Long-lasting stress sensitisation

Stressful experiences in humans can result in a spectrum of long-term changes in behavioural, autonomic and hormonal responsivity. An extreme form of such alterations is found in patients with post-traumatic stress disorder (PTSD). A number of animal models has been developed in which intense stressful experiences (shocks, social confrontations) result in longterm altered responsivity of behavioural, autonomic and hormonal responses to aversive challenges which mimic many of the changes seen in PTSD. These models of stress-induced sensitisation are beginning to generate a better understanding of the vulnerability factors, time-course and underlying neuronal substrates of the long-term disturbances experienced by humans as a result of stressful life events.     

Inhibition of platelet function by contrast media: iopamidol and ioxaglate versus iothalamate. Work in progress

The effects of an ionic contrast agent, meglumine iothalamate (Conray-60), and two newer low-osmolality radiographic contrast media, sodium meglumine ioxaglate (Hexabrix) and iopamidol (B-15,000), on platelet aggregation and secretion responses were studied. All three agents inhibited platelet responses during stimulation with adenosine diphosphate (ADP), epinephrine, and collagen. Platelet function was inhibited by iothalamate at concentrations of 11 mg iodine/ml and above, and by the newer agents at concentrations above 30 mg iodine/ml. Addition of exogenous calcium decreased the iothalamate-induced inhibition of aggregation but did not improve dense granule secretion. There was no consistent effect of exogenous calcium on platelet inhibition by iopamidol and ioxaglate. These studies indicate that the newer agents inhibit platelet function less than iothalamate does, and that chelation of Ca2+ may not be the major mechanism of platelet inhibition by contrast agents.     

Identification of Candida species in the clinical laboratory: a review of conventional,commercial, and molecular techniques

In healthy individuals, Candida species are considered commensal yeasts of the oral cavity. However, these microorganisms can also act as opportunist pathogens, particularly the so‐called non‐albicans Candida species that are increasingly recognized as important agents of human infection. Several surveys have documented increased rates of C. glabrata, C. tropicalis, C. guilliermondii, C. dubliniensis, C. parapsilosis, and C. krusei in local and systemic fungal infections. Some of these species are resistant to antifungal agents. Consequently, rapid and correct identification of species can play an important role in the management of candidiasis. Conventional methods for identification of Candida species are based on morphological and physiological attributes. However, accurate identification of all isolates from clinical samples is often complex and time‐consuming. Hence, several manual and automated rapid commercial systems for identifying these organisms have been developed, some of which may have significant sensitivity issues. To overcome these limitations, newer molecular typing techniques have been developed that allow accurate and rapid identification of Candida species. This study reviewed the current state of identification methods for yeasts, particularly Candida species.     

Effect of a benzodiazepine receptor agonist and corticotropin-releasing hormone receptor antagonists on long-term foot-shock-induced increase in defensive withdrawal behavior

RATIONALE: Traumatic life events can induce long-term alterations in neuronal substrates, which may ultimately lead to the development of anxiety disorders. It has been postulated that corticotropin-releasing hormone (CRH) plays an important role in anxiety-like behavior. OBJECTIVES: (1) To study the long-term effects of a single foot-shock experience on defensive withdrawal (DW) behavior in rats. (2) To examine the effects of the benzodiazepine anxiolytic drug chlordiazepoxide on the behavior of preshocked and control rats in the DW test. (3) To study the role of endogenous CRH in the long-term stress-induced increase in DW behavior. METHODS: (1) Rats were exposed to a single session of foot shocks or exposed to the grid cage without receiving any shocks. Two, six and ten weeks later, rats were tested in the DW tests (2, 3). In subsequent experiments, rats were exposed to foot shocks or exposed to the grid cage without receiving any shocks, and 2 weeks later the effect of pharmacological treatments on the behavioral response in the DW test was investigated. Chlordiazepoxide (1, 5, 10 mg/kg BW, i.p.) and the CRH antagonists D-Phe CRH(12-41) (0.2, 1, 5 microg per rat, i.c.v.) and alpha-helical CRH(9-41) (5 microg per rat, i.c.v.) were injected 30 min before the test. RESULTS: A single session of foot shocks induced a long-term increase in DW behavior, which persisted after repeated testing for at least 10 weeks. Chlordiazepoxide decreased the latency but did not affect time spent in light, distance moved, or the number of entries in the open field. D-Phe CRH(12-41) had no behavioral effects. alpha-Helical CRH(9-41) increased the time spent outside the box, primarily as a result of effects of alpha-helical CRH(9-41) in controls. CONCLUSION: These data demonstrate that preshocked rats display long-term increased anxiety-like behavior in the DW test but that CRH is unlikely to be involved in its expression.     

