary proopiomelanocortin (POMC) and glucocorticoid receptor (GR) mRNA also were localized and quantified by in situ hybridization. RESULTS: During umbilical cord occlusions fetal arterial oxygen pressure (approximately 17 mmHg) and pH (approximately 0.05) decreased, and carbon dioxide pressure increased (approximately 8 mmHg) as measured on days 1 and 4, but with no cumulative blood gas or pH change over successive occlusions for any of the 4 study days. Plasma ACTH increased, as measured after cord occlusion and over the course of successive cord occlusions on days 1 and 4, and returned to control values by the next day. The cumulative increase in ACTH was much less on day 4 than day 1 (15 +/- 3 compared with 101 +/- 25 pg/mL, P <.05). Plasma cortisol increased, as measured after cord occlusion and over the course of successive cord occlusions on day 4 only (2.7 +/- 0.4 to 4. 7 +/- 0.3 ng/mL, P <.05). POMC mRNA increased 2.5-fold in the pars distalis of the pituitaries from cord occlusion compared to control fetuses, but was unchanged in the pars intermedia. GR mRNA, which was detected in the pars distalis only, was unaltered. CONCLUSION: Repetitive umbilical cord occlusion in the preterm ovine fetus resulted in the activation of the HPA axis, with increased adrenocortical responsiveness over time, and involved differential regulation of POMC mRNA expression in the pars distalis and pars intermedia of the pituitary, but with no change in GR.     

Cord occlusion techniques for selective termination in monochorionic twins

We wished to determine the optimal method for cord obliteration to perform selective reduction in complicated monochorionic (MC) twin pregnancies under different clinical conditions. For this purpose, we reviewed our experience and the available published literature and unpublished reports. Indications were a cardiac twin pregnancy, twins discordant for fetal anomaly, and severe feto-fetal transfusion syndrome where one twin had a very poor prognosis. Data were available for the following techniques: cord embolization, fetoscopic cord ligation, laser coagulation, monopolar coagulation and bipolar cautery. Unfortunately the data are heterogeneous, incomplete and reports are only sporadic. Cord embolization using coils or sclerosants has a high failure rate and can no longer be recommended. In 23 published cases of fetoscopic cord ligation a failure rate of 10% was reported. After successful ligation an overall fetal survival rate of 71% but a risk of preterm prelabor rupture of the membranes (PPROM) of 30% was documented. Four cases of monopolar coagulation have been published--all in a cardiac twin pregnancies. In three cases the abdominal aorta was coagulated prior to 20 weeks and complete cessation of flow was demonstrated. In 10 cases of bipolar cord coagulation, all procedures were technically successful. Nine of 10 were performed under ultrasound guidance through a single port. In 2 cases, frank PPROM occurred, leading to induction of labor. The other eight fetuses were born at 35 weeks or more. Nd:YAG coagulation of the cord was much more sporadically described; the success of the procedure seems to be clearly dependant on gestational age. In all our attempts prior to 20 weeks, we failed in only one out of 6 cases. In summary, there is little data to perform meaningful comparisons of available techniques for umbilical cord occlusion. Based on practical and technical considerations we use the following clinical algorithm: prior to 21 weeks, we attempt to coagulate the cord with Nd:YAG laser. If this is unsuccessful, or for gestations beyond 21 weeks, bipolar cord coagulation is currently our other method of choice. Sonoendoscopic cord ligation is reserved as backup procedure if neither of these methods are successful.