Pharmacological management of neuropathic pain following spinal cord injury

Spinal cord injury (SCI) has a number of severe and disabling consequences, including chronic pain, and around 40% of patients develop persistent neuropathic pain. Pain following SCI has a detrimental impact on the patient's quality of life and is a major specific healthcare problem in its own right. Thus far, there is no cure for the pain and oral pharmaceutical intervention is often inadequate, commonly resulting in a reduction of only 20-30% in pain intensity. Neuropathic pain sensations are characterized by spontaneous persistent pain and a range of abnormally evoked responses, e.g. allodynia (pain evoked by normally non-noxious stimuli) and hyperalgesia (an increased response to noxious stimuli). Neuropathic pain following SCI may be present at or below the level of injury. Oral pharmacological agents used in the treatment of neuropathic pain act either by depressing neuronal activity, by blocking sodium channels or inhibiting calcium channels, by increasing inhibition via GABA agonists, by serotonergic and noradrenergic reuptake inhibition, or by decreasing activation via glutamate receptor inhibition, especially by blocking the NMDA receptor. At present, only ten randomized, double-blind, controlled trials have been performed on oral drug treatment of pain after SCI, the results of most of which were negative. The studies included antidepressants (amitriptyline and trazodone), antiepileptics (gabapentin, pregabalin, lamotrigine and valproate) and mexiletine. Gabapentin, pregabalin and amitriptyline showed a significant reduction in neuropathic pain following SCI. Cannabinoids have been found to relieve other types of central pain, and serotonin noradrenaline reuptake inhibitors as well as opioids relieve peripheral neuropathic pain and may be used to treat patients with SCI pain.     

BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study

Germline BRCA1/2 testing of breast and ovarian cancer patients is growing rapidly as the result affects both treatment and cancer prevention in patients and relatives. Through the DNA-BONus study we offered BRCA1/2 testing and familial risk assessment to all new patients with breast (N=893) or ovarian (N=122) cancer diagnosed between September 2012 and April 2015, irrespective of family history or age, and without prior face-to-face genetic counselling. BRCA1/2 testing was accepted by 405 (45.4%) and 83 (68.0%) of the patients with breast or ovarian cancer, respectively. A pathogenic BRCA1/2 variant was found in 7 (1.7%) of the breast cancer patients and 19 (22.3%) of the ovarian cancer patients. In retrospect, all BRCA1/2 mutation carriers appeared to fulfill current criteria for BRCA1/2 testing. Hospital Anxiety and Depression Scale (HADS) scores showed that the mean levels of anxiety and depression were comparable to those reported for breast and gynecological cancer patients in general, with a significant drop in anxiety symptoms during a 6-month follow-up period, during which the test result was forwarded to the patients. These results show that BRCA1/2 testing is well accepted in newly diagnosed breast and ovarian cancer patients. Current test criteria based on age and family history are sufficient to identify most BRCA1/2 mutation carriers among breast cancer patients. We recommend germline BRCA1/2 testing in all patients with epithelial ovarian cancer because of the high prevalence of pathogenic BRCA1/2 variants.     

Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO‐AML study

Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO‐AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0–18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO‐AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non‐trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3‐ITD mutations (58%). The 5‐year event‐free survival for patients with +8 alone was 50% and 5‐year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3‐ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3‐ITD in +8 alone. © 2016 Wiley Periodicals, Inc.     

Congenital anomalies of the upper gastrointestinal tract.

A wide spectrum of congenital anomalies may affect the upper gastrointestinal tract, including anomalies of the esophagus (e.g., atresia, fistulas, webs, duplications, vascular rings), stomach (e.g., congenital gastric outlet obstruction, duplications), and duodenum (e.g., atresia, annular pancreas, duplications, malrotation). The evaluation of affected patients can require multiple imaging modalities for diagnosis and surgical planning. Radiography is often diagnostic and specific and can usually provide important clues to help determine the optimal diagnostic procedure. Neonates with complete gastric or upper intestinal obstruction do not usually require further radiologic evaluation after radiography: Barium studies are usually contraindicated, and complementary procedures (e.g., ultrasound [US], computed tomography [CT]) are not usually helpful and may even delay surgery, resulting in death. Nevertheless, US has become important in the evaluation of the pediatric gastrointestinal tract and is being used in an increasing number of applications. CT and magnetic resonance imaging are unsuitable for general screening but provide superb anatomic detail and added diagnostic specificity. They are especially useful in demonstrating esophageal duplications and vascular rings as well as associated abnormalities. However, the decision to perform a given imaging examination should be considered carefully to avoid inconvenience or unnecessary radiation exposure to the patient or delays in surgical correction. Quality control programs should be in place to ensure safe, effective radiologic practice through use of up-to-date equipment and good imaging technique.     

Modulation of the Gene Network Connected to Interferon-γ in Liver Regeneration from Oval Cells

Suppression subtractive hybridization was used to clone genes associated with proliferation of oval cells in rat liver regenerating after a 70% partial hepatectomy combined with the feeding of 2-acetylaminofluorene. A subset of the identified genes comprised interferon-gamma receptor alpha subunit (IFN-gammaRalpha), gp91phox, interleukin-1beta (IL-1beta), lymphocyte function-associated molecule-1alpha (LFA-1), eukaryotic initiation factor-2-associated 67-kd protein (eIF-2-associated 67-kd protein), and alpha-fetoprotein, which constitute part of the cellular program modulated by IFN-gamma. Therefore, expression analysis performed by Northern blotting and immunohistochemistry were extended to include IFN-gamma, the IFN-gamma receptor beta subunit (IFN-gammaRbeta), three secondary response genes induced by interaction of IFN-gamma with IFN-gamma receptor complexes, ie, IL-1beta-converting enzyme (ICE), intercellular adhesion molecule-1 (ICAM-1), and urokinase-type plasminogen activator receptor (uPAR), and a cytokine inducing IFN-gamma expression, ie, interleukin-18 (IL-18). The Northern blot analysis showed that all examined genes were modulated when progenitor-like oval cells were activated and recruited for liver regeneration. Immunohistochemistry localized the subunits of the IFN-gamma receptor complex, IFN-gammaRalpha and IFN-gammaRbeta, the secondary response genes uPAR and ICAM-1, the IFN-gamma-inducing factor IL-18, and ICE to the ductular structures of oval cells. In contrast, during liver regeneration after a 70% partial hepatectomy, only modulation of IL-1beta and ICE was observed. Our results, therefore, indicate that IFN-gamma-mediated events may be particularly important when cells in the bile ductules must respond to liver damage by production of ductular oval cells.     

