Italian Intersociety Recommendations on pain management in the emergency setting (SIAARTI, SIMEU, SIS 118, AISD, SIARED, SICUT, IRC).

BACKGRAUND: Pain is the primary reason for admission to the Emergency Department (ED). However, the management of pain in this setting is often inadequate because of opiophagia, fear of excessive sedation, and fear of compromising an adequate clinical assessment. METHODS: An intersociety consensus conference was held in 2010 on the assessment and treatment of pain in the emergency setting. This report is the Italian Intersociety recommendations on pain management in the emergency department setting. RESULTS: The list of level A recommendations includes: 1) use of IV acetaminophen for opioid sparing properties and reduction of opioid related adverse events; 2) ketamine-midazolam combination preferred over fentanyl-midazolam fentanyl-propofol in pediatric patients; 3) boluses of ketamine IV (particularly in the population under the age of 2 years and over the age of 13) can lead to impairment of the upper airways, including the onset of laryngospasm, requiring specific expertise and skills for administration; 4) the use of ketamine increases the potential risk of psychomotor agitation, which can happen in up to 30% of adult patients (this peculiar side effect can be significantly reduced by concomitant systemic use of benzodiazepines); 5) for shoulder dislocations and fractures of the upper limbs, the performance of brachial plexus block reduces the time spent in ED compared to sedation; 6) pain relief and the use of opioids in patients with acute abdominal pain do not increase the risk of error in the diagnostic and therapeutic pathway in adults; 7) in newborns, the administration of sucrose reduces behavioural responses to blood sampling from a heel puncture; 8) in newborns, breastfeeding or formula feeding during the procedure reduces the measures of distress; 9) in pediatric patients, non-pharmacological techniques such as distraction, hypnosis and cognitive-behavioural interventions reduce procedural pain caused by the use of needles; 10) in pediatric patients, preventive application of eutectic mixtures of prilocaine and lidocaine allows arterial and venous samples to be taken in optimum conditions; 11) in pediatric patients, the combination of hypnotics (midazolam) and N2O is effective for procedural pain, but may be accompanied by loss of consciousness. CONCLUSION: The diagnostic-therapeutic pathway of pain management in emergency should be implemented, through further interdisciplinary trials, in order to improve the EBM level of specific guidelines.

Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4-benzoquinone that inhibits 5-lipoxygenase.

BACKGROUND AND PURPOSE: 1,4-Benzoquinones are well-known inhibitors of 5-lipoxygenase (5-LOX, the key enzyme in leukotriene biosynthesis), but the molecular mechanisms of 5-LOX inhibition are not completely understood. Here we investigated the molecular mode of action and the pharmacological profile of the novel 1,4-benzoquinone derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id) in vitro and its effectiveness in vivo. EXPERIMENTAL APPROACH: Mechanistic investigations in cell-free assays using 5-LOX and other enzymes associated with eicosanoid biosynthesis were conducted, along with cell-based studies in human leukocytes and whole blood. Molecular docking of RF-Id into the 5-LOX structure was performed to illustrate molecular interference with 5-LOX. The effectiveness of RF-Id in vivo was also evaluated in two murine models of inflammation. KEY RESULTS: RF-Id consistently suppressed 5-LOX product synthesis in human leukocytes and human whole blood. RF-Id also blocked COX-2 activity but did not significantly inhibit COX-1, microsomal PGE2 synthase-1, cytosolic PLA2 or 12- and 15-LOX. Although RF-Id lacked radical scavenging activity, reducing conditions facilitated its inhibitory effect on 5-LOX whereas cell stress impaired its efficacy. The reduced hydroquinone form of RF-Id (RED-RF-Id) was a more potent inhibitor of 5-LOX as it had more bidirectional hydrogen bonds within the 5-LOX substrate binding site. Finally, RF-Id had marked anti-inflammatory effects in mice in vivo. CONCLUSIONS AND IMPLICATIONS: RF-Id represents a novel anti-inflammatory 1,4-benzoquinone that potently suppresses LT biosynthesis by direct inhibition of 5-LOX with effectiveness in vivo. Mechanistically, RF-Id inhibits 5-LOX in a non-redox manner by forming discrete molecular interactions within the active site of 5-LOX.

Natural compounds in anti-leukaemic therapy: a review.

Human leukemia results from multiple mutations that lead to abnormalities in the expressions and functions of genes that maintain the delicate balance between proliferation, differentiation and apoptosis. Continued research on the molecular aspects of leukemia cells has resulted in the developments of several potentially useful therapeutic agents. Discovery of new cellular and/or molecular pathways enabling innate or acquired resistance of cancers to current chemotherapeutics to be overcome is therefore of crucial importance if one wants to efficiently combat those cancers associated with dismal prognoses. In this concern, natural compounds are regarded as new chemical entities for the development of drugs against various pharmacological targets, including cancer, and, above all, leukemia.

