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Tibial dyschondroplasia is a skeletal abnormality characterized by an avascular plug of cartilage in the metaphysis of the long bones of rapidly growing birds. An avascular, thickened growth plate also occurs in vitamin D/calcium-deficient rickets. This research was conducted to evaluate tibial dyschondroplasia and rachitic tissue for factors shown to be important in normal growth plate vascularization. Immunohistochemical analysis demonstrated the presence of vascular endothelial growth factor, its receptor Flk-1, and matrix metalloproteinases MMP-9 and MMP-13 to be present in all tissues examined. In most cases, immunostaining was intracellular, except near blood vessels where the matrix was also stained. The results suggest that, for the four proteins examined, disruption of their expression is not a key factor in the development of these avascular cartilage lesions in avians. The relationship of these observations to the pathology of tibial dyschondroplasia is discussed.

There is evidence that changes in arterial P(CO(2)) (P(a,CO(2))), as well as P(O(2)), influence neuroendocrine function. The hyponatraemia and fluid retention (cor pumonale) seen in chronic obstructive pulmonary disease (COPD) and type II respiratory failure is associated with increased vasopressin release. This study examines the specific effects of altered P(a,CO(2)) on hormone release from the posterior and anterior pituitary. The study was performed in 20 ventilated ICU patients in the late recovery phase of their illness. None had primary respiratory disease. Control blood samples were taken and the alveolar ventilation was then adjusted to allow the P(a,CO(2)) increase or decrease for a period of 3 h, during which time further blood samples were taken for the determination, by radioimmmunoassy of vasopressin, oxytocin, growth hormone and cortisol. Urine output and electrolyte concentrations were also measured. Circulating concentrations of growth hormone and oxytocin increased with increasing P(a,CO(2)). Vasopressin release showed a similar pattern up to a P(a,CO(2)) of approximately 6.0 kPa, above which vasopressin concentrations were inversely related to P(a,CO(2)). There was no significant effect on cortisol concentrations. No significant effects were established in urinary parameters during the short period of this study. Thus an increase in CO(2) is associated with stimulated pituitary hormone release. The effect on the neurohypophysial hormones may account for the fluid retention and hyponatraemia seen in COPD and hence provide a rationale for treatment.

To determine the effects of hypoxia on energy state and intracellular pH (pHi) in resting pulmonary and systemic arterial smooth muscles, we used31P nuclear magnetic resonance spectroscopy and colorimetric and enzymatic assays to measure pHi; intracellular concentrations of ATP, phosphocreatine, creatine, and Pi; and phosphorylation potential in superfused tissue segments from porcine proximal intrapulmonary and superficial femoral arteries. Under baseline conditions ([Formula: see text] 467 ± 12.1 mmHg), energy state and total creatine (phosphocreatine + creatine) concentration were lower and pHiwas higher in pulmonary arteries. During hypoxia ([Formula: see text] 23 ± 2.4 mmHg), energy state deteriorated more in femoral arteries than in pulmonary arteries. pHifell in both tissues but was always more alkaline in pulmonary arteries. Reoxygenation reversed the changes induced by hypoxia. These results suggest that production and/or elimination of ATP and H+was different in resting pulmonary and systemic arterial smooth muscles under baseline and hypoxic conditions. Because energy state and pHiaffect a wide variety of cellular processes, including signal transduction, contractile protein interaction, and activities of ion pumps and channels, further investigation is indicated to determine whether these differences have functional significance.

Tissues vary considerably in their sensitivity to hypoxia. Neurological cells tolerate hypoxia for only a few minutes whereas bladder smooth muscle may survive for several days without oxygen. This has important implications in the management of oxygen transport and monitoring of tissue hypoxia in critically ill patients. Regional oxygen transport and cellular use are often neglected but are important in maintaining tissue function and overall survival ### Delivery to organs and tissues The mechanisms controlling oxygen distribution are incompletely understood but involve a series of convective and diffusive processes. Convective oxygen transport refers to the bulk movement of oxygen in air or blood and depends on active, energy consuming processes generating flow in the tracheobronchial tree and circulation. Diffusive transport refers to the passive movement of oxygen down its concentration gradient across tissue barriers, including the alveolar-capillary membrane, and across the extracellular matrix between the tissue capillaries and individual cells to mitochondria. The amount of diffusive oxygen movement depends on the oxygen tension gradient and the diffusion distance. Effect of oxygen tension gradient and diffusion distance on availability of oxygen to cells In many critically ill patients tissue hypoxia is due to disordered regional distribution of blood flow both between and within organs. Regional and microcirculatory distribution of cardiac output is determined by a complex interaction of endothelial, receptor, neural, metabolic, and pharmacological factors working on small resistance arterioles and precapillary sphincters. In critical illness, particularly sepsis, hypotension and loss of normal autoregulation cause shunting and tissue hypoxia in some organs despite high global oxygen delivery and mixed venous saturation. The perfusion pressure is an important determinant of regional perfusion, but adrenaline or noradrenaline given to maintain systemic blood pressure may reduce regional distribution, particularly to the renal and splanchnic capillary beds. Severe tissue hypoxia due to capillary microthrombosis in critically ill patient with meningococcal septicaemia …

