Erythema of rosacea is thought to result from abnormal cutaneous vasomotor activity. Brimonidine tartrate (BT) is a highly selective α2-adrenergic receptor agonist with vasoconstrictive activity.
To determine the optimal concentration and dose regimen of topical BT gel for the treatment of erythema of rosacea and to evaluate its efficacy and safety.
In study A, 122 subjects were randomized to receive a single application of BT 0·07%, 0·18%, 0·5% or vehicle. In study B (4-week treatment and 4-week follow-up), 269 subjects were randomized to receive BT 0·5% once daily, BT 0·18% once daily, vehicle once daily, BT 0·18% twice daily or vehicle twice daily. Evaluations included Clinician’s Erythema Assessment (CEA), Patient’s Self-Assessment (PSA), Chroma Meter measurements and adverse events.
In study A, a single application of topical BT gel reduced facial erythema in a dose-dependent fashion. A significant difference between BT 0·5% and vehicle in Chroma Meter redness value was observed from 30 min to 12 h after application. In study B, BT 0·5% once daily had a statistically superior success profile (defined as a two-grade improvement on both CEA and PSA over 12 h) compared with vehicle once daily on days 1, 15 and 29 (all P < 0·001). No tachyphylaxis, rebound of erythema or aggravation of other disease signs (telangiectasia, inflammatory lesions) was observed. All regimens were safe and well tolerated with similarly low incidence of adverse events.
Once-daily BT gel 0·5% is well tolerated and provides significantly greater efficacy than vehicle gel for the treatment of moderate to severe erythema of rosacea.
Psychostimulant abuse continues to present legal, socioeconomic and medical challenges as a primary psychiatric disorder, and represents a significant comorbid factor in major psychiatric and medical illnesses. To date, monotherapeutic drug treatments have not proven effective in promoting long-term abstinence in psychostimulant abusers. In contrast to clinical trials utilizing monotherapies, combinations of dopamine (DA) agonists and selective 5-HT3, 5HT2A/2C, or NK1 antagonists have shown robust efficacy in reversing behavioral and neurobiological alterations in animal models of psychostimulant abuse. One important temporal requirement for these treatments is that the 5-HT or NK1 receptor antagonist be given at a critical time window after DA agonist administration. This requirement may reflect a necessary dosing regimen towards normalizing underlying dysfunctional neural circuits and “addiction memory” states. Indeed, chronic psychostimulant abuse can be conceptualized as a consolidated form of dysfunctional memory maintained by repeated drug- or cue-induced reactivation of neural circuit and subsequent reconsolidation. According to this concept, the DA agonist given first may reactivate this memory circuit, thereby rendering it transiently labile. The subsequent antagonist is hypothesized to disrupt reconsolidation necessary for restabilization, thus leading progressively to a therapeutically-mediated abolishment of dysfunctional synaptic plasticity. We propose that long-term abstinence in psychostimulant abusers may be achieved not only by targeting putative mechanistic pathways, but also by optimizing drug treatment regimens designed to disrupt the neural processes underlying the addicted state.
Cocaine; Methamphetamine; Synaptic plasticity; Addiction; Substance abuse; Pharmacological treatment
Psychostimulant abuse represents a psychiatric disorder and societal concern that has been largely unamenable to therapeutic interventions. We have previously demonstrated that the 5-HT3 antagonist ondansetron or non-selective 5-HT2A/2C antagonist ketanserin administered 3.5 hours following daily pergolide, a non-selective DA agonist, reverses previously established cocaine sensitization. The present study was conducted to evaluate whether the same treatments or delayed pairing of pergolide with the antidepressant mirtazapine can also reverse consolidated methamphetamine (METH) behavioral sensitization. Sprague-Dawley rats received METH infusion via osmotic minipumps (25 mg/kg/day, s.c.) for 7 days, with accompanying daily injections of escalating METH doses (0–6 mg/kg, s.c.). This regimen takes into account the faster elimination of METH in rats, and is designed to replicate plasma METH concentrations with superimposed peak drug levels as observed during METH binging episodes in humans. Following a 7-day METH withdrawal, ondansetron (0.2 mg/kg, s.c.), ketanserin (1.0 mg/kg, s.c.), or mirtazapine (10 mg/kg, i.p.) was administered 3.5 hours after pergolide injections (0.1 mg/kg, s.c., qd) for 7 days. Behavioral sensitization as a model of METH abuse was assessed 14 days after the combination treatment cessation (i.e., day 28 of METH withdrawal) through an acute challenge with METH (0.5 mg/kg, i.p.). Pergolide combined with ondansetron or ketanserin reversed METH behavioral sensitization, but pergolide-mirtazapine combination was ineffective. The role of reactivation of addiction “circuit” by a non-selective DA agonist, and subsequent reconsolidation blockade through 5-HT3 or 5-HT2 antagonism in reversal of METH sensitization and treatment of METH addiction is discussed.
