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The body cholesterol pool increases with decreasing plasma-high-density-lipoprotein (H.D.L.) but is unrelated to the plasma concentrations of total cholesterol and other lipoproteins. This finding supports existing evidence that H.D.L. facilitates the uptake of cholesterol from peripheral tissues and its transport to the liver for catabolism and excretion. Plasma-H.D.L., is reduced in several conditions associated with an increased risk of future ischaemic heart-disease (I.H.D.), namely hypercholesterolaemia, hypertriglyceridaimia, male sex, obesity, and diabetes mellitus, while subjects with existing clinical I.H.D. have lower levels of H.D.L. than healthy subjects within the same community. It is proposed that a reduction of plasma-H.D.L. concentration may accelerate the development of atherosclerosis, and hence I.H.D., by impairing the clearance of cholesterol from the arterial wall.

We evaluated the use of pulsed electromagnetic-field stimulation to affect the rate of healing or incorporation of segmental autogenous cortical bone grafts in the dog in vivo. This non-invasive method of electrical stimulation has been implicated in increasing bone osteogenesis or augmentation of the repair process in the canine fibular osteotomy. We utilized two-month and six-month stimulation protocols. At six months, all of the animals were evaluated biomechanically using rapid-loading torsional testing. Histological evaluation using tetracycline labeling was used to evaluate cumulative new-bone formation and porosity, while graft-host time to union was evaluated roentgenographically every two weeks. Recent reports have implied that particular pulse configurations might be effective in improving graft revascularization and incorporation. The results of our investigation indicated that there was no significant effect on the biomechanical strength, histological presentation, or time to union with either two months or six months of pulsed electromagnetic-field stimulation using the particular waveform described.

Current hypotheses regarding the causes of human benign prostatic hyperplasia have implicated both steroid hormone imbalance and tissue interactions. To examine the role of the latter we have further investigated the phenomenon of urogenital sinus-induced hyperplasia of the adult mouse ventral prostate. Urogenital sinuses (UGS) or purified urogenital mesenchyme (UGM) from C3H mice were implanted into the ventral prostates or coagulating glands of 50- to 90-day-old BALB/c-nu/nu hosts. The animals were sacrificed at 15, 30, and 180 days postimplantation to establish time dependence. Wet weight and DNA content were used as measures of net growth. Glucose phosphate isomerase (GPI) isozyme analysis was used to determine the relative contributions of C3H and BALB/c cells to the enlarged chimeric ventral prostates. It was determined that the induced growth is time-dependent and that the UGS induces 2- to 4-fold more growth than UGM. GPI analysis shows that UGM-induced growth was composed primarily of host-derived cells whereas the UGS is composed nearly equally of host- and implant-derived cells. Histologic analysis reveals that the UGS implants induce marked epithelial proliferation. The proliferating glands occur in clusters, and the epithelium within the glands appears cribriform. Foci of postobstructive cystic atrophy are also found. Remnants of the implanted UGS are still present even at 180 days postimplantation. UGM-induced growth is of a more subtle nature and appears morphologically similar to the sham-operated controls. In view of the morphologic similarity with human disease, as well as the time and hormonal dependence of UGS-induced ventral prostatic hyperplasia, this model represents the basis for a unified hypothesis regarding the roles of tissue interaction and hormonal milieu in human benign prostatic hyperplasia.