Synthesis and cytotoxic activity of new ß-carboline derivatives.

On the basis of harmine and 1-methoxy-canthin-6-one chemical structures, a series of novel 1,4-disubstituted and 1,4,9-trisubstituted ß-carbolines and tetracyclic derivatives were designed and synthesized. Cytotoxic activities of these compounds in vitro were investigated in a human tumor cell line panel. Almost all compounds demonstrated interesting cytotoxic activities in particular against prostate cancer cells PC-3 with IC50 in the low micromolar range. Compound X was found to be the most potent one with IC50 value of 8.0 µM; this suggests further studies with models of prostate cancer.

Differential diagnosis of T2 hyperintense spinal cord lesions: part B.

Hyperintense spinal cord signal on T2-weighted images is seen in a wide-ranging variety of spinal cord processes. Causes including simple MR artefacts, trauma, primary and secondary tumours, radiation myelitis and diastematomyelia were discussed in Part A. The topics discussed in Part B of this two part series include multiple sclerosis, subacute combined degeneration of the spinal cord, cord infarction, arteriovenous shunts, transverse myelitis, neurosarcoidosis, AIDS-associated vacuolar myelopathy, and syringohydromyelia. Characterization of the abnormal areas of T2 signal as well as their appearance on other MR imaging sequences, when combined with clinical context and laboratory investigations, will often allow a unique diagnosis, or at least aid in narrowing the differential diagnosis. A wide range of instructive cases is discussed here, with review of the published reports focusing on pertinent MR features to aid in diagnosis.

Increased detections of leptomeningeal presentations in men with hormone refractory prostate cancer: an effect of improved systemic therapy?

Metastases from prostate cancer occur largely in bone through a haematogenous route. Metastatic spread of prostate cancer to the leptomeninges was rarely seen in the past. However, there has been a recent increase in presentations of leptomeningeal spread from prostate cancer in our institutions. Between 2004 and 2006, four patients were diagnosed with metastatic prostate cancer with leptomeningeal metastases in our centres. All four patients had hormone refractory prostate cancer and had previously had chemotherapy. The median survival of these patients was approximately 15 months from the time of hormone refractoriness. The prognosis of leptomeningeal metastasis secondary to metastatic prostate cancer is poor, ranging from 2 to 7 months as seen in our series. New cases of leptomeningeal metastases seen in our series are hypothesized to be secondary to the use of effective modern systemic treatments. A parallel might be drawn with the increased rate of central nervous system metastases in breast cancer since the introduction of effective cytotoxic treatments and more recently targeted therapies. We suggest the clinicians to be aware of the potential change of natural history and pattern of progression in metastatic prostate cancer.

Dissociative responses to conscious and non-conscious fear impact underlying brain function in post-traumatic stress disorder.

BACKGROUND: Dissociative reactions in post-traumatic stress disorder (PTSD) have been regarded as strategic responses that limit arousal. Neuroimaging studies suggest distinct prefrontal responses in individuals displaying dissociative and hyperarousal responses to threat in PTSD. Increased prefrontal activity may reflect enhanced regulation of limbic arousal networks in dissociation. If dissociation is a higher-order regulatory response to threat, there may be differential responses to conscious and automatic processing of threat stimuli. This study addresses this question by examining the impact of dissociation on fear processing at different levels of awareness. METHOD: Functional magnetic resonance imaging (fMRI) with a 1.5-T scanner was used to examine activation to fearful (versus neutral) facial expressions during consciously attended and non-conscious (using backward masking) conditions in 23 individuals with PTSD. Activation in 11 individuals displaying non-dissociative reactions was compared to activation in 12 displaying dissociative reactions to consciously and non-consciously perceived fear stimuli. RESULTS: Dissociative PTSD was associated with enhanced activation in the ventral prefrontal cortex for conscious fear, and in the bilateral amygdala, insula and left thalamus for non-conscious fear compared to non-dissociative PTSD. Comparatively reduced activation in the dissociative group was apparent in dorsomedial prefrontal regions for conscious fear faces. CONCLUSIONS: These findings confirm our hypotheses of enhanced prefrontal activity to conscious fear and enhanced activity in limbic networks to non-conscious fear in dissociative PTSD. This supports the theory that dissociation is a regulatory strategy invoked to cope with extreme arousal in PTSD, but this strategy appears to function only during conscious processing of threat.

[Mycoplasma pneumoniae is not a respiratory pathogen only: two case reports of ''atypical'' clinical presentations]. / Il Mycoplasma pneumoniae non è solo un patogeno respiratorio: presentazione di due casi con manifestazioni ''atipiche''.

Mycoplasma pneumoniae is a common intracellular pathogen, which is responsible for infections of the respiratory tract, particularly in patients between 5 and 30 years of age. Nevertheless, there is increasing evidence that Mycoplasma pneumoniae plays a role in determining clinical presentations different from the respiratory ones. Among extra pulmonary complications skin eruptions are more frequent than others, even with severe clinical features such as Stevens Johnson syndrome. It is important to note that dermatological involvement can occur before, during or after the appearance of respiratory symptoms or without them. We report two patients whose onset of symptoms was not a respiratory tract disease, as usual in Mycoplasma pneumoniae infections, but prolonged and high grade fever with a relevant skin involvement pointing out the importance of researching Mycoplasma pneumoniae in the pathogenesis of peculiar clinical features. The first patient is a 4-year-old boy with signs of Stevens Johnson syndrome while the second patient is a 16-year-old girl with red-purple maculae on both legs and arms; in both cases we detected Mycoplasma IgM antibodies as a part of differential diagnosis. We discuss below the immunological mechanism by which Mycoplasma pneumoniae can determine the clinical features shown by our patients.

Amygdala and ventral anterior cingulate activation predicts treatment response to cognitive behaviour therapy for post-traumatic stress disorder.

BACKGROUND: Although cognitive behaviour therapy (CBT) is the treatment of choice for post-traumatic stress disorder (PTSD), approximately half of patients do not respond to CBT. No studies have investigated the capacity for neural responses during fear processing to predict treatment response in PTSD. METHOD: Functional magnetic resonance imaging (fMRI) responses of the brain were examined in individuals with PTSD (n=14). fMRI was examined in response to fearful and neutral facial expressions presented rapidly in a backwards masking paradigm adapted for a 1.5 T scanner. Patients then received eight sessions of CBT that comprised education, imaginal and in vivo exposure, and cognitive therapy. Treatment response was assessed 6 months after therapy completion. RESULTS: Seven patients were treatment responders (defined as a reduction of 50% of pretreatment scores) and seven were non-responders. Poor improvement after treatment was associated with greater bilateral amygdala and ventral anterior cingulate activation in response to masked fearful faces. CONCLUSIONS: Excessive fear responses in response to fear-eliciting stimuli may be a key factor in limiting responses to CBT for PTSD. This excessive amygdala response to fear may reflect difficulty in managing anxiety reactions elicited during CBT, and this factor may limit optimal response to therapy.

Differential diagnosis of T2 hyperintense spinal cord lesions: Part A.

Hyperintense spinal cord signal on T2-weighted images is seen in a wide-ranging variety of spinal cord processes including; simple MR artefacts, congenital anomalies and most disease categories. Characterization of the abnormal areas of T2 signal as well as their appearance on other MR imaging sequences, when combined with clinical context and laboratory investigations, will often allow a unique diagnosis, or at least aid in narrowing the differential diagnosis. A wide range of instructive cases is discussed here with review of the published reports focusing on pertinent MR features to aid in diagnosis.

Achilles tendon imaging.

The Achilles tendon is the largest and strongest tendon in the body, yet one of the most commonly injured. Tendon degeneration is a relatively common disorder, predisposing to tears and often associated with paratenonitis. Numerous other diseases involve the Achilles tendon, some with classic imaging appearances, others with non-specific appearances. The aim of this pictorial essay is to review the radiographic, computed tomographic, ultrasonographic and MR appearances of the normal and diseased Achilles tendon.

An unusual clinical and biochemical presentation of ornithine transcarbamylase deficiency in a male patient.

We report a male patient with a history of recurrent idiopathic vomiting, normal plasma ammonia and glutamine concentrations in acute phase, who died at 3 years of age. Ornithine transcarbamylase deficiency was diagnosed after detecting elevated urinary orotate concentrations in a sample collected just before death, and the diagnosis was confirmed by DNA analysis.

A novel mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome detected by neonatal screening for galactosaemia.

A patient affected by Fanconi-Bickel syndrome detected by neonatal screening for galactosaemia is reported. Molecular studies of the GLUT2 gene led to the identification of a novel mutation of the glucose transporter.

Risk factors for fractures of the wrist, shoulder and ankle: the Blue Mountains Eye Study.

Few studies have examined risk factors for fractures of the wrist, shoulder or ankle. The Blue Mountains Eye Study is a population-based longitudinal study in 3654 people aged 49 years or older resident in an area west of Sydney, Australia. Detailed eye examinations and interviews were carried out at baseline (1992-3) and after 5 years (1997-9). Information about fractures sustained during follow-up were collected by a combination of self-report and a search of hospital radiology records. After 4.7 years follow-up subjects had sustained 53 fractures of the distal forearm, 20 fractures of the proximal humerus and 33 ankle fractures. In multivariate models factors independently associated with wrist fractures in women were no vigorous exercise in the past 2 weeks (relative risk RR 0.4, 95% CI 0.2-0.9) and ever use of HRT (RR 0.4, 95% CI 0.1-1.0). Factors independently associated with ankle fractures were male sex (RR 0.3, 95% CI 0.1-0.8) and visual field loss (RR 2.8, 95% CI 1.2-6.6). These findings are in keeping with other studies, and suggest that different types of osteoporotic fracture have different, if overlapping, sets of risk factors.