methamphetamine sensitization reversal; pergolide; ondansetron; ketanserin; mirtazapine; psychostimulant abuse
Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [11C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction.
cocaine addiction; dopaminergic signaling; human brain; human brain imaging; Period 2 gene
Negative pressure wound therapy (NPWT) and vessel loop assisted
closure are two common methods used to assist with the closure of
fasciotomy wounds. This retrospective review compares these two
methods using a primary outcome measurement of skin graft requirement.
A retrospective search was performed to identify patients who
underwent fasciotomy at our institution. Patient demographics, location
of the fasciotomy, type of assisted closure, injury characteristics,
need for skin graft, length of stay and evidence of infection within
90 days were recorded.
A total of 56 patients met the inclusion criteria. Of these,
49 underwent vessel loop closure and seven underwent NPWT assisted
closure. Patients who underwent NPWT assisted closure were at higher
risk for requiring skin grafting than patients who underwent vessel
loop closure, with an odds ratio of 5.9 (95% confidence interval
1.11 to 31.24). There was no difference in the rate of infection
or length of stay between the two groups. Demographic factors such
as age, gender, fracture mechanism, location of fasciotomy and presence
of open fracture were not predictive of the need for skin grafting.
This retrospective descriptive case series demonstrates an increased
risk of skin grafting in patients who underwent fasciotomy and were
treated with NPWT assisted wound closure. In our series, vessel
loop closure was protective against the need for skin grafting.
Due to the small sample size in the NPWT group, caution should be
taken when generalising these results. Further research is needed
to determine if NPWT assisted closure of fasciotomy wounds truly
leads to an increased requirement for skin grafting, or if the vascular
injury is the main risk factor.
Fasciotomy; Negative pressure wound therapy; NPWT; Vessel loop closure; Infection; Complications
Methylphenidate (MPH) is a stimulant drug that amplifies dopamineric and noradrenergic signaling in the brain, which is believed to underlie its cognition enhancing effects. However, the neurobiological effects by which MPH improves cognition are still poorly understood. Here, functional magnetic resonance imaging (fMRI) was used together with working memory (WM) and visual attention (VA) tasks to test the hypothesis that 20 mg oral MPH would increase activation in the dorsal attention network (DAN) and deactivation in the default mode network (DMN) as well as improve performance during cognitive tasks in healthy men. The group of subjects that received MPH (MPH group; N = 16) had higher activation than the group of subjects who received no medication (control group: N = 16) in DAN regions (parietal and prefrontal cortex, regions increasingly activated with increased cognitive load) and had increased deactivation in the insula and posterior cingulate cortex (regions increasingly deactivated with increased cognitive load) and these effects did not differ for the VA and the WM tasks. These findings provide the first evidence that MPH enhances activation of the DAN whereas it alters DMN deactivation. This suggests that MPH (presumably by amplifying dopamine and noradrenergic signaling) modulates cognition in part through its effects on DAN and DMN.
BOLD-fMRI; dopamine; cognition; brain function; stimulants; MPH
In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for “biologically equivalent dose”, from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be “triangulated” to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion “How Fractionation Really Works”. BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation.
Substantial knowledge has been gained in the pathological findings following naturally occurring spinal cord injury (SCI) in dogs and cats. The molecular mechanisms involved in failure of neural regeneration within the central nervous system, potential therapeutics including cellular transplantation therapy, neural plasticity, and prognostic indicators of recovery from SCI have been studied. This 2-part review summarizes 1) basic science perspectives regarding treating and curing spinal cord injury, 2) recent studies that shed light on prognosis and recovery from SCI, 3) current thinking regarding standards of care for dogs with SCI, 4) experimental approaches in the laboratory setting, and 5) current clinical trials being conducted in veterinary medicine. Part I presents timely information on the pathophysiology of spinal cord injury, challenges associated with promoting regeneration of neurons of the central nervous system, and experimental approaches aimed at developing treatments for spinal cord injury.
Here, we assessed the effects of sleep deprivation (SD) on brain activation and performance to a parametric visual attention task. Fourteen healthy subjects underwent functional magnetic resonance imaging of ball-tracking tasks with graded levels of difficulty during rested wakefulness (RW) and after 1 night of SD. Self-reports of sleepiness were significantly higher and cognitive performance significantly lower for all levels of difficulty for SD than for RW. For both the RW and the SD sessions, task difficulty was associated with activation in parietal cortex and with deactivation in visual and insular cortices and cingulate gyrus but this pattern of activation/deactivation was significantly lower for SD than for RW. In addition, thalamic activation was higher for SD than for RW, and task difficulty was associated with increases in thalamic activation for the RW but not the SD condition. This suggests that thalamic resources, which under RW conditions are used to process increasingly complex tasks, are being used to maintain alertness with increasing levels of fatigue during SD. Thalamic activation was also inversely correlated with parietal and prefrontal activation. Thus, the thalamic hyperactivation during SD could underlie the reduced activation in parietal and blunted deactivation in cingulate cortices, impairing the attentional networks that are essential for accurate visuospatial attention performance.
brain function; functional connectivity; sleep deprivation; visuospatial attention
Dopamine is involved in drug reinforcement but its role in addiction is less clear. Here we describe PET imaging studies that investigate dopamine’s involvement in drug abuse in the human brain. In humans the reinforcing effects of drugs are associated with large and fast increases in extracellular dopamine, which mimic those induced by physiological dopamine cell firing but are more intense and protracted. Since dopamine cells fire in response to salient stimuli, supraphysiological activation by drugs is experienced as highly salient (driving attention, arousal, conditioned learning and motivation) and with repeated drug use may raise the thresholds required for dopamine cell activation and signaling. Indeed, imaging studies show that drug abusers have marked decreases in dopamine D2 receptors and in dopamine release. This decrease in dopamine function is associated with reduced regional activity in orbitofrontal cortex (involved in salience attribution; its disruption results in compulsive behaviors), cingulate gyrus (involved in inhibitory control; its disruption results in impulsivity) and dorsolateral prefrontal cortex (involved in executive function; its disruption results in impaired regulation of intentional actions). In parallel, conditioning triggered by drugs leads to enhanced dopamine signaling when exposed to conditioned cues, which then drives the motivation to procure the drug in part by activation of prefrontal and striatal regions. These findings implicate deficits in dopamine activity—inked with prefrontal and striatal deregulation—in the loss of control and compulsive drug intake that results when the addicted person takes the drugs or is exposed to conditioned cues. The decreased dopamine function in addicted individuals also reduces their sensitivity to natural reinforcers. Therapeutic interventions aimed at restoring brain dopaminergic tone and activity of cortical projection regions could improve prefrontal function, enhance inhibitory control and interfere with impulsivity and compulsive drug administration while helping to motivate the addicted person to engage in non-drug related behaviors.
Positron emission tomography; Orbitofrontal cortex; Cingulate gyrus; Dorsolateral prefrontal cortex; Dopamine D2 receptors; Reward; Predisposition; Salience; Raclopride; Fluoro-deoxyglucose
This case report illustrates three learning points about cervical fractures in ankylosing spondylitis, and it highlights the need to manage these patients with the neck initially stabilised in flexion. We describe a case of cervical pseudoarthrosis that is a rare occurrence after fracture of the cervical spine with ankylosing spondylitis. This went undetected until the development of myelopathic symptoms many months later. The neck was initially stabilised in flexion using tongs, and then slowly extended before anterior and posterior fixation was performed. The myelopathic symptoms resolved, and the patient had a good result at 18 months. We conclude that any increased movement of the spine after trauma in ankylosing spondylitis must be considered suspect and fully investigated.