The high factor VII coagulant (VIIc) activity in men at high risk of coronary heart disease suggests that restoring normal hemostatic activity with appropriate oral anticoagulants might constitute effective primary prevention. A pilot study was therefore undertaken of a randomized, double-blind, placebo-controlled trial of long-term, low-dose warfarin therapy. Middle-aged men at high risk (mean VIIc 120% of standard) but without clinical coronary heart disease or contraindications to anticoagulants were randomized to warfarin or placebo. The initial warfarin dose (2.5 mg/day) was increased at intervals to lower VIIc to 70% of standard and increase the prothrombin time international normalized ratio to 1.6. The control participants received the same dose sequence of placebo. The pilot study confirmed the feasibility of the design, the absence of any increased risk of serious bleeding, and the high compliance and low withdrawal rate from randomized treatment. Accordingly, a full-scale thrombosis prevention trial has been launched, which, in addition to low-dose warfarin, includes a low-dose aspirin regimen (75 mg/day) in a factorial design. The aim of this trial is to produce a 30% reduction in coronary heart disease in 6,000 high-risk men aged 45 to 69 years. The men will receive either separate or combined therapy and will be followed up for 5 years. Evidence so far indicates that the risk of bleeding in those receiving combined therapy will be no higher than that in those taking aspirin alone.

Numerous fixation techniques have been described to obtain successful proximal interphalangeal (PIP) joint arthrodesis. By use of the Herbert screw for compression, 50 (98%) out of 51 PIP joints were fused within 6 weeks. Biomechanically, PIP joint arthrodeses using the Herbert screw in cadaver joints were comparable to tension band arthrodeses evaluated by three-point bending. Herbert screw arthrodesis of the PIP joint achieves a high fusion rate with minimal external protection provided certain technical details are followed.

Chronic verapamil administration has been shown to reduce the renal dysfunction, glomerular sclerosis, and mortality in partially nephrectomized rats; the mechanism is unknown. Therefore, the present micropuncture study examines the effect of verapamil on glomerular hemodynamics of Munich-Wistar rats 4 wk after five-sixths nephrectomy. Whole-kidney function was similar in nephrectomized rats treated with verapamil (Nx-VER) and saline (Nx-SAL), and glomerular filtration rate (GFR) was one-third of control. Both Nx-VER and Nx-SAL rats exhibited a similar degree of glomerular hyperperfusion and hyperfiltration. However, mean glomerular capillary hydrostatic pressure difference (delta P) was lower in Nx-VER than Nx-SAL rats (42.4 +/- 1.2 vs. 47.2 +/- 1.0 mmHg, P less than 0.005) because of an increase in Bowman's space hydrostatic pressure (PBS) in Nx-VER rats (15.5 +/- 0.8 vs. Nx-SAL 11.9 +/- 0.7 mmHg, P less than 0.005). Glomerular ultrafiltration coefficient (LpA) was significantly lower in Nx-SAL (P less than 0.005) than in Nx-VER or control rats. Urinary protein excretion and the magnitude of glomerular sclerosis in Nx-SAL and Nx-VER rats were not different. In conclusion, chronic VER administration normalizes LpA and reduces delta P, by increasing PBS, in Nx rats, alterations that neutralize each other, leading to the constancy of single-nephron GFR.

Factor VII was assayed in healthy adults and pregnant women by a coagulation method (VIIc) and a procedure (VIIt) based upon activation of factor X. Although VIIc and VIIt were highly correlated (r 0.8) they apparently measured different aspects of VII activity. This difference was related to plasma lipid concentrations. Plasma VIIc showed independent positive associations in vivo with VIIt, cholesterol and triglyceride concentrations, but was unaffected by in vitro adjustment of plasma lipoprotein concentrations. The difference between assays might be due to differing reactivities of VII. The VIIc assay measures VII in its in vivo proportions as the single-chain protein and fully active double-chain form (alpha VIIa). In VIIt, all VII is converted to alpha VIIa before measurement. Thus an increase in VIIc but not VIIt with increasing lipid concentrations reflects an increased proportion of VII as alpha VIIa, possibly secondary to activation of the contact system. This effect may explain at least part of the increased VIIc and normal VIIt in pregnancy, and the increased VIIc of hyperlipidaemias in general. The relative values of VIIc and VIIt are proposed as a measure of flux within the coagulation system, and as a measure of coagulability in hyperlipidaemia and other states.