The evolution and genesis of supraventricular waltz & duet

Objective. This study documents and traces the evolution of triple rhythm (Waltz) linking the great veins, corresponding systemic or pulmonary venous sinuses and pectinated right or left atrium in frog, turtle, snake and human hearts. Alternating rhythm (duet) between systemic and pulmonary veins has also been documented in these hearts. Material Studied. The hearts of six dead hammer-head sharks were examined with the naked eye. Air-breathing, fresh-water fish (three Channa striata and three Indian catfish) were anaesthetised with ketamine and their pharynx insufflated with oxygen. Six frogs, three turtles, and two snakes were anaesthetised, intubated and ventilated. Contractions of the exposed hearts of these animals were correlated with their electrocardiograms using superimposed videos. The human heart was observed carefully during surgery through median sternotomy or anterolateral thoracotomy by visual inspection especially during instillation of or recovery from cardioplegia. Digital videos were taken and studied in slow motion replay later. Observations. In the air-breathing fish, Channa striata and Indian catfish and presumably the shark, the cardinal veins and thin walled sinus venosus do not contract. In the frog, turtle, and snake there is sequential contraction of the systemic veins, systemic venous sinus and pectinated right atrium. Likewise, there is waltz on the arterial side. There is a duet between systemic and pulmonary veins, contractions of the former preceding the latter in the frog, turtle and snake. The observations are similar in the human heart except that the inferior vena cava does not contract. Conclusions. There is sequential contraction of the superior vena cava, the systemic venous sinus and the pectinated part of the right atrium in the human heart. Likewise, there is a waltz linking the terminal pulmonary veins, pulmonary venous sinus and pectinated part of the left atrium in the human heart. This waltz or triple rhythm, as well as a duet between the systemic and pulmonary veins are seen in frog, turtle and snake. The duet is also observable in the human heart, during recovery from cardioplegia. It is likely that the waltz and duet are conducted by a neurogenic mechanism. Clinical Implications. The understanding, preservation and restoration of the mechanism sustaining supraventricular waltz and duet is relevant to surgical and interventional procedures for control of atrial arrhythmia, Fontan circulation, technique for cardiac transplantation and planning atriotomies.     

Gene therapy for diabetic peripheral neuropathy: A randomized,placebo‐controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor

AbstractVM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3‐1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3‐1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3‐1 was change from baseline in the mean 24‐h Numerical Rating Scale (NRS) pain score. In DPN 3‐1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well‐tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3‐1. In DPN 3‐1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3‐1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3‐1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long‐lasting pain‐relieving effects of VM202 observed in DPN 3‐1b warrant another rigorous phase III study. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Nonviral gene therapy can be used safely and practically to treat DPN.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.     

Reduced cooperativeness and reward-dependence in depression with above-normal plasma vasopressin concentration

The neuropeptide vasopressin is centrally involved in the regulation of social behaviour and response to stress. We previously found support for a subcategory of depression defined by above-normal plasma vasopressin (AVP) concentration. This subcategory is validated by a positive family history of depression and correlating plasma AVP and cortisol concentrations. The data support the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression. The aim of the present study was to test whether above-normal plasma AVP concentration in depression is related to personality characteristics reflecting a specific social behaviour style. The data of 78 patients from a previously investigated sample were reanalysed. Fifty-eight patients were available after 2 years, 15 of whom with initially above-normal plasma AVP. The dimensions of the Temperament and Character Inventory (TCI) were scored, with particular focus on the dimensions of Cooperativeness (CO) and Reward-dependence (RD). Normative subjects and other depressed subjects were used as controls. After full remission, patients with initially above-normal AVP had low CO compared with normal and patient controls. During depression, these patients had both low CO and low RD compared with normal controls and low RD compared with patient controls. Low CO is a presumably premorbid trait and reduced RD a state-dependent characteristic in depression with above-normal plasma AVP. The low CO further supports the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression.