Early experience of a local pathway on the waiting time for MRI in patients presenting to a UK district general hospital with suspected cauda equina syndrome.

AIM: This study evaluated the impact of the Salisbury Protocol for Assessment of Cauda Equina Syndrome (SPACES) on the waiting time for MRI in patients presenting with suspected Cauda Equina Syndrome (sCES) within a UK district general hospital. PATIENTS AND METHODS: All consecutive patients undergoing an MRI scan in our hospital, for sCES, over a 12 month period, prior to and following the introduction of SPACES, were identified. Patient's gender, age, MRI diagnosis, time from MRI request to imaging and outcome were recorded. RESULTS: In the year prior to the introduction of SPACES, 66 patients underwent MRI for sCES, out of which 10.6% had cauda equina compression (CEC), 63.5% had other spinal pathology and 25% had a normal scan. In the year after introduction of SPACES, 160 patients underwent MRI for sCES out of which 6.2% had CEC, 70.7% had other spinal pathology and 23% had a normal scan. Despite the referrals for sCES increasing by more than 2-fold following the introduction of SPACES, the median time from MRI request to scan decreased from 9.1 to 4.2 hours (p = 0.106, Mann-Whitney-U) and the number of patients transferred to the regional hub hospital decreased from 7 to 3. CONCLUSION: Implementation of SPACES for patients with sCES resulted in a substantial reduction in waiting time for MRI and decreased the number of transfers to the regional hub hospital. Based on our early experience, we encourage other centres within the UK to introduce such a pathway locally, to improve the management of patients with sCES.

Bone induction at physiological doses of BMP through localization by clay nanoparticle gels.

Bone Morphogenic Protein 2 (BMP2) can induce ectopic bone. This ability, which first motivated the widespread application of BMP2 in fracture healing and spinal arthrodesis has, more recently, been indicated as one of several serious adverse effects associated with the supra-physiological doses of BMP2 relied upon for clinical efficacy. Key to harnessing BMPs and other agents safely and effectively will be the ability to localize activity at a target site at substantially reduced doses. Clay (Laponite) nanoparticles can self assemble into gels under physiological conditions and bind growth factors for enhanced and localized efficacy. Here we show the ability to localize and enhance the activity of BMP2 to achieve ectopic bone formation at doses within the sub-microgram per ml range of concentrations sufficient to induce differentiation of responsive cell populations in vitro and at approximately 3000 fold lower than those employed in clinical practice.

The local infiltration of analgesia following total knee replacement: a review of current literature.

Controversy remains regarding the optimal post-operative analgesic regimen following total knee replacement. A delicate balance is required between the provision of adequate pain relief and early mobilisation. By reviewing 29 randomised trials we sought to establish whether local infiltration of analgesia directly into the knee during surgery provides better pain relief and a more rapid rehabilitation. Although we were able to conclude that local infiltration can provide improved post-operative pain relief, and to suggest the most promising technique of administration, there is no evidence that it reduces hospital stay.

Percutaneous dynamic hip screw.

We present the results of a technique of dynamic hip screw insertion through a very small incision, typically 2-2.5 cm. The technique is performed using a standard dynamic hip screw set and requires no additional equipment. We compared the results to those of an age and sex-matched group who had undergone the operation through a traditional approach. We compared the time spent in theatre, the pre- and post-operative haemoglobin concentration, haematocrit and prevalence of wound infection. Thirteen consecutive cases were performed by one surgeon using the percutaneous technique. There were nine females and four males with a mean age of 84 years (range 62-96 years). Each had a 135 degrees four-hole plate. The mean post-operative drop in haemoglobin concentration in the percutaneous group was 2.2 g/dl (range 0-4.4 g/dl) compared to 3.5 g/dl (range 1.2-5.4 g/dl) in the control group (p = 0.014). The mean haematocrit drop was 0.07 (range 0-0.12) in the percutaneous group compared to 0.10 (range 0.03-0.17) in the control group (p = 0.017). The mean theatre time with the percutaneous technique was 57 min (range 40-75 min) and in the control group, 60 min (range 30-95 min). There were no wound problems. It is likely that this minimally invasive technique offers a better clinical outcome at no extra expense and warrants further evaluation in a larger study.