The phosphorylation of a normal cellular protein of molecular weight 34,000 (34K) is enhanced in Rous sarcoma virus-transformed chicken embryo fibroblasts apparently as a direct consequence of the phosphotransferase activity of the Rous sarcoma virus-transforming protein pp60src. We have prepared anti-34K serum by using 34K purified from normal fibroblasts to confirm that the transformation-specific phosphorylation described previously occurs on a normal cellular protein and to further characterize the nature of the protein. In this communication, we also show that the phosphorylation of 34K is also increased in cells transformed by either Fujinami or PRCII sarcoma virus, two recently characterized avian sarcoma viruses whose transforming proteins, although distinct from pp60src, are also associated with phosphotransferase activity. Moreover, comparative fingerprinting of tryptic phosphopeptides shows that the major site of phosphorylation of 34K is the same in all three cases.

Although it is generally acknowledged that matrix vesicles and alkaline phosphatase are required for cartilage calcification, their precise role in initiation or propagation of mineralization remains controversial. We have investigated this problem in a neoplastic model of chondrogenesis, the Swarm rat chondrosarcoma. During serial transplantation these malignant chondrocytes fail to undergo terminal differentiation and do not calcify. To facilitate the study of maturational events in this neoplasm we have developed an intraperitoneal model which grows as discrete free floating tumor nodules. The youngest cells are those on the exterior and maturation progresses towards the center. Ultrastructural examination of the tumor reveals the presence of numerous matrix vesicles in the interterritorial matrix of immature and mature cells. Histochemical localization of alkaline phosphatase reveals a distribution of enzyme activity which varies with the state of maturation of the cells. The most immature cells express large amounts of enzyme on their plasmalemma and in inter-territorial matrix vesicles. The older cells lose membrane activity but maintain activity in their matrix vesicles. These results suggest that while matrix vesicles and/or alkaline phosphatase may be necessary for calcification to proceed, their mere presence is by itself insufficient to initiate or maintain the process.

The epidemiological characteristics of platelet aggregability were established in 958 participants in the Northwick Park Heart Study. The main analyses were based on the dose of adenosine diphosphate at which primary aggregation occurred at half its maximum velocity. Aggregability increased with age in both sexes, was greater in whites than blacks (particularly among men), and tended to decrease with the level of habitual alcohol consumption. Aggregability was, however, greater in women than men and in nonsmokers than smokers. There was no relation between aggregability on the one hand and obesity, current or past oral contraceptive use, menopausal state, or blood cholesterol and triglyceride concentrations on the other. Aggregability was somewhat, though not significantly, higher in men with a history of ischaemic heart disease and in those with electrocardiographic evidence of ischaemia than in those without. There was a strong association between the plasma fibrinogen concentration and aggregability. The widely held concept of platelet aggregability and its implications is probably an oversimplification. In the prevention of thrombosis it may be as useful to consider modifying external influences on platelet behaviour, such as plasma fibrinogen concentration or thrombin production, as it is to rely solely on platelet active agents.

Uteroglobin, a secretory protein of rabbit uterine epithelium, was localized by the direct immunoperoxidase method in control and hCG-induced pseudopregnant rabbits. In control rabbits, uteroglobin was confined to the apical cytoplasm of nearly all cells of the endometrial epithelium. The induction of pseudopregnancy resulted in a pronounced continuing increase, through 4 days post-hCG administration, in the absolute number of epithelial cells engaged in uteroglobin synthesis. Furthermore, the endoplasmic reticulum was more intensely stained for uteroglobin than in the epithelial cells of control rabbit endometrium. Thus, the increased production of uteroglobin, in response to hormonal stimulation, appears to be achieved both through an increase in the amount of uteroglobin synthesized by a given cell as well as by an increase in the number of cells involved in uteroglobin synthesis. Concurrent with the increase in the number of cells synthesizing uteroglobin, an increase in the number of unstained cells first appeared at the second day of pseudopregnancy, during the period of maximal epithelial proliferation. However, within those cells containing uteroglobin on the second day following injection with hCG, most staining was limited to the perinuclear membrane. At various times following hCG administration, a number of scattered cells, intensely stained for uteroglobin, were observed in the uterine epithelium. Based upon ultrastructural studies, failure to exclude trypan blue, and the presence of intra-mitochondrial uteroglobin, they were identified as either dead or dying cells.