Mammalian life and the bioenergetic processes that maintain cellular integrity depend on a continuous supply of oxygen to sustain aerobic metabolism. Reduced oxygen delivery and failure of cellular use of oxygen occur in various circumstances and if not recognised result in organ dysfunction and death. Prevention, early identification, and correction of tissue hypoxia are essential skills. An understanding of the key steps in oxygen transport within the body is essential to avoid tissue hypoxia. Red blood cells entering a capillary Although oxygen is the substrate that cells use in the greatest quantity and on which aerobic metabolism and cell integrity depend, the tissues have no storage system for oxygen. They rely on a continuous supply at a rate that precisely matches changing metabolic requirements. If this supply fails, even for a few minutes, tissue hypoxaemia may develop resulting in anaerobic metabolism and production of lactate. ### Key steps in oxygen cascade Oxygen transport from atmosphere to mitochondria. Values given in parenthesis are for a healthy 70 kg adult breathing air (FiO2 0.21) at standard barometric pressure View this table: Partial pressures of oxygen at sea level (101 kPa) Oxygen transport from environmental air to the mitochondria of individual cells occurs as a series of steps. The heart, lungs, and circulation extract oxygen from the atmosphere and generate a flow of oxygenated blood to the tissues to maintain aerobic metabolism. The system must be energy efficient (avoiding unnecessary cardiorespiratory work), match oxygen distribution with metabolic demand, and allow efficient oxygen transport across the extravascular tissue matrix. At the tissue level, cells must extract oxygen from the extracellular environment and use it efficiently in cellular metabolic processes. Arterial oxygen tension (PaO2 …

Oxygen is widely available and commonly prescribed by medical and paramedical staff. When administered correctly it may be life saving, but oxygen is often given without careful evaluation of its potential benefits and side effects. Like any drug there are clear indications for treatment with oxygen and appropriate methods of delivery. Inappropriate dose and failure to monitor treatment can have serious consequences. Vigilant monitoring to detect and correct adverse effects swiftly is essential. Oxygen is often poorly prescibed. This drug chart was for a severely hypoxaemic patient with pneumonia and mild chronic obstructive pulmonary disease. The risk of carbon dioxide retention was secondary to the danger of severe hypoxaemia and inadequate oxygen was life threatening In a recent hospital survey 21% of oxygen prescriptions were inappropriate and 85% of patients were inadequately supervised. Similar studies report that oxygen is prescribed inappropriately in general practice. To ensure safe and effective treatment prescriptions should cover the flow rate, delivery system, duration, and monitoring of treatment. Tissues require oxygen for survival. Delivery depends on adequate ventilation, gas exchange, and circulatory distribution. Tissue hypoxia occurs within 4 minutes of failure of any of these systems because the oxygen reserves in tissue and lung are relatively small. The physiological and pathological mechanisms that result in tissue hypoxia will be discussed in later articles. They can be classified into two main groups: those causing arterial hypoxaemia and those causing failure of the oxygen-haemoglobin transport system without arterial hypoxaemia. More than one mechanism may contribute to tissue hypoxia, and predicting the response to supplemental oxygen requires careful evaluation of these functions. #### Checklist for safe prescribing of oxygen

The acute respiratory distress syndrome continues to be a major medical problem. Despite recent advances in treatment, such as the use of nitrogen monoxide (NO), extracorporeal membrane oxygenation (ECMO) and specialized ventilatory techniques in maintaining adequate oxygenation, mortality still remains high. The presence of activated neutrophils coupled with high inspired oxygen concentrations provide conditions that favour increased oxidative stress and this has focused attention on the possible role of free radical species in both the initiation and propagation of ARDS. Although there is evidence implicating increased free radical activity in ARDS, much of this is from animal models and the role of intervention in such processes has not been established. Although antioxidant therapy has been suggested as a possible treatment for ARDS the current literature is less than convincing. We examine the available data from human studies and suggest possible further studies and future therapeutic goals.

A series of experiments was conducted to test the hypothesis that vitamin D utilization may not be as efficient in chicks with tibial dyschondroplasia (TD). The basal diet contained 1.0% Ca and 0.45% available P with no supplemental cholecalciferol (D3). Chicks from low TD (LTD) and high TD (HTD) selected lines were fed diets supplemented with various levels of vitamin D compounds and examined for rickets and TD. When chicks were fed a D3-deficient diet containing only 1.25 micrograms/kg added D3, HTD chicks had a greater incidence of severe rickets than LTD chicks (P < 0.05). The LTD chicks did not exhibit TD when fed a diet containing adequate (20 micrograms/kg) D3. The LTD chicks fed a diet supplemented with 5 micrograms/kg D3, however, had 22% incidence of TD. When HTD chicks were fed diets supplemented with 5 micrograms/kg D3 [control diet that meets NRC (1994) requirement for D3], 20 micrograms/kg D3, 5 micrograms/kg 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] or the combination of both D3 (20 micrograms/kg) and 1,25-(OH)2D3 (5 micrograms/ kg), TD incidence was highest in HTD chicks fed the control diet. When HTD chicks were fed diets with an increased dietary level of 1,25-(OH)2D3 (10 micrograms/kg) further reduction of TD incidence (P < 0.05) occurred. A potentially toxic level (Soares et al., 1983) of 1,25-(OH)2D3 (15 micrograms/kg) fed to HTD chicks resulted in still greater suppression of incidence of TD even though growth and feed intake in HTD chicks was greater than those of LTD chicks. It is concluded that the development of TD in HTD chicks is associated with subnormal ability to metabolize vitamin D.