Arousal dissociates amygdala and hippocampal fear responses: evidence from simultaneous fMRI and skin conductance recording.

The experience and appraisal of threat is essential to human and animal survival. Lesion evidence suggests that the subjective experience of fear relies upon amygdala-medial frontal activity (as well as autonomic arousal), whereas the factual context of threat stimuli depends upon hippocampal-lateral frontal activity. This amygdala-hippocampus dissociation has not previously been demonstrated in vivo. To explore this differentiation, we employed functional magnetic resonance imaging (fMRI) and simultaneous skin conductance response (SCR) measures of phasic arousal, while subjects viewed fearful versus neutral faces. fMRI activity was subaveraged according to whether or not the subject evoked an arousal SCR to each discrete face stimulus. The fMRI-with arousal and fMRI-without arousal data provided a distinct differentiation of amygdala and hippocampal networks. Amygdala-medial frontal activity was observed only with SCRs, whereas hippocampus-lateral frontal activity occurred only in the absence of SCRs. The findings provide direct evidence for a dissociation between human amygdala and hippocampus networks in the visceral experience versus declarative fact processing of fear.

Diabetes and risk of fracture: The Blue Mountains Eye Study.

OBJECTIVE: To examine associations between measures of diabetes and risk of fracture in a population-based sample of older Australians. RESEARCH DESIGN AND METHODS: This was a prospective study of 3,654 subjects aged 49 years and older who were residents in the Blue Mountains, west of Sydney, Australia. At baseline, subjects were asked questions about history and treatment of diabetes, and fasting blood samples were taken. Photographs were taken of the retina and lens to grade retinopathy and cataract. Details of fractures (excluding rib and vertebral fractures) were collected by a combination of self-report and medical record searches; all fractures were radiologically confirmed. RESULTS: After 2 years of follow-up, we found that several diabetes-related factors were significantly associated (in multivariate models) with increased risk of all fractures combined, including presence of diabetic retinopathy (adjusted RR 5.4, 95% CI 2.7-10.8), diabetes duration > or = 10 years (3.3, 1.3-8.2), cortical cataract involving > or = 25% of the lens area (2.5, 1.3-4.7), and insulin treatment (5.9, 2.6-13.5). The proximal humerus was the only individual fracture site associated with diabetes. Diabetic retinopathy (10.3, 2.2-48.0), diabetes duration (for > or = 10 years duration; 11.4, 2.4-54.2), and insulin treatment (18.8, 4.0-88.7) were all associated with proximal humerus fracture. CONCLUSIONS: These data suggest a significantly increased risk of fracture associated with diabetic retinopathy, advanced cortical cataract, longer diabetes duration, and insulin treatment. However, there are some shortcomings in this study that may limit these findings.

Magnetic resonance imaging (MRI) and diseases of the liver and biliary tract. Part 1. Basic principles, MRI in the assessment of diffuse and focal hepatic disease.

Magnetic resonance imaging (MRI) relies on the physical properties of unpaired protons in tissues to generate images. Unpaired protons behave like tiny bar magnets and will align themselves in a magnetic field. Radiofrequency pulses will excite these aligned protons to higher energy states. As they return to their original state, they will release this energy as radio waves. The frequency of the radio waves depends on the local magnetic field and by varying this over a subject, it is possible to build the images we are familiar with. In general, MRI has not been sufficiently sensitive or specific in the assessment of diffuse liver disease for clinical use. However, because of the specific characteristics of fat and iron, it may be useful in the assessment of hepatic steatosis and iron overload. Magnetic resonance imaging is useful in the assessment of focal liver disease, particularly in conjunction with contrast agents. Haemangiomas have a characteristic bright appearance on T2 weighted images because of the slow flowing blood in dilated sinusoids. Focal nodular hyperplasia (FNH) has a homogenous appearance, and enhances early in the arterial phase after gadolinium injection, while the central scar typically enhances late. Hepatic adenomas have a more heterogenous appearance and also enhance in the arterial phase, but less briskly than FNH. Hepatocellular carcinoma is similar to an adenoma, but typically occurs in a cirrhotic liver and has earlier washout of contrast. The appearance of metastases depends on the underlying primary malignancy. Overall, MRI appears more sensitive and specific than computed tomography with contrast for the detection and evaluation of malignant lesions.