Lipoteichoic acid inhibits interleukin-2 (IL-2) function by direct binding to IL-2.

Lipoteichoic acid (LTA) is associated with the cell envelope of most gram-positive bacteria. Although previously thought to act mainly as a virulence factor by virtue of its adhesive nature, evidence is now provided that LTA can also suppress the function of interleukin-2 (IL-2), an autocrine growth factor for T cells. LTA from four separate bacterial strains lowered the levels of detectable IL-2 during a peripheral blood mononuclear cell response to the antigen tetanus toxoid (TT). T-cell proliferation in response to TT was similarly inhibited by LTA. In contrast, levels of detectable gamma interferon increased. In addition, LTA inhibited IL-2 detection by enzyme-linked immunosorbent assay (ELISA) and blocked the proliferative response of an IL-2-dependent T-cell line to soluble IL-2. Further studies using ELISA demonstrated that LTA blocks IL-2 detection and function by binding directly to IL-2. Flow cytometric analysis revealed that IL-2 binding to T cells is inhibited in the presence of purified LTA but not LTA plus anti-LTA monoclonal antibody. In summary, these studies demonstrate a novel effect of LTA on the immune response through direct binding to IL-2 and inhibition of IL-2 function. Importantly, gram-positive organisms from which LTA is obtained not only play an important role in the pathology of diseases such as bacterial endocarditis, septic shock, acute respiratory distress syndrome, and multiple organ failure but also comprise a significant portion of commensal populations within the human host. Inhibition of IL-2 function by LTA may represent yet another mechanism by which gram-positive bacteria dampen the host immune response and facilitate survival. Thus, LTA provides a potential target for therapeutic intervention when gram-positive organisms are involved.

Two distinct stages in the transition from naive CD4 T cells to effectors, early antigen-dependent and late cytokine-driven expansion and differentiation.

Efficient peptide presentation by professional APC to naive and effector CD4 T cells in vitro is limited to the first 1-2 days of culture, but is nonetheless optimum for effector expansion and cytokine production. In fact, prolonging Ag presentation leads to high levels of T cell death, decreased effector expansion, and decreased cytokine production by recovered effectors. Despite the absence of Ag presentation beyond day 2, T cell division continues at a constant rate throughout the 4-day culture. The Ag-independent later stage depends on the presence of IL-2, and we conclude optimum effector generation depends on an initial 2 days of TCR stimulation followed by an additional 2 days of Ag-independent, cytokine driven T cell expansion and differentiation.

Differences in IgG subclass do not effect immune complex-enhanced T cell activation despite differential binding to antigen presenting cells.

Ag presentation to CD4 T cells is a critical event in the generation of protective immunity. IgG, in the form of IgG-pathogen (Ag) complexes, is capable of mediating FcgammaR-dependent Ag presentation, and thereby enhanced T cell activation. Therefore, it is important to understand the ability of the individual human IgG subclasses to function in enhanced T cell activation. We hypothesized that increased delivery of Ag to monocyte FcgammaR by high affinity human IgG subclasses, IgG1 and IgG3, would lead to increased Ag presentation, as compared to low affinity IgG subclasses, IgG2 and IgG4. To create immune complexes, we linked biotinylated IgG subclasses to biotinylated Ag via an avidin bridge, and examined T cell responses to them. Although IgG2- and IgG4-Ag complexes bound to monocytes at significantly lower levels than those made with IgG1 and IgG3, we observed no significant difference in the ability of the four human IgG subclasses to mediate enhanced T cell activation. Studies suggest the explanation for this dichotomy lies within the first 24 h of Ag processing, and that processing efficiency may vary with IgG subclass. They also suggest the existence of a highly efficient, and selective processing pathway, which is dependent on IgG subclass, and can compensate for low level production and FcgammaR binding of IgG2- and IgG4-Ag complexes.

Inhibition of interleukin-2 by a Gram-positive bacterium, Streptococcus mutans.