BACKGROUND: The mechanism causing peripheral oedema in hypoxaemic chronic obstructive pulmonary disease has not been established. Vasopressin, a powerful antidiuretic hormone involved in salt and water homeostasis, is released in response to acute hypoxia. However, the effect of prolonged hypoxaemia on hypothalamic and pituitary release of the magnocellular hypothalamic hormones, vasopressin and oxytocin, has not previously been studied. METHODS: Male Wistar rats were randomly allocated to either normobaric, hypoxic (10% O2) or control (21% O2) environmental chambers. An initial series of experiments examined plasma vasopressin concentration, osmolality, sodium concentration, packed cell volume (PCV), and weight gain at weekly intervals (n = 4-6) for six weeks. The maximum increase in plasma vasopressin concentration and PCV occurred after five weeks. In a second experiment vasopressin and oxytocin concentrations in the hypothalamus, pituitary gland, and plasma were measured in eight control and eight hypoxic rats after five weeks in the environmental chambers. RESULTS: In rats exposed to environmental hypoxia PCV increased (p < 0.001) and weight gain decreased (p < 0.05) compared with controls. The plasma vasopressin concentration increased progressively from a baseline of 1.36 (0.2) pmol/l (n = 6) to a maximum of 4.38 (0.8) pmol/l (n = 6; p < 0.01) during the first five weeks of environmental hypoxia (difference 3.02 (95% CI 1.18 to 4.86)). Plasma osmolality and sodium concentration were unchanged in hypoxic rats compared with controls during the six week period. The hypothalamic vasopressin concentration was increased (p < 0.001) after five weeks of environmental hypoxia (91.6 (4.8) pmol/ hypothalamus) compared with controls (57.4 (5.1) pmol/hypothalamus), the difference being 34.2 pmol/hypothalamus (95% CI 21.6 to 46.5). The pituitary vasopressin concentration was unchanged. In hypoxic rats hypothalamic oxytocin (59.6 (3.2) pmol/hypothalamus) was greater (p < 0.01) than in controls (42 (3.8) pmol/hypothalamus), a difference of 17.6 pmol/ hypothalamus (95% CI 8.7 to 26.5). Similarly, the plasma oxytocin concentration was increased (p < 0.05) in hypoxic rats (6.78 (1.2) pmol/l) compared with controls (3.3 (0.8) pmol/l), a difference of 3.48 pmol/l (95% CI 0.89 to 6.07). The pituitary oxytocin concentration was unchanged in the two groups. CONCLUSIONS: These results demonstrate an increase in hypothalamic production of vasopressin and oxytocin in rats during prolonged hypoxaemia. Increased plasma concentrations of neurohypophysial hormones would be expected to impair sodium and water homeostasis in patients with hypoxaemia. However, the absence of change in the plasma osmolality and sodium concentrations in this study and previous clinical investigations suggests that compensatory mechanisms modulate the actions of both vasopressin and oxytocin. A reduction in renal blood flow or decreased renal responsiveness to the neurohypophyseal hormones may be involved.

Although frequently unrecognized, hypoxic pulmonary vascular disease is an important cofactor in the morbidity and mortality of a wide spectrum of disease processes. The hypoxic response incorporates two distinct phases, the acute hypoxic vasoconstrictor response and vascular remodelling associated with prolonged alveolar hypoxia. Understanding of the mechanisms causing both processes has increased rapidly and may result in the near future in specific treatment aimed at correcting underlying physiological abnormalities. However, currently available therapies remain limited to correction of the hypoxaemia and generalized non-specific pulmonary vasodilatation. The recent development of inhaled NO therapy represents a significant advance in the management of the acute hypoxic pulmonary vasoconstriction occurring during critical illness.

Osteopontin (OPN) gene expression and alkaline phosphatase activity were evaluated in the epiphyseal growth plates of normal chickens and in diet-induced tibial dyschdroplasia (TD)-afflicted chickens. In the normal growth plate, OPN gene was expressed by a) cells of the subperichondrial zone surrounding the articular cartilage, b) a narrow layer of hypertrophic chondrocytes at the hypertrophic zone, and c) lower hypertrophic chondrocytes at the zone of matrix calcification and endochondral bone formation. The latter two layers were separated by OPN-negative chondrocytes. Osteopontin gene was not expressed throughout the zone of articular cartilage in the nonhypertrophic or upper hypertrophic portions of the growth plate cartilage. Only at sites of calcification of the lower hypertrophic zone was the expression of the OPN gene associated with alkaline phosphatase activity. In all TD lesions, regardless of the induction procedure, the layer of chondrocytes of the lower hypertrophic zone expressing the OPN gene and the layer of OPN-negative cells separating the two areas of OPN-expressing cells were grossly enlarged. This resulted in a wide discontinuity between the chondrocytes of the lower hypertrophic zone expressing the OPN gene and the cells expressing the OPN gene that are associated with mineralization. In TD, no alkaline phosphatase activity was detected within the growth plate cartilage, but normal OPN gene expression was observed at the subperichondrium zone and at the zone of endochondral bone formation. The results of this study suggest that in the epiphyseal growth plate, OPN expression is not restricted to sites of bone calcification.