Ankylosing spondylitis; Cervical fracture; Pseudoarthrosis
Carbon dioxide embolism is a rare but potentially devastating complication of laparoscopy. To determine the effects of insufflation pressure on the mortality from carbon dioxide embolism, six swine had intravascular insufflation with carbon dioxide for 30 seconds using a Karl Storz insufflator at a flow rate of 35 mL/kg/min. The initial insufflation pressure was 15 mm Hg. Following recovery from the first embolism, intravascular insufflation using a pressure of 20 mm Hg at the same flow rate was performed in the surviving animals. Significantly less carbon dioxide (8.3 ± 2.7 versus 16.7 ± 3.9 ml/kg; p < 0.02) was insufflated intravascularly at 15 mm Hg than at 20 mm Hg pressure. All of the pigs insufflated at 15 mm Hg pressure with a flow rate of 35 mL/kg/min survived. In contrast, 4 of the 5 pigs insufflated at 20 mm Hg pressure died. The surviving pig died when insufflated with 25 mm Hg pressure following an embolism of 15.7 ml/kg. Intravascular injection was often associated with an initial rise in end-tidal carbon dioxide tension, followed by a rapid fall in all cases where the embolism proved fatal. Insufflation should be begun with a low pressure and a slow flow rate to limit the volume of gas embolized in the event of inadvertent venous cannulation. Insufflation should immediately be stopped if a sudden change in end-tidal carbon dioxide tension occurs.
Laparoscopy; Insufflation; Gas embolism; Carbon dioxide
The Healthcare Administrator's Associate is a collection of portable tools designed to support analysis of data retrieved via the Internet from diverse distributed healthcare information systems by means of the InfoSleuth system of distributed software agents. Development of these tools is part of an effort to enhance access to diverse and geographically distributed healthcare data in order to improve the basis upon which administrative and clinical decisions are made.
We have developed a faculty research interests resource by "mining" MEDLINE for relationships that are not directly queryable through the normal MEDLINE schema. Faculty citations are retrieved and World-Wide Web pages built to interconnect authors, their citations, and the MeSH terms that have been assigned to these citations. The design and development of the resource are discussed and examples of the results illustrated.
The potential applications of operative laparoscopy have expanded with improvements in technology and instrumentation. With newly developed techniques to complete both pelvic and paraaortic lymph node dissection, the use of the laparoscope has increased in patients with pelvic malignancies. Gynecologic oncologists are currently incorporating the techniques of operative laparoscopy in the management of patients with cervical, endometrial, and ovarian cancer. Multicenter prospective clinical trials are necessary to further define the role of laparoscopy in gynecologic oncology.
To facilitate networked discovery and information retrieval in the biomedical domain, we have designed a system for automatic assignment of Medical Subject Headings to documents retrieved from the World-Wide Web. Our prototype implementations show significant promise. We describe our methods and discuss the further development of a completely automated indexing tool called the "Web-MeSH Medibot."
Categorization by Reference is a novel text classification technique that examines the existing classifications of the citations found in an as-yet unclassified text to determine what terms should be assigned to that text. The existence of the Medical Subject Headings and MEDLINE make the biomedical domain a prime candidate for application of this technique. We describe our approach and implementation of a prototype, presenting some results of our initial tests. We further discuss refinements that could improve the precision of the technique, and describe its possible use in categorizing portions of the World-Wide Web.
ASOP is a proposed method for future medical record notation. This permutation of the original POMR-SOAP method is necessary to provide the standardized workflow and medical nomenclature which will be essential for automated medical record systems and forms-based encounter recording. The development of an ASOP system is dependent on tools to map assessment to appropriate terminology within a universal medical dictionary and generate intelligent queries across the World-Wide-Web. In this study we intend to demonstrate the need for change in the POMR system and highlight some of the current tools in development to make the ASOP method the medical record notation system of choice.