A consultant team's evaluation of a system for distributing and controlling medications in a large teaching hospital is described. Through interviews with key personnel from administration, pharmacy, nursing, and the medical staff, an interdisciplinary research group identified problems in the reliability and response times of the hospital's existing medication system. After assessing staff expectations regarding acceptable standards for medication errors and response times and their attitudes toward proposed changes in the medication system, medication-error rates were determined using a pharmacist-observer method. Observations during 34 five-hour periods on four nursing units were conducted over a 17-day period. Medication-error rates were calculated as the frequency of medication errors during the observation period divided by the total opportunities for error (OE), which were defined as doses ordered plus unauthorized doses given. Response times for processing "now," "stat," and routine orders were also determined using work-sampling methods. The total medication-error rate for the nursing units studied was 9% excluding wrong-time errors; more than a third of doses were given more than 30 minutes before or after their scheduled administration times. Response times for "now" and "stat" orders averaged about 23 minutes, in conformance with the desired standard of 30 minutes. However, processing of routine orders required an average of two hours and seven minutes, much of which was attributed to delays in the messenger service. The basic design of the existing unit dose medication system contributed to problems in the reliability and efficiency of the system.

The recognized similarities between developing embryonic tissues and neoplastic cells have led to a number of experimental demonstrations which indicate that inductive microenvironments can alter the malignant phenotype. In postnatal life a morphogenetic cascade resembling endochondral bone development can be induced by s.c. implantation of demineralized diaphyseal bone matrix. We have examined the ability of this microenvironment to alter the phenotype of the transplantable Swarm rat chondrosarcoma in mixed implants. Neoplastic chondrocytes could be distinguished from host cells by nuclear morphometry since the nuclear area of the neoplastic chondrocytes was 2 to 3 times larger than that of comparable host-derived chondrocytes. Through the first 7 days post-implantation tumor cells in the presence of morphogenetically active matrix are morphologically indistinguishable from those implanted with morphogenetically inactivated matrix or implanted by themselves. With the advent of host cell chondrogenesis, however, adjacent neoplastic cells begin to undergo chondrolysis and calcification. Only those cells in the immediate proximity of host morphogenetic foci appear affected. An average of 26.7 +/- 7.0% (SD) of the implant surface areas examined revealed such changes. Chondrosarcoma cells implanted by themselves or in the presence of morphogenetically inactivated bone matrix underwent no such changes. These results suggest that factors released from host cells induced to undergo bone morphogenesis are capable of altering the differentiated phenotype of neoplastic cells.

A community survey of factor VII coagulant activity (VIIc) and the lipoprotein profile in non-fasting plasma of middle-aged men in NW London was undertaken to search for the determinants of VIIc in the general community. The data demonstrates that associations between VIIc and the plasma concentrations of cholesterol and of triglycerides previously shown in the general population can be explained by the strong and positive associations between VIIc and the large lipoprotein particles, chylomicrons, VLDL and IDL. Consistent with the possibility that the concentration of large lipoproteins determines the in vivo reactivity of factor VII, the association between VIIc and the ratio of lipid in the d greater than 1.019 fraction to the total plasma lipid was also highly significant but negative. The observed correlations between VIIc and lipoproteins smaller than VLDL may be the product of the interrelations that exist between the lipoprotein fractions in plasma. However, the associations between VIIc and the chylomicron lipid concentrations are especially strong when allowance is made for the considerable bias towards zero in the observed correlation, due to large within-person variance in chylomicron concentration.