Implementing new acute oxygen guidelines will require education, resources, and a change in culture

The effects of long-term consumption of 1 and 5 ppm of Cd on Cd, Cu, Fe, and Zn concentrations in milk and a variety of tissues of first-lactation dairy cows was investigated. Thirty-six Holstein heifers were allocated to three groups and fed similar diets differing only in the concentration of Cd (.25, 1, and 5 ppm) for a 394-d period before calving. One- and 5-ppm Cd concentrations were achieved using CdCl2. Liver, kidney cortex, and muscle were biopsied from one-half of the heifers of each group before Cd supplementation and again from the same heifers within 5 d after parturition. Colostrum and milk were sampled throughout the 150 d of lactation. Urine was sampled after an average of 450 d of Cd exposure. At slaughter (after an average of 554 d), 11 tissues were sampled from 12 cows representing all treatment groups. During the first 394 d, Cd accumulated in kidney and liver with increasing dietary concentrations of Cd but did not further increase by 554 d. However, by 554 d Cd had also accumulated in the adrenal glands, ovaries, spleen, and uteri of cows consuming 5 ppm of Cd. Dietary Cd did not influence the concentration of Cd, Cu, Fe, or Zn in colostrum or milk. However, urine pH, Zn, and K were lower in cows consuming 5 ppm of Cd. Liver Cu was reduced by 1 and 5 ppm of Cd at both 394 and 554 d.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-six postpubertal Holstein heifers were allocated to three groups and fed the same diet, which differed only in the concentration of Cd: control group (.25 ppm of Cd), low-Cd group (1 ppm of Cd), and high-Cd group (5 ppm of Cd). Cadmium was supplemented to the low-Cd and high-Cd groups using CdCl2. Liver, kidney cortex, and abdominal muscle were biopsied for mineral analysis from one-half of the heifers of each group before Cd supplementation and again from the same animals within 5 d after parturition, 394 d later. Blood, liver, and muscle were collected from each calf within 5 h after birth. In the dam, 5 ppm of dietary Cd caused a 62-, 27-, and 4-fold increase in Cd of the kidney, liver, and muscle, respectively; kidney Zn and Fe increased (76%) and decreased (33%), respectively, whereas the serum Cu was reduced (31%). Liver Cu was reduced to 40 and 17% by dietary Cd of 1 and 5 ppm, respectively, in the dams. Calves from dams consuming 5 ppm of Cd had a 29 and 43% reduction in liver Cu and Zn, respectively. In these same calves, packed cell volume, hemoglobin concentration, and serum Cu were decreased by 17, 18, and 25%, respectively, whereas serum Zn was increased (55%). Serum sodium and potassium were reduced by 4 and 13%, respectively, and blood urea nitrogen was increased by 63% in calves from dams consuming 5 ppm of Cd. Feeding primigravid dairy cattle up to 5 ppm of Cd as CdCl2 throughout gestation did not influence the concentration of Cd in the neonate but caused reductions in liver Cu and Zn; teratogenesis was not apparent.

odel-based compartmental analysis was used to describe data on the whole body kinetics of copper metabolism in rats. Data were collected on recovery of radio-copper in plasma, liver, skin, skeletal muscle, bile, and feces for 3 days after the injection of 10 micrograms iv of copper labeled with 64Cu. Data on copper masses and on 64Cu kinetics were analyzed by the stimulation, analysis, and modeling computer programs. Observed data were fit to a 16-component “working hypothesis” model; fractional transfer coefficients were estimated, and steady-state compartment masses and copper transfer rates were calculated. The model postulates a rapid turnover of plasma nonceruloplasmin (NCp) copper (8.5 h-1), which exchanged a large amount of copper with extrahepatic tissues (16 micrograms/h) as well as liver (13 micrograms/h). In comparison, ceruloplasmin (Cp) transferred relatively little copper to tissues (less than 1 microgram/h). NCp copper is postulated to be the precursor for biliary copper. Regarding the intracellular metabolism of copper in hepatic and extrahepatic tissues, the data were compatible with a faster turning-over compartment that exchanged copper with NCp and a slower turning-over compartment with input from Cp. In the liver, the slower turning-over compartment was the copper present in peak II (mol mass 30,000–40,000 Da); this received much of its input from the faster turning-over compartment (peak III), which was hypothesized to represent, in large part, copper in metallothionein.

We report two cases of severe cardiac tamponade following cardiac surgery. In each case a haemorrhagic collection resulted in a localised tamponade. The clinical presentation in both cases was atypical and, although the possibility of tamponade was considered, the absence of classical signs delayed diagnosis until echocardiography was performed. These cases illustrate the varied presentation of tamponade after cardiac surgery which may be localised, highlighting the need for a high level of clinical suspicion and early use of echocardiography to make a prompt diagnosis. The transoesophageal echocardiogram may have particular relevance in the detection of localised collections causing a tamponade effect. The cases indicate that post-operative cardiac tamponade occurs over a wide time-scale following surgery and that anticoagulation may be a contributing factor.

There is evidence that changes in arterial P(CO(2)) (P(a,CO(2))), as well as P(O(2)), influence neuroendocrine function. The hyponatraemia and fluid retention (cor pumonale) seen in chronic obstructive pulmonary disease (COPD) and type II respiratory failure is associated with increased vasopressin release. This study examines the specific effects of altered P(a,CO(2)) on hormone release from the posterior and anterior pituitary. The study was performed in 20 ventilated ICU patients in the late recovery phase of their illness. None had primary respiratory disease. Control blood samples were taken and the alveolar ventilation was then adjusted to allow the P(a,CO(2)) increase or decrease for a period of 3 h, during which time further blood samples were taken for the determination, by radioimmmunoassy of vasopressin, oxytocin, growth hormone and cortisol. Urine output and electrolyte concentrations were also measured. Circulating concentrations of growth hormone and oxytocin increased with increasing P(a,CO(2)). Vasopressin release showed a similar pattern up to a P(a,CO(2)) of approximately 6.0 kPa, above which vasopressin concentrations were inversely related to P(a,CO(2)). There was no significant effect on cortisol concentrations. No significant effects were established in urinary parameters during the short period of this study. Thus an increase in CO(2) is associated with stimulated pituitary hormone release. The effect on the neurohypophysial hormones may account for the fluid retention and hyponatraemia seen in COPD and hence provide a rationale for treatment.

