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.     

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.     

Barrier properties of vernix caseosa

Experiments are described which show that vernix caseosa has a mechanical barrier effect if it is deposited in an unbroken layer. Specific antibacterial properties were not detected in vernix. It is suggested that vernix is best left on a newborn infant because of its mechanical obstruction to bacterial passage.     

A 17-year-old with rash, fever, myalgias, and nephritis

Patients on hemodialysis are at increased risk for developing active tuberculosis (TB) after primary infection. Although this increased risk is well documented, the prevalence of TB infection, as indicated by a positive tuberculin skin test (TST), is not well described. End-stage renal disease is also known to be a risk factor for skin test anergy, but the rate of anergy in hemodialysis patients is unclear. We sought to identify rates of anergy and TST positivity in patients at four hemodialysis units in St Louis, Missouri, from June 1996 through August 1996. Data obtained from patients and medical records included age, years on hemodialysis, medical history, and basic laboratory data. Patients without a history of TB or a positive TST had a TST with Tubersol, as well as candida and tetanus controls, placed by the Mantoux method. Tests were read 48 hours later. Of the patients enrolled at these units, 307 of 331 (93%) were evaluated. Patients had a mean age of 58 years (range, 19 to 91 years) and had been on hemodialysis for a mean of 3.7 years (range, 1 week to 18.7 years). Blacks made up 81% of the population. A history of a positive TST was obtained from 24 patients (8%), and an additional seven (2%) had a history of active TB. Of the 276 patients tested, 93 did not respond to either control antigen, but five of these patients had a positive TST, leaving 88 (32%) anergic. Anergy was related to age, immunosuppressive drug use, and the reagents used, but not to urea reduction ratio. Positive TSTs were found in 17 of 188 of nonanergic patients (9%) (6% of all tested patients). Overall, 48 of 307 patients (16%) had a positive TST or history of TB. TB or a positive TST was associated with liver disease and peptic ulcer disease, but not socioeconomic status. All 17 newly identified TST-positive patients received chest radiographs. No new cases of active TB were found. Only two of 17 of these patients (12%) were started on isoniazid (INH) prophylaxis. We identified high rates of TST positivity and anergy in the hemodialysis patients tested. Hemodialysis patients should receive regular TST screening, and INH prophylaxis needs to be more strongly encouraged. Studies are ongoing to define the rate of TST conversion over time.