A bioassay, based on tumorigenicity, has been developed to determine the mechanism whereby the blastocyst of the mouse controls malignant expression of embryonal carcinoma. The assay is based upon the incidence of tumors obtained when known numbers of cells of the 402AX strain of embryonal carcinoma are injected into strain 129 mice, compared to the incidence obtained when the same number of embryonal carcinoma cells are incorporated into Swiss-Webster blastocysts that are then injected in strain 129 animals. The results indicate that the blastocyst can regulate one embryonal carcinoma cell consistently; it may have a slight effect on three, but it cannot regulate four or five of them. The position of the embryonal carcinoma cell in the blastocyst is important. Regulation occurs if the embryonal carcinoma cell is placed in the blastocoele cavity, but enhancement of tumorigenicity is obtained if it is placed between the zona pellucida and the trophectoderm. By contrast, the blastocyst is unable to regulate a single B-16 melanoma cell placed in the blastocoele cavity, indicating a degree of specificity for the regulatory process.

Fasting serum high-density lipoprotein (HDL) cholesterol, other lipid concentrations and related characteristics have been measured in 87% of 261 residents aged over 5 years on the small isolated island of Salt Cay, Turks and Caicos Isles. Only one subject, a hypertensive woman, had a major electrocardiographic Q wave abnormality, and none of the islanders had clinical coronary heart disease. These findings, together with local clinical experience indicated a low incidence of coronary heart disease in this community. Adult mean concentrations of HDL cholesterol (1.6 mmol/l) and serum total triglyceride (0.81 mmol/l) were relatively high and low respectively compared with those of men and women in North American communities. Unlike findings in North America, there was no significant sex difference in HDL cholesterol concentration apparent in adulthood and this was not explained by sex differences in alcohol consumption (positively correlated with HDL cholesterol in both sexes) or adiposity (negatively correlated with HDL cholesterol in men only). Residents who were recovering from an epidemic of mild upper respiratory infection had on average a 9% reduction in HDL cholesterol concentration compared with the remainder of the community. The lipoprotein lipid pattern in these people is consistent with a low cardiovascular risk status, and might account for the apparent absence of coronary heart disease on the island.

Vitamin A and C content of red marrow from vertebrae of Good and Choice grade steers was determined so that the nutritional contribution of marrow to mechanically separated meat (MSM) could be more fully defined. Vitamin A and C values for marrow were higher than those reported for muscle but the slightly higher levels in MSM than in hand boned meat are nutritionally insignificant., (Copyright © 1986. Published by Elsevier Ltd.)

To assess the extent to which current dietary habits conform with the national nutritional guidelines aimed at reducing the high national mortality from coronary heart disease (CHD), 203 of 275 men (74 per cent) aged 40-59 years in a London community provided a weighed record of all food and drink consumed over 5 d. Satisfactory records were returned by 170 men weighing at least 75 per cent of their intakes, including 43 on medical or self-imposed diets. Mean (s.d.) energy intake was 2476 (590) kcal (10.38 MJ), comprising 37 per cent fat, 42 per cent carbohydrate, 14.7 per cent protein and 6.3 per cent alcohol. Butter or butter spreads were used by 53 per cent, sunflower margarine by 29 per cent and low fat spreads by 13 per cent; lard or dripping was used by 23 per cent of households as the main cooking fat. Intakes of vitamins and trace elements were generally above recommended amounts. These results are closely comparable with the only similar studies for the UK undertaken in Wales and Scotland. Compared with national guidelines, only 32 per cent of men met the short-term goals for fat intake, and even fewer the long-term goals. Carbohydrate and fibre intake remained too low. Alcohol intake exceeded the short-term goal (5 per cent of energy of less) in 36 per cent of men. Greater public health effort will be needed to reduce fat intake further for primary prevention of CHD, particularly as habitual intake is probably underestimated by the weighed dietary record.