Parathyroid hormone-related peptide (PTHrP) has been shown to be essential for normal endochondral bone formation. Along with Indian hedgehog (Ihh), it forms a paracrine regulatory loop that governs the pace of chondrocyte differentiation. However, the source of PTHrP for this regulatory loop is not clear. While one hypothesis has suggested the periarticular perichondrium as the source of PTHrP for growth plate regulation, other data utilizing immunohistochemistry and in situ hybridization would indicate that growth plate chondrocytes themselves are the source of this peptide. The data described in this report supports the view that postnatal growth plate chondrocytes have the ability to synthesize this important regulatory peptide. Immunohistochemistry of tissue sections showed that PTHrP protein was evident throughout the chick epiphysis. PTHrP was seen in chondrocytes in the periarticular perichondrium, the perichondrium adjacent to the growth plate, the prehypertrophic zone of the growth plate, and the hypertrophic zone of the growth plate. However, cells in the proliferative zone, as well as some chondrocytes in the deeper layers of articular cartilage were predominantly negative for PTHrP. PTHrP was detected by Western blotting as a band of 16,400 Da in extracts from hypertrophic chondrocytes, but not from proliferative cells. RT-PCR detected PTHrP mRNA in both proliferative and hypertrophic growth plate chondrocytes, as well as in articular chondrocytes. PTH/PTHrP receptor mRNA was detected by Northern blotting in growth plate, but not articular chondrocytes. Thus, we conclude that most of the PTHrP present in the epiphyseal growth plate of the juvenile chick originates in the growth plate itself. Furthermore, the presence of large amounts of PTHrP protein in the hypertrophic zone supports the concept that PTHrP has other functions in addition to regulating chondrocyte differentiation.

Lupus patients admitted to the intensive care unit (ICU) are often very sick with multiorgan dysfunction and are thought to do poorly. The prevalence of antiphospholipid, or Hughes’, syndrome (APS) in lupus patients seen in outpatients is variously reported in different series but is approximately 30% [1]. APS is reported to be associated with increased mortality in patients with systemic lupus erythematosus (SLE) independent of other variables [2]. The prevalence of APS in critically ill lupus patients might, therefore, be expected to be higher than in the outpatient population. However this prevalence has not been ascertained and despite evidence of increasing survival in lupus patients [3], the outcome of lupus patients following critical illness requiring ICU admission has not been established. In fact, there is only one report examining presenting features, prognostic factors and outcome after ICU admission in lupus patients [4]. Based in two South African teaching hospitals, 30 patients were included who were admitted to ICU between 1982 and 1993. Admissions were required for a number of different indications, the most common being infection (37%). Prognosis was shown to be poor, with a 53% mortality on or shortly after discharge from ICU. Only the presence of renal disease was identified as a poor prognostic marker, significantly reducing the survival from the time of diagnosis of SLE. Unfortunately, lack of antiphospholipid antibody data precluded analysis of their effect on outcome. Thus the effect of APS on ICU mortality and long-term survival has not hitherto been investigated.

Chronic hypoxia is associated with altered pulmonary vasoreactivity, and it has been suggested that an increased response to voltage-dependent vasodilators may relate to enhanced Ca++ entry via voltage-dependent channels, secondary to depolarization. Few studies have been performed on small pulmonary arteries, and it is unknown whether they are depolarized after chronic hypoxia. We examined the resting membrane potential, and the actions of voltage-dependent (verapamil, levcromakalim) and -independent (isoproterenol, forskolin, papaverine) vasodilators in small ( approximately 300 microm internal diameter) pulmonary arteries from chronically hypoxic rats. The resting membrane potential was more positive in arteries after chronic hypoxia (control: -60 +/- 0.5 mV; hypoxic: -54.4 +/- 1.1 mV; P.01), and this was reflected by a shift to the left of the response curves for K+ and 4-aminopyridine. In arteries constricted with prostaglandin F2alpha the response to verapamil and levcromakalim was increased after chronic hypoxia, although maximum prostaglandin F2alpha-induced tension was unchanged, which implies a reduction in voltage-independent constrictor mechanisms. Although vasorelaxation to isoproterenol was depressed in arteries from hypoxic rats, forskolin-induced relaxation was enhanced substantially, and because the response to the phosphodiesterase inhibitor papaverine was unchanged, we suggest that this reflects an up-regulation of adenylate cyclase. In conclusion, chronic hypoxia resulted in a significant depolarization in small pulmonary arteries, but this may explain only partly the increased efficacy of voltage-dependent vasodilators. Whether the reduction in voltage-independent constrictor mechanisms is related to the apparent up-regulation of adenylate cyclase remains to be elucidated.