Biodistribution of liposomal I-VIP in rat using gamma camera

Vasoactive intestinal peptide (VIP), a 28 amino-acid peptide was labeled with ¹³¹I and encapsulated into liposomes. ¹³¹I-VIP or liposomal ¹³¹I -VIP was administered intravenously into the rats. The distribution was studied by a gamma camera and established by counting the radioactivity in the removed organs. The elimination half-life for the liposomal ¹³¹I-VIP in both blood and lungs was significantly longer (5.29 and 9.28 min, respectively) than that obtained after the administration of ¹³¹I-VIP (0.62 and 3.18 min, respectively). Dynamic scans using a gamma camera after the administration of liposomal ¹³¹I-VIP showed a higher uptake of the liposomal form into the lungs compared with ¹³¹I-VIP. The lack of VIP in asthmatics has been shown in previous studies. However, the clinical investigations using VIP were disappointing most probably due to the rapid degradation of the peptide in the bronchial tract. This in fact is supported by our previous study, in which we demonstrated that VIP had a half-life of 0.45 min in blood. We conclude that the encapsulation of VIP in liposomes prolongs its elimination half-life in plasma and enhances its uptake in lungs. This observation may increase the clinical use of VIP in both diagnostic and therapy.     

A novel phantom design for emission tomography enabling scatter- and attenuation-”free” single-photon emission tomography imaging

A newly designed technique for experimental single-photon emission tomography (SPET) and positron emission tomography (PET) data acquisition with minor disturbing effects from scatter and attenuation has been developed. In principle, the method is based on discrete sampling of the radioactivity distribution in 3D objects by means of equidistant 2D planes. The starting point is a set of digitised 2D sections representing the radioactivity distribution of the 3D object. Having a radioactivity-related grey scale, the 2D images are printed on paper sheets using radioactive ink. The radioactive sheets can be shaped to the outline of the object and stacked into a 3D structure with air or some arbitrary dense material in between. For this work, equidistantly spaced transverse images of a uniform cylindrical phantom and of the digitised Hoffman rCBF phantom were selected and printed out on paper sheets. The uniform radioactivity sheets were imaged on the surface of a low-energy ultra-high-resolution collimator (4 mm full-width at half-maximum) of a three-headed SPET camera. The reproducibility was 0.7% and the uniformity was 1.2%. Each rCBF sheet, containing between 8.3 and 80 MBq of ^99mTcO₄ ^– depending on size, was first imaged on the collimator and then stacked into a 3D structure with constant 12 mm air spacing between the slices. SPET was performed with the sheets perpendicular to the central axis of the camera. The total weight of the stacked rCBF phantom in air was 63 g, giving a scatter contribution comparable to that of a point source in air. The overall attenuation losses were <20%. A second SPET study was performed with 12-mm polystyrene plates in between the radioactive sheets. With polystyrene plates, the total phantom weight was 2300 g, giving a scatter and attenuation magnitude similar to that of a patient study. With the proposed technique, it is possible to obtain ”ideal” experimental images (essentially built up by primary photons) for comparison with ”real” images degraded by photon scattering and attenuation losses. The method can serve as a tool for experimental validation and intercomparison of attenuation and scatter correction methods. Moreover, the large flexibility of this phantom design will allow investigations of arbitrary activity distributions and autoradiography or other imaging techniques such as PET, x-ray computed tomography or magnetic resonance imaging. Received 8 August and in revised form 21 September 1999     

Population cost-effectiveness of the Triple P parenting programme for the treatment of conduct disorder: an economic modelling study

Parenting programmes are the recommended treatments of conduct disorders (CD) in children, but little is known about their longer term cost-effectiveness. This study aimed to evaluate the population cost-effectiveness of one of the most researched evidence-based parenting programmes, the Triple P—Positive Parenting Programme, delivered in a group and individual format, for the treatment of CD in children. A population-based multiple cohort decision analytic model was developed to estimate the cost per disability-adjusted life year (DALY) averted of Triple P compared with a ‘no intervention’ scenario, using a health sector perspective. The model targeted a cohort of 5–9-year-old children with CD in Australia currently seeking treatment, and followed them until they reached adulthood (i.e., 18 years). Multivariate probabilistic and univariate sensitivity analyses were conducted to incorporate uncertainty in the model parameters. Triple P was cost-effective compared to no intervention at a threshold of AU$50,000 per DALY averted when delivered in a group format [incremental cost-effectiveness ratio (ICER) = $1013 per DALY averted; 95% uncertainty interval (UI) 471–1956] and in an individual format (ICER = $20,498 per DALY averted; 95% UI 11,146–39,470). Evidence-based parenting programmes, such as the Triple P, for the treatment of CD among children appear to represent good value for money, when delivered in a group or an individual face-to-face format, with the group format being the most cost-effective option. The current model can be used for economic evaluations of other interventions targeting CD and in other settings.