Various stapling devices have been applied to create the small gastric pouch necessary for effective weight loss in morbid obesity, but it is unclear as to which staple line arrangement provides the most reliable gastric wound healing. Five variants of staple lines (Groups I-V) were used to create a gastric partition in 47 adult mongrel dogs (20-30 kg). Staple-line arrangements were as follows: Group I (n = 10)--two superimposed double rows (TA-90), Group II (n = 10)--prototype staple line of four rows 2.03 mm apart, Group III (n = 12)--two double rows of staples 6.5 mm apart, Group IV (n = 10)--prototype staple line of two double rows of staples 0.64 mm apart, and Group V (n = 5)--a single double-row staple line (TA-90). Staple lines were examined at 2, 4, 8, and 13-16 weeks for evidence of healing, histology, tensile strength, and collagen (hydroxyproline) content. Significant differences in staple-line disruption rates were found between all groups (chi 2, P less than 0.01). The prototype four-row staple line (Group II) had the most significant parameters of wound repair determined by biochemical evidence of wound healing and enhanced tensile strength. Staple-line arrangement appears to be an important determinant of gastric wound healing and may influence the rate of postoperative gastric partition disruption.

We have investigated the structure of the photosynthetic membrane in a mutant of barley known to lack a chlorophyll-binding protein. This protein is thought to channel excitation energy to photosystem II, and is known as the "light-harvesting chlorophyll-protein complex." Extensive stacking of thylakoids into grana occurs in both mutant and wild-type chloroplasts. Examination of membrane internal structure by freeze-fracturing indicates that only slight differences exist between the fracture faces of mutant and wild-type membranes. These differences are slight reductions in the size of particles visible on the EFs fracture face, and in the number of particles seen on the PFs fracture face. No differences can be detected between mutant and wild-type on the etched out surface of the membrane. In contrast, tetrameric particles visible on the etched inner surface of wild-type thylakoids are extremely difficult to recognize on similar surfaces of the mutant. These particles can be recognized on inner surfaces of the mutant membranes when they are organized into regular lattices, but these lattices show a much closer particle-to-particle spacing than similar lattices in wild-type membranes. Although several interpretations of these data are possible, these observations are consistent with the proposal that the light-harvesting chlorophyll-protein complex of photosystem II is bound to the tetramer (which is visible on the EFs face as a single particle) near the inner surface of the membrane. The large tetramer, which other studies have shown to span the thylakoid membrane, may represent an assembly of protein, lipid, and pigment comprising all the elements of the photosystem II reaction. A scheme is presented which illustrates one possibility for the light reaction across the photosynthetic membrane.

Scalp and skull necrosis often follow high voltage electrical injury to the head. Classically reconstruction of the scalp and skull is performed after sequestration of the necrotic bone. The relatively frequent complication of epidural infection, however, detracts from this approach. As an alternative we have attempted to induce regeneration of devitalized bone by covering it with a vascular tissue flap. A typical patient is described in this report with results which indicate that at least partial regeneration of the necrotic tissue can occur, thus one-stage management of such wounds is possible.

The Northwick Park Heart Study (NPHS) has investigated the thrombotic component of ischaemic heart disease (IHD) by the inclusion of measures of haemostatic function. Among 1511 white men aged between 40 and 64 at the time of recruitment, 109 subsequently experienced first major events of IHD. High levels of factor VII coagulant activity and of plasma fibrinogen were associated with increased risk, especially for events occurring within 5 years of recruitment. These associations seemed to be stronger than for cholesterol, elevations of one standard deviation in factor VII activity, fibrinogen, and cholesterol being associated with increases in the risk of an episode of IHD within 5 years of 62%, 84%, and 43% respectively. Multiple regression analyses indicated independent associations between each of the clotting factor measures and IHD but not between the blood cholesterol level and IHD incidence. The risk of IHD in those with high fibrinogen levels was greater in younger than in older men. Much of the association between smoking and IHD may be mediated through the plasma fibrinogen level. The biochemical disturbance leading to IHD may lie at least as much in the coagulation system as in the metabolism of cholesterol.