Tibialdyschondroplasia (TD) is a disease characterized by the formation of an avascular, non-mineralized lesion along the mature face of the epiphyseal growth plate in rapidly growing chickens. In the normal growth plate, cells progress from a proliferative phase to hypertrophy where the tissue is vascularized and replaced by trabecular bone. In TD, cells apparently cease their development early in the transition to hypertrophy. These diseased cells are not removed by vascularization nor does mineralization occur. The resulting lesion increases in size as proliferative cells continue to divide in the absence of removal and replacement of cartilage by bone. This laboratory has previously reported that cells of the TD lesion have the morphological appearance of necrotic cells or in some cases apoptotic cells. In this study we examine in more detail the status of cells comprising the TD lesion using molecular techniques. Genomic DNA isolated from cells of severe TD lesions show the nucleosomal laddering indicative of apoptosis, while DNA isolated from proliferative and hypertrophic cells does not. This result was confirmed by the use of the Cell Death Detection ELISA which shows quantitatively that cells from severe TD lesions contain nearly twice as many nucleosomal fragments as cells from the hypertrophic zone while proliferative chondrocytes do not have significant fragmentation. In situ examination of the epiphyseal growth plate with terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) clearly shows that the cells of the severe TD lesion are apoptotic. Cells from smaller lesions are stained to a lesser extent or not at all by TUNEL. We believe that the apoptosis seen in TD is a secondary effect of the disease and not its primary cause.

Gene expression and alkaline phosphatase (AP) activity, associated with chondrocyte differentiation, were evaluated in the epiphyses of normal and tibial dyschondroplasia (TD)-afflicted turkeys. In the normal turkey growth plate (GP), osteopontin (OPN) and type X collagen genes were expressed by the hypertrophic cells in both GP and secondary ossification center, parallel to manifestation of AP activity. Collagen type II gene expression was restricted to the nonhypertrophic chondrocytes at the upper part of the GP. OPN or collagen type X genes were not expressed within the TD lesion. However, these genes were expressed in areas proximal and distal to the lesion, suggesting that after reaching partial differentiation, chondrocytes within the developing TD lesion de-differentiate into cells that resemble chondrocytes in the prehypertrophic zone. This suggestion is supported by the observation that the cells in the lesion expressed the collagen type II gene. In some cases, the TD lesion was invaded by fibroblastlike cells that did not exhibit any AP activity or expressed the OPN gene. No lesions were observed in the secondary ossification centers.

Basic fibroblast growth factor (bFGF) is a permissive mitogen for cultured chondrocytes and has been localized in the specific zones of the epiphyseal growth plate. In this study, we demonstrate that bFGF present in cartilage originates from within the cellular constituents of this tissue. Utilizing reverse transcription coupled to the polymerase chain reaction (PCR), bFGF mRNA was found in extracts of cartilage tissue. Immunocytochemical studies revealed that bFGF was present intracellularly in freshly isolated proliferative chondrocytes and in the extracellular matrix (ECM) after 24 h of culture. Western blot analysis of protein extracts from isolated proliferative chondrocytes identified a bFGF immunoreactive species with a molecular weight of approximately 18 kDa. In situ hybridization confirmed the presence of bFGF mRNA in freshly isolated proliferative chondrocytes. The bFGF in the ECM seemed to be sequestered and not available for biological activity, since these cells still required exogenous bFGF for cell proliferation. This sequestered bFGF could be released to stimulate cell proliferation when cultures were treated with plasmin, a proteolytic enzyme. These data support the hypothesis that bFGF is synthesized by chondrocytes and functions as an autocrine/paracrine mitogen via its deposition into the ECM with subsequent release from the ECM of cartilage being a critical step in biological activity. In addition, the study provides further evidence that locally produced bFGF plays an important role in normal growth and development of cartilage tissue.

Enzymes play an important role in the food industry in both traditional and novel products. The ancient processes of brewing and cheese-making rely on enzyme activity at various stages of manufacture. In brewing, the malting of grain develops amylase and protease activities, which then act on the starch and protein reserves of the grain during mashing to produce fermentable sugars and other nutrients on which yeast can grow. By a process of trial and error, brewers over the millennia have optimised conditions for malting and mashing despite their lack of knowledge of enzymes. In the same way, the slaughter of animals for meat was developed so that the quality of the meat was improved. The importance of resting animals prior to slaughter, killing them without trauma and hanging the meat for several days was recognised before the role of enzymes in the process was known. It is now known that resting animals prior to slaughter ensures that sufficient glycogen is present in the muscle to act as a substrate for enzymes post mortem. The role of post mortem glycolysis and natural muscle proteases in the conversion of muscle to meat is also understood and has led to attempts to improve further the process, and therefore the quality of the meat.

An experiment was conducted to determine whether differences in the electrocardiograms (EKGs) of broilers reared at simulated high altitude from the day of hatch can be used to predict which birds are developing ascites. In three replicate experiments, conducted with 100 broilers per replicate, birds were reared at a simulated altitude of 3000 meters or at ambient atmospheric pressure. Lead I, II, and III EKGs were obtained from all birds on days 0, 14, 28, and 42. No consistent significant differences were seen on day 0 in the amplitude of the R or S wave or total amplitude of the QRS complex when broilers that developed ascites while being reared at simulated high altitude were compared with unaffected birds reared at simulated high altitude and with birds reared at ambient atmospheric pressure. On days 14 and 28, the average amplitude of the S wave and the total amplitude of the QRS complex were significantly higher in the ascites group than in the two other groups. Packed cell volumes were significantly higher in birds reared at simulated high altitude at all sampling days (days 14, 28, and 42) than in those reared at ambient atmospheric pressure, and they were significantly higher in the ascites group on day 28 than in the two other groups. Birds in the ascites group weighed significantly less than the two other groups by day 14, and this trend persisted.