It is established that duplication in vitro of that amount of Ca2+ (2.5 mM) and Mg2+ (1.5 mM) present in blood permits vegetative growth of Yersinia pestis with repression of virulence factors encoded by the Lcr plasmid (Lcr+); similar simulation of intracellular fluid (no Ca2+ and 20 mM Mg2+) promotes bacteriostasis with induction of these virulence determinants. However, proliferation of yersiniae in mice occurs primarily within necrotic focal lesions (supplied by Ca(2+)-deficient host cell cytoplasm) within visceral organs rather than in Ca(2+)-sufficient blood. The present study addressed this enigma by defining conditions necessary for achieving vegetative growth of Lcr+ yersiniae at 37 degrees C in simulated intracellular fluid. Maximum optical densities were increased by substitution of K+ for Na+ and elimination of Cl-; the combination of Na+ plus L-glutamate was selectively toxic to Lcr+ cells. This phenomenon was attributed in part to the absence of aspartase in Y. pestis (a lesion known to facilitate massive accumulation of L-aspartate via transamination of the oxalacetate pool by L-glutamate). Replacement of L-glutamate by exogenous L-aspartate or alpha-ketoglutarate reversed this toxicity by favoring retention of oxalacetate. Proliferation of Lcr+ cells in a medium containing K+ and L-aspartate but lacking added Ca2+ and Na+ was markedly enhanced by increasing the concentration of fermentable carbohydrate. Accordingly, in the worst-case scenario (i.e., added Na+, Cl-, and L-glutamate), Lcr+ yersiniae underwent restriction of growth after one doubling, and in the best-case scenario (i.e., added K+ and L-aspartate), the organisms completed more than five doublings, thereby achieving full-scale growth. Both of these Ca(2+)-deficient media promoted maximum induction of Mg(2+)-induced V antigen, a virulence factor encoded by the Lcr plasmid.
Over the past 60 years, dose-response patch test studies by various methods have been conducted in an attempt to identify the minimum elicitation threshold (MET) concentration of hexavalent chromium (Cr(VI)) that produces an allergic response in Cr(VI) sensitive subjects. These data are not adequate, however, to provide an accurate estimate of the MET because of the variability in the patch testing techniques and the variability in diagnostic criteria used. Furthermore, the data were not reported in terms of mass of allergen per surface area of skin (mg Cr/cm2-skin), which is necessary for conducting occupational or environmental health risk assessments. Thus the purpose of this study was to determine the MET (mg allergen/cm2) for Cr(VI) and trivalent chromium (Cr(III)) by patch testing techniques. A patch test method that delivers a controlled amount of allergen per surface area of skin was used. A group of 54 Cr(VI) sensitised volunteers were patch tested with serial dilutions of Cr(VI) and Cr(III) to determine the cumulative response rate at several concentrations. The results indicate that the 10% MET for Cr(VI) based on the cumulative response was 0.089 micrograms Cr(VI)/cm2-skin. Only one of the 54 volunteers may have responded to 33 micrograms Cr(III)/cm2-skin, otherwise Cr(III) was unable to produce allergic contact dermatitis in these highly sensitive volunteers. Two supplemental studies were also conducted to assess whether the surface area of the patch and the concentration of Cr(VI) in the patch (related to patch thickness) were likely to influence the results. The data from these studies were used to assess the risk of developing allergic contact dermatitis due to contact with Cr(VI) and Cr(III) in soil. The findings indicated that soil concentrations at least as high as 450 ppm Cr(VI) and 165,000 ppm Cr(III) should not pose an allergic contact dermatitis hazard for at least 99.99% of the people in the community who might be exposed.
Recent research has focused on increasing the power of medical information systems by incorporating time into the database system. A problem with much of this research is that it fails to differentiate between historical time and future time. The concept of bitemporal lifespan presented in this paper overcomes this deficiency. Bitemporal lifespan supports the concepts of valid time and transaction time and allows the integration of past, current, and future information in a unified model. The concept of bitemporal lifespan is presented within the framework of the Extended Entity-Relationship model. This model permits the characterization of temporal properties of entities, relationships, and attributes. Bitemporal constraints are defined that must hold between entities forming "isa" hierarchies and between entities and relationships. Finally, bitemporal extensions are presented for database query languages in order to provide natural high-level operators for bitemporal query expressions.