Generation of an effective cellular immune response is key to the successful development of both humoral and cellular immune defences against most pathogens. However, while the type of cellular immune response elicited by any given pathogen is dictated by the entire array of antigens and molecules which comprise that pathogen, most studies of human immune responses to bacterial pathogens tend to focus on selected antigens. This is a result, in part, of a desire to find those antigens that will generate a desired immune response, as well as limited technology for monitoring the complex array of responses generated by an intact organism. Utilizing Streptococcus mutans as a model Gram-positive organism, a novel flow cytometric assay that permits the identification of individual cells within a responding population, and highly sensitive cytokine assays, we show for the first time that CD8 T cells and natural killer (NK) cells comprise a significant component of the response to this organism in humans. This is despite the fact that CD8 T cells are traditionally thought to respond to endogenously derived antigens only. In addition, we provide the first evidence that a Gram-positive organism can actively inhibit interleukin-2 (IL-2), an important autocrine growth factor for T cells. The latter observation could represent an additional mechanism by which Gram-positive organisms evade host defences.

Hyperventilation-induced cerebral ischemia in panic disorder and effect of nimodipine.

Basilar artery blood flow was measured by transcranial Doppler ultrasonography before and during hyperventilation in nine patients with panic disorder and nine normal comparison subjects. The hyperventilation-induced decrease in basilar artery blood flow was significantly greater in patients with panic attacks than in comparison subjects. Two patients with decreases in basilar flow greater than 80% were successfully treated with nimodipine, a centrally active calcium channel blocker.

An antiserum to atrial natriuretic factor (ANF) cross-reacts with neurophysins in the hypothalamo-neurohypophysial system of rat brain.

The distribution of atrial natriuretic factor (ANF)-like reactivity was examined in rat brain and heart by immunohistochemistry. Immunostaining in heart was confined to atrial myocytes. In the hypothalamus, ANF-absorbable immunoreactivity was observed in magnocellular perikarya of the paraventricular and supraoptic nuclei, and in their projections to the neural lobe of the pituitary gland. No staining was seen in the preoptic or arcuate hypothalamic nuclei or in brain stem nuclei as previously reported by other investigators. The patterns of reactivity for ANF reported here is similar to that observed for neurophysins (NPs). Comparison of sequence data between rat ANF-28 and bovine NPs revealed three regions of 3 amino acid homology between these hypothalamic peptides. Preabsorption of the ANF antiserum with Affigel-coupled bovine NP I also resulted in complete elimination of all "ANF-immunoreactivity" in both atrium and hypothalamus. Cross-reactivity of the ANF antiserum with bovine NP I and II was further confirmed by Western blot analysis. Our findings suggest that ANF antisera can cross-react with NPs if they are directed against the shared antigenic epitopes; complete elimination of staining by preabsorption of the antibody with the immunogen, therefore, does not guarantee authenticity of localization. These observations may have relevance to an earlier study which reported on the existence of ANF-immunoreactivity in oxytocin neurons of the hypothalamus.

High concentrations of neuropeptide Y in pituitary portal blood of rats.

Pituitary portal blood was collected from urethane-anesthetized rats and examined for the presence of neuropeptide Y (NPY) using high-performance liquid chromatography and radioimmunoassay. Other rats were perfused with fixative, and coronal sections through the hypothalamus and median eminence were processed for immunohistochemical localization of NPY. Combined high-performance liquid chromatography and radioimmunoassay analysis of pituitary portal plasma and systemic plasma revealed a single peak of NPY immunoreactivity which corresponded in retention time to synthetic porcine NPY. Increasing amounts of portal or systemic plasma produced displacement curves which were parallel to the NPY standard curve. The concentration of NPY immunoreactivity in portal plasma (52.0 +/- 4.0 ng/ml, mean +/- SEM) was three times greater (p less than 0.005) than in systemic plasma (16 +/- 4.5 ng/ml). NPY-labeled fibers were observed in the external zone of the median eminence in the vicinity of hypothalamo-hypophyseal portal vessels. The observation of significantly higher concentrations of NPY immunoreactivity in the portal plasma supports the hypothesis that NPY may be released from the hypothalamus to affect pituitary function.

Beta-adrenergic control of atrial natriuretic factor secretion from dispersed rat atrial myocytes.