The primary function of the heart and lungs is to generate a flow of oxygenated blood to respiring tissues to sustain aerobic metabolism. Teleologically, such a transport system has several basic requirements. It should be energy efficient, avoiding unnecessary cardiorespiratory work, but it should be sensitive to the fluctuating demands of cellular metabolism. Ideally, metabolic demand and oxygen distribution should be matched regionally when at rest, during exercise, and in different disease states. Finally, oxygen should pass efficiently across the extravascular tissue matrix. The mechanisms that control oxygen distribution are complex and not completely understood. In the critically ill patient, these mechanisms may have an important role in determining the clinical outcome. The relationship between oxygen delivery and consumption has not been clearly established despite considerable investigation during the last decade. However, these variables are often measured to define a population of critically ill patients in whom oxygen consumption is limited by oxygen delivery, the state of so-called delivery-dependent oxygen consumption or pathologic supply dependency. The recent literature in critical care and many leading intensive care units has emphasized the importance of raising oxygen delivery to "supranormal" levels in an attempt to satisfy the increased metabolic demands of these patients. This practice has been justified by the observation that increasing oxygen delivery improves oxygen debt and outcome in postoperative surgical patients requiring intensive care. In the severely hypovolemic patient, most physicians would agree that volume replacement to improve oxygen delivery must be beneficial. However, in patients with more complex problems, including sepsis, cardiovascular collapse, and hypoxic hypoxemia, controlled trials to examine the influence of such strategies on clinical outcome have produced conflicting data. Several methodologic factors may have contributed to these contradictory and often controversial results. These factors include failure to define the disease and patient population adequately, the relationship between the time of investigation and the evolution of the disease process, and the accuracy and frequency of measurement.(ABSTRACT TRUNCATED AT 400 WORDS)

The antitussive activity of levodropropizine (S(-)3-(4-phenyl-piperazine-1-yl)-propane-1,2-diol, DF 526, CAS 99291-25-5) was evaluated after oral administration to the conscious dog. Levodropropizine had a good antitussive activity, comparable with, but having a longer duration of action than dropropizine, the racemate from which it is derived. The antitussive activity of levodropropizine in the dog was approximately 1/20 of that of codeine phosphate.

Recent work has shown that hydroxylysylpyridinoline (HP), a non-reducible cross-link that stabilizes the collagen fibril network, is significantly greater (over 10-fold) in dyschondroplastic cartilage than in normal growth-plate cartilage in the tibiotarsi of chickens with homocysteine-induced tibial dyschondroplasia (TD). In the present study, broiler chicks with a genetic disposition to TD, as well as normal broiler chicks on a copper-deficient diet alone or supplemented with copper and thiram, were raised for 3 to 4 weeks (Expts. 1 and 2). Their dyschondroplastic cartilage from the proximal tibiotarsus was collected and analyzed for HP as well as lysylpyridinoline (LP) cross-links. Normal growth plate cartilage was obtained from chicks on the copper-deficient diet supplemented with copper. In a third experiment, another set of broiler chicks was raised on a corn/soybean meal-based diet with or without homocysteine, and their articular and sternal cartilage were isolated for cross-link analysis. In the first two experiments, dyschondroplastic cartilage from all birds with induced TD had higher HP and LP concentrations than growth-plate cartilage from birds without TD, although the ratios of HP to LP varied. In the third experiment, the sternal and articular cartilage from birds with homocysteine-induced TD appeared normal, having similar HP concentrations in the same types of cartilage in birds without TD.

Domiciliary oxygen is prescribed widely and often with benefit. However, patients with chronic lung disease, in whom its efficacy is proven, continue to be denied adequate assessment and treatment. It is time to ensure that this expensive treatment is given to those who will benefit in a manner that maximizes the improvement in the quality of life.

Tissues require oxygen for survival. Its delivery depends on adequate ventilation, gas exchange and distribution in the circulation. Many causes of hypoxaemia can be corrected by adding oxygen to the inspired air but response is variable and must be measured.

Rats were maintained in chambers and breathed air (control, n=8) or an atmosphere containing 10% oxygen (hypoxic, n=10) for 35 days. On completion of the experiment the hypoxic animals weighed less than the controls (hypoxic, 290 ± 11.7g; control, 339 ± 19.2g; means ± S.E.M., p

In patients with severe theophylline toxicity charcoal haemoperfusion is the recommended method for rapid reduction of serum theophylline levels. However, access to this technique is limited in most hospitals. This case report shows that continuous venovenous haemofiltration, a technique available in most hospitals, is an effective alternative to charcoal haemoperfusion.

In a prospective study of 72 human immunodeficiency virus (HIV) positive patients presenting with fever and breathlessness, a non-invasive management protocol, incorporating a scanning technique using radioactively labelled diethylenetriamine penta acetate (DTPA) and sputum induction, was found to be highly sensitive and specific in the early detection of Pneumocystis carinii pneumonia (PCP). At presentation, the DTPA scan was abnormal in 34 of 36 cases of PCP, irrespective of smoking history, whilst the chest radiograph was diffusely abnormal in 21 cases. Sputum induction identified 7 of 14 patients with PCP in the first six months of its use and 7 of 10 patients over the last six months. The DTPA lung scan and induced sputum examination are non-invasive techniques which can be used to investigate out-patients. In combination they detected all cases of PCP at presentation, reduced the need for bronchoscopy, resulted in a low case fatality (5.4%) and reduced the need for admission.

Young broiler chicks were more sensitive to copper toxicity when they were fed diets deficient or marginal in calcium content. Growth rate was depressed and liver copper concentration was increased under these conditions. Chicks fed a casein-gelatin diet were more sensitive to copper toxicity than those fed a corn-soybean meal diet. Addition of phytic acid to the casein-gelatin basal diet enhanced copper toxicity as evidenced by effects on growth rate and liver copper content. Measurements of intestinal and biliary copper content suggested that the influence of calcium on copper toxicity was mediated via intestinal absorption rather than through influences on copper excretion.

An experiment with a factorial arrangement of treatments was conducted using five levels of dietary calcium and two levels of zeolite A. When dietary calcium was deficient or marginal, zeolite A improved calcium utilization, as evidenced by improved growth rate and a reduction in rachitic lesions. There was little benefit from adding zeolite A to diets adequate in calcium. The effect of zeolite A on the incidence of tibial dyschondroplasia was inconsistent.

The objective of this presentation is to relate the abundance and mobility of Cd in components of terrestrial ecosystems with implications for land utilization of sewage sludge. The uptake of Cd by crop plants is a function of the quantity of the element in the soil plus other soil factors affecting the Cd ion activity or electrochemical potential at the plant root surface. The natural abundance of Cd in soils has been reported as 0.5 mug/g which is higher than the background level of 0.2 mug/g found in soils studied in Pennsylvania. Experimental results indicate that the plant availability of Cd increases with each soil addition. While the plant availability of Cd is decreased by liming to increase soil pH, it has not been possible to add Cd salts or sewage sludge Cd without significantly increasing plant uptake. Field studies have shown that land application of sewage sludge can be expected to increase the Cd concentration of corn leaves from a range of 0.05-0.1 mug/g to 1-3 mug/g. Two years after the last application of sludge which added up to 10 ppm Cd to the surface soil, corn grain, sorghum grain, wheat grain, and potatoes showed a 10- to 15-fold increase in Cd over background levels. Studies were conducted with chicks, laying hens, and meadow voles (Microtus Pennsylvanias) to assess the impact of this increase in plant Cd upon the food chain. Corn and sorghum plants were grown on soils with either inorganic or sludge fertilizer for the purpose of producing herbage for use in feeding trials with meadow voles. Eight diets and a synthetic control diet were formulated to study the effect of source (plant vs. inorganic) of Cd on tissue accumulation. Significant accumulation of Cd occurred in kidney and liver, but not muscle, of voles fed diets containing sludge fertilized corn (1.09 mug/g) or sludge fertilized sorghum (2.76 mug/g). The source of Cd had little influence on tissue accumulation. In studies with broiler chicks and laying hens, natural diets containing 0.2 ppm Cd were supplemented with 3 ppm of this element. As with the meadow voles, Cd readily accumulated in liver and kidney. Although the results were not statistically significant, 3 ppm dietary Cd doubled muscle Cd content. There was no transfer of Cd to egg in a long term (12 month) experiment with laying hens. Soil management programs have been developed to maintain animal dietary levels of Cd at less than 1.0 mug/g from the use of sewage sludge on land in Pennsylvania. However, it is concluded that this level over time may cause a significant accumulation of Cd in animal tissues. Interpretation of these results in relation to those for human intake of Cd and the long range health effects of Cd is required for the proper monitoring of sewage sludge applications on land used for production of crops which enter the food chain.

A CHOLINE deficiency is readily produced in chicks by feeding a diet low in choline or certain choline precursors. The effect of choline deficiency in laying hens, however, is less clear. McCollum et al. (1912) fed a diet containing 70 parts ground polished rice previously extracted with hot alcohol and 30 parts of dried skimmed milk to laying hens and found that more lecithin was present in eggs produced by these hens than had been consumed in the diet. Therefore, these investigators concluded that large amounts of lecithin were synthesized by laying hens. Abbott and DeMasters (1940), using a diet similar to McCollum’s supplemented with other vitamins, found that addition of choline to this basal diet increased egg production, prevented weight loss, and reduced liver fat. When diets have been studied which were low in methionine and vitamin B12, good responses were obtained from the addition of choline to diets…

HIGGINS, Richert and Westerfeld (1956) observed normal development in chicks which received a purified casein diet containing approximately 0.02 mg. molybdenum per kg. of diet. An apparent molybdenum deficiency, however, was produced by feeding sodium tungstate. Tungstate feeding decreased growth rate, xanthine dehydrogenase activity and uric acid excretion, all of which were reversed by the addition of molybdenum to the diet. Reid et al. (1956) reported that chicks and turkey poults responded to additional dietary molybdenum when fed a purified diet containing isolated soybean protein. Further results by Kurnick et al. (1957) and Reid et al. (1957) indicated that tissue xanthine dehydrogenase activity as well as growth rate was increased by molybdenum supplementation of the basal diet. Using practical and purified diets, Teekel and Watts (1959) observed no beneficial effect from molybdenum supplementation when the chicks came from dams which received a regular diet. However, when the dams received a …