Adrenergic control of atrial natriuretic factor (ANF) secretion was studied using perifused, dispersed atrial myocytes. ANF secretion was stimulated by as little as 1 nM epinephrine (EPI) or the beta-adrenergic agonist isoproterenol (ISO). The response to EPI was completely blocked by equimolar propranolol but not by phenoxybenzamine suggesting that, at least in this system, the adrenergic control of ANF secretion is mediated by beta-adrenergic receptors.

Provision of immunisation--the Gazankulu experience.

Following the outbreak of poliomyelitis in Gazankulu in 1982, the immunisation services in Gazankulu were thoroughly examined. As a result of this, a comprehensive immunisation policy for Gazankulu was accepted in November 1986. The broad aim of the policy is to provide effective immunisation to all Gazankulu residents against tuberculosis, diphtheria, pertussis, tetanus, poliomyelitis and measles. A specific objective is that by the end of 1987, 85% of under-5s should have been vaccinated against these six diseases and by the end of 1990 this percentage should be 97%. The detailed strategies to reach these objectives are highlighted. Within the framework of the objectives, the policy allows different areas to formulate individual strategies. Programme monitoring and community involvement are two crucial aspects of the policy and these are discussed in detail. The early successes and difficulities in implementing this policy are discussed.

Atrial natriuretic factor in maternal and fetal sheep.

To determine atrial natriuretic factor (ANF) concentrations in the circulation and body fluids of adult pregnant sheep and their fetuses, pregnant ewes were anesthetized with pentobarbital sodium, and the fetuses were exteriorized for sampling. ANF concentration, as measured by radioimmunoassay, was 47 +/- 6 (SE) pg/ml in maternal plasma, which was significantly higher than the 15 +/- 3 pg/ml in maternal urine. In the fetus, plasma ANF concentration was 265 +/- 49 pg/ml, 5.6 times that in maternal plasma. No umbilical arterial and venous difference in ANF concentration was observed. Fetal urine ANF concentration (13 +/- 2 pg/ml) was significantly lower than that in fetal plasma, and was similar to that measured in amniotic and allantoic fluid. In chronically catheterized maternal and fetal sheep, fetal plasma ANF was again 5.1 times that in maternal plasma, and these levels were not different from those measured in acutely anesthetized animals. These results demonstrate that immunoreactive ANF is present in the fetal circulation at levels higher than those found in the mother. The low concentration of ANF in fetal urine suggests that ANF is probably metabolized and/or reabsorbed by the fetal kidney.

Noncalcium-dependent modulation of in vitro atrial natriuretic factor release by extracellular osmolality.

Recent reports have described modulation of atrial natriuretic factor (ANF) secretion by atrial stretch, increased Na+ concentration, and a variety of hormones and neurotransmitters. One problem in the study of ANF secretion has been the isolation of stimulatory effects from interference due to rhythmic myocardial contraction. To avoid this problem, rat atria were dispersed, the myocytes were suspended in a polyacrylamide gel matrix, and the resulting cell column was perifused with a physiological buffer. The secretion of ANF immunoactivity was markedly stimulated by increases in extracellular osmolality, regardless of the solute (NaCl, KCl, or glucose). This effect did not require extracellular Ca2+, nor could it be mimicked by depolarizing concentrations of K+ in an isotonic medium. Functional viability of this model was demonstrated by significant dose-related increases in ANF release in response to as little as 1 nM epinephrine. The dissociation of ANF secretion from depolarization-induced changes in Ca2+ flux is unusual and may represent an adaptation to the dual roles of the atrial myocyte, contraction and secretion.

Supersensitive endocrine response to physostigmine in dopamine-depleted rats: a model of depression?

Depressed patients exhibit an abnormal "supersensitive" increase in the plasma concentration of several pituitary hormones following intravenous injection of the acetyl cholinesterase inhibitor physostigmine (PHY). In the present study, we examined the effects of PHY treatments on the plasma concentrations of prolactin (PRL) and adrenocorticotrophic hormone (ACTH) in the rat. Physostigmine (0-0.6 mg/kg, s.c.) produced a dose-dependent increase in PRL and ACTH immunoreactivity in unoperated animals. Neurotoxin-induced depletion of brain dopamine (DA) or norepinephrine (NE) did not significantly alter baseline plasma PRL or ACTH values. Following depletion of brain DA, but not NE, animals exhibited a "supersensitive" increase in plasma ACTH values, which was evidenced by a sixfold left shift in the dose-response properties of PHY. These results suggest that there are intriguing parallels between the abnormal endocrine response to PHY demonstrated by depressed patients and that demonstrated by rats following depletion of central nervous system (CNS) DA levels.

Oxytocin inhibits ACTH and peripheral catecholamine secretion in the urethane-anesthetized rat.

Oxytocin (OT) generally has a stimulatory effect on ACTH secretion both in vitro and in vivo. As part of a study of ACTH-releasing factors in hypophysial portal blood, the effects of i.v. OT administration on plasma ACTH levels were tested in urethane-anesthetized rats. Surprisingly, i.v. injection of 10 micrograms OT lowered plasma ACTH levels by about 35% (P less than 0.01). It was reasoned that this paradoxical inhibition of ACTH secretion by OT might be mediated by inhibition of the unusually high rate of peripheral catecholamine secretion in this model. Measurement of plasma catecholamines before and after i.v. administration of 10 micrograms OT revealed a 53% inhibition of EPI (P less than 0.01) and 43% inhibition of NE (P less than 0.05). Administration of the beta-adrenergic antagonist propranolol (400 micrograms) 15 min before the beginning of the experiment completely blocked the inhibitory effects of OT on ACTH secretion and in fact unmasked the stimulatory effects of OT normally seen in conscious animals and in vitro. Superfused bisected adrenal glands exposed to 10(-6) M OT for 10 min secreted more than 30% less EPI and NE than control adrenals suggesting that the inhibition of EPI and NE secretion by OT in vivo occurs, at least in part, directly at the level of the adrenal. The data support the hypothesis that peripheral catecholamines may at times be directly involved in the control of ACTH secretion and also suggest that OT, which has recently been identified in the adrenal medulla, may have important paracrine functions in the regulation of adrenal catecholamine secretion.

Vasopressin and oxytocin: hypothalamic modulators of the stress response: a review.

ACTH secretion is primarily controlled by hypothalamic secretion of corticotropin releasing factor (CRF) into pituitary portal blood. However arginine vasopressin (AVP) and oxytocin (OT) can modulate the actions of CRF and at times may be important mediators of stress-induced ACTH secretion. The relative contributions of CRF, AVP, and OT to the control of ACTH secretion vary with different types of stress. In general, AVP stimulates ACTH secretion in all species studied. OT also stimulates ACTH release in rats but is inhibitory in primates. The involvement of AVP and OT in the control of ACTH secretion may have important implications for physiological and pathological conditions associated with activation of the hypothalamo--hypophysial--adrenal cortical axis.

Role of oxytocin in the modulation of ACTH release in women.

To determine if oxytocin (OT) may have a modulatory role on corticotropin-releasing factor (CRF) and vasopressin (AVP) mediated ACTH-cortisol release in women, serial experiments were performed in which saline, OT, AVP and CRF were administered singly or in combinations. OT administration (2 IU intravenous bolus followed by 111 mIU/min infusion for 3 h) maintained a circulating concentration of 7.7 X 10(-8) M and did not significantly influence basal, AVP or CRF-induced ACTH-cortisol release. In contrast, OT inhibited significantly the potentiating effect of AVP on CRF-stimulated ACTH-cortisol release. These findings suggest that OT and AVP may modulate, in a reciprocal fashion, the CRF-mediated ACTH release and support the contention that OT may be involved in the neuroendocrine response to stress in women.

Stress-specific modulation of ACTH secretion by oxytocin.

The role of oxytocin (OT) in regulating stress-induced ACTH secretion was investigated by immunoneutralization of endogenous OT with an antiserum raised against synthetic OT. Rats were subjected to one of three stresses: novel environment, tail-hang, or ether. In otherwise untreated rats, ACTH levels rose at least 3-fold in response to all three stresses whereas OT levels increased only in response to tail-hang and ether. Injection of a highly specific antiserum to OT 60 min before the experiment inhibited the ACTH response to tail-hang and ether by 64 and 56%, respectively, but had no effect on the ACTH response to novel environment stress. The data support a physiologic role for OT in the control of ACTH secretion but suggest that it is not until OT levels rise in response to stress that the effects of OT are expressed.