Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer

Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.

Effect of low-level laser therapy on pain levels in patients with temporomandibular disorders: a systematic review

Temporomandibular disorders (TMD) are characterized by the presence of temporomandibular joint (TMJ) and/or masticatory muscle pain and dysfunction. Low-level laser is presented as an adjuvant therapeutic modality for the treatment of TMD, especially when the presence of inflammatory pain is suspected. Objective: To systematically review studies that investigated the effect of low level laser therapy (LLLT) on the pain levels in individuals with TMD. Material and Methods: The databases Scopus, embase, ebsco and PubMed were reviewed from January/2003 to October/2010 with the following keywords: laser therapy, low-level laser therapy, temporomandibular joint disorders, temporomandibular joint dysfunction syndrome, temporomandibular joint, temporomandibular, facial pain and arthralgia, with the inclusion criteria for intervention studies in humans. exclusion criteria adopted were intervention studies in animals, studies that were not written in english, Spanish or Portuguese, theses, monographs, and abstracts presented in scientific events. Results: After a careful review, 14 studies fit the criteria for inclusion, of which, 12 used a placebo group. As for the protocol for laser application, the energy density used ranged from 0.9 to 105 J/cm², while the power density ranged from 9.8 to 500 mW. The number of sessions varied from 1 to 20 and the frequency of applications ranged from daily for 10 days to 1 time per week for 4 weeks. A reduction in pain levels was reported in 13 studies, with 9 of these occurring only in the experimental group, and 4 studies reporting pain relief for both the experimental group and for the placebo. Conclusion: Most papers showed that LLLT seemed to be effective in reducing pain from TMD. However, the heterogeneity of the standardization regarding the parameters of laser calls for caution in interpretation of these results. Thus, it is necessary to conduct further research in order to obtain a consensus regarding the best application protocol for pain relief in patients with TMD.

Laser therapy and pain-related behavior after injury of the inferior alveolar nerve: possible involvement of neurotrophins

Nerve-related complications have been frequently reported in dental procedures, and a very frequent type of occurrence involves the inferior alveolar nerve (IAN). The nerve injury in humans often results in persistent pain accompanied by allodynia and hyperalgesia. In this investigation, we used an experimental IAN injury in rats, which was induced by a Crile hemostatic clamp, to evaluate the effects of laser therapy on nerve repair. We also studied the nociceptive behavior (von Frey hair test) before and after the injury and the behavioral effects of treatment with laser therapy (emitting a wavelength of 904 nm, output power of 70 Wpk, a spot area of *0.1 cm2, frequency of 9500 Hz, pulse time 60 ns and an energy density of 6 J/cm2). As neurotrophins are essential for the process of nerve regeneration, we used immunoblotting techniques to preliminarily examine the effects of laser therapy on the expression of nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF). The injured animals treated with laser exhibited an improved nociceptive behavior. In irradiated animals, there was an enhanced expression of NGF (53%) and a decreased BDNF expression (40%) after laser therapy. These results indicate that BDNF plays a locally crucial role in pain-related behavior development after IAN injury, increasing after lesions (in parallel to the installation of pain behavior) and decreasing with laser therapy (in parallel to the improvement of pain behavior). On the other hand, NGF probably contributes to the repair of nerve tissue, in addition to improving the pain-related behavior.

Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans

[EN] A universal O2 sensor presumes that compensation for impaired O2 delivery is triggered by low O2 tension, but in humans, comparisons of compensatory responses to altered arterial O2 content (CaO2) or tension (PaO2) have not been reported. To directly compare cardiac output (QTOT) and leg blood flow (LBF) responses to a range of CaO2 and PaO2, seven healthy young men were studied during two-legged knee extension exercise with control hemoglobin concentration ([Hb] = 144.4 +/- 4 g/l) and at least 1 wk later after isovolemic hemodilution ([Hb] = 115 +/- 2 g/l). On each study day, subjects exercised twice at 30 W and on to voluntary exhaustion with an FIO2 of 0.21 or 0.11. The interventions resulted in two conditions with matched CaO2 but markedly different PaO2 (hypoxia and anemia) and two conditions with matched PaO2 and different CaO2 (hypoxia and anemia + hypoxia). PaO2 varied from 46 +/- 3 Torr in hypoxia to 95 +/- 3 Torr (range 37 to >100) in anemia (P < 0.001), yet LBF at exercise was nearly identical. However, as CaO2 dropped from 190 +/- 5 ml/l in control to 132 +/- 2 ml/l in anemia + hypoxia (P < 0.001), QTOT and LBF at 30 W rose to 12.8 +/- 0.8 and 7.2 +/- 0.3 l/min, respectively, values 23 and 47% above control (P < 0.01). Thus regulation of QTOT, LBF, and arterial O2 delivery to contracting intact human skeletal muscle is dependent for signaling primarily on CaO2, not PaO2. This finding suggests that factors related to CaO2 or [Hb] may play an important role in the regulation of blood flow during exercise in humans.

Relationship between pain and anxiety in rats

Clinically, it is well known that neuropathic pain often induces comorbid symptoms such as anxiety. In turn, also anxiety has been associated with a heightened experience of pain. Although, the link between pain and anxiety is well recognized in humans, the neurobiological basis of this relationship remains unclear. Therefore, the aim of the current study was to investigate the influence of neuropathic pain on anxiety and vice versa in rats by assessing not only pain-related behaviour but also by discovering possible key substrates which are responsible for the interrelation of pain and anxiety.rnIn rats with a chronic constriction of the sciatic nerve (CCI model) anxiety-like behaviour was observed. Since anxiety behaviour could be completely abolished after the treatment of the pure analgesic drugs gabapentin and morphine, we concluded that anxiety was caused by the strong persistent pain. Furthermore, we found that the neuropeptides oxytocin and vasopressin were upregulated in the amygdala of CCI rats, and the intra-amygdala treatment of an oxytocin antagonist but not the vasopressin antagonist could reduce anxiety-like behaviour in these animals, while no effect on mechanical hypersensitivity was observed. These data indicate that oxytocin is implicated in the underlying neuronal processes of pain-induced anxiety and helps to elucidate the pathophysiological mechanisms of neuropathic pain. rnTo assess the influence of trait anxiety on pain sensation in rats, we determined mechanical hypersensitivity after sciatic nerve lesion (CCI) in animals selectively bred for high anxiety or low anxiety behaviour. The paw withdrawal thresholds were significantly decreased in high anxiety animals in comparison to low anxiety animals 2 and 3 weeks after surgery. In a second model state anxiety was induced by the sub-chronic injection of the anxiogenic drug pentylentetrazol in naive rats. Pain response to mechanical stimuli was increased after pharmacologically-induced anxiety. These results provided evidence for the influence of both trait and state anxiety on pain sensation. rnThe studies contribute to the elucidation of the relationship between pain and anxiety. We investigated that the neuropathic pain model displays sensory as well as emotional factors of peripheral neuropathy. Changes in expression levels of neuropeptides in the central nervous system due to neuropathic pain may contribute to the pathophysiology of neuropathic pain and its related symptoms in animals which might also be relevant for human scenarios. The results of the current study also confirm that anxiety plays an important role in the perception of pain. rnA better understanding of pain behaviour in animals might improve the preclinical profiling of analgesic drugs during development. The study highlights the potential use of the rat model as a new preclinical tool to further investigate the link between pain and anxiety by determining not only the sensory reflexes after painful stimuli but also the more complex pain-related behaviour such as anxiety.rn

Effects of low-density lipoprotein receptor-related protein 4 and apolipoprotein E isoforms on bone metabolism in vivo

LRP4, member of the LDLR family, is a multifunctional membrane-bound receptor that is expressed in various tissues. The expression of LRP4 by osteoblasts, its novel interaction with Wnt-signaling inhibitors Dkk1 and SOST, and the lower levels of activated beta-catenin in different bone locations described here, adds another player to the long list of established factors that modulate canonical Wnt-signaling in bone. By demonstrating that in addition to Wise, LRP4 is able to interact with two additional important modulators of Wnt- and BMP-signaling, our perspective of the complexity of the integration of BMP and Wnt-signaling pathways on the osteoblast surface has expanded further. Nevertheless the recently described association of both the SOST and LRP4 genes with BMD in humans, together with our findings suggest that LRP4 plays a physiologically important role in the skeletal development and bone metabolism not only in rodents, but in humans as well. The efficiency with which LRP4 binds both SOST and Dkk1, presumably at the osteoblastic surface, LRP4 may act as a sink and competes with LRP5/6 for the binding of these Wnt antagonists, which then are no longer available for suppression of the signal through the LRP5/6 axis. rnApoE, a 299 amino acid glycoprotein, is a crucial regulator in the uptake of triglyceride, phospholipids, cholesteryl esters, and cholesterol into cells. ApoE has been linked to osteoporosis, and such a role is further strengthened by the present of a high bone mass phenotype in ApoE null mice. Until recently, the effects of respective ApoE isoforms E2, E3, and E4, and their impact on bone metabolism, have been unclear. Here we report that respective human ApoE knockin mice display diverse effects on bone metabolism. ApoE2 mice show decreased trabecular bone volume per total volume in femoral bone and lumbar spine in comparison to ApoE3 and E4 animals. In this context, urinary bone resorption marker DPD is increased in these animals, which is accompanied by a low ratio of osteoclastogenesis markers OPG/RANKL. Interestingly, serum bone formation markers ALP and OCN are diminished in ApoE4 mice. In contrast to this finding, ApoE2 mice show the lowest bone formation of all groups in vivo. These findings cannot be explained by the low receptor-affinity of ApoE2 and subsequent decreased uptake of triglyceride-rich lipoproteins by osteoblasts, resulting in elevated levels of undercarboxylated osteocalcin. Thus, other crucial pathways relevant for bone metabolism, e. g. Wnt/beta-catenin-signaling pathways, must be, compared to the ApoE3/4 isoforms, more affected by the ApoE2 isoform.

Implementazione dell'algoritmo filtered back-projection (FBP) per architetture low-power di tipo systems-on-chip

Il presente lavoro di tesi, svolto presso i laboratori dell'X-ray Imaging Group del Dipartimento di Fisica e Astronomia dell'Università di Bologna e all'interno del progetto della V Commissione Scientifica Nazionale dell'INFN, COSA (Computing on SoC Architectures), ha come obiettivo il porting e l’analisi di un codice di ricostruzione tomografica su architetture GPU installate su System-On-Chip low-power, al fine di sviluppare un metodo portatile, economico e relativamente veloce. Dall'analisi computazionale sono state sviluppate tre diverse versioni del porting in CUDA C: nella prima ci si è limitati a trasporre la parte più onerosa del calcolo sulla scheda grafica, nella seconda si sfrutta la velocità del calcolo matriciale propria del coprocessore (facendo coincidere ogni pixel con una singola unità di calcolo parallelo), mentre la terza è un miglioramento della precedente versione ottimizzata ulteriormente. La terza versione è quella definitiva scelta perché è la più performante sia dal punto di vista del tempo di ricostruzione della singola slice sia a livello di risparmio energetico. Il porting sviluppato è stato confrontato con altre due parallelizzazioni in OpenMP ed MPI. Si è studiato quindi, sia su cluster HPC, sia su cluster SoC low-power (utilizzando in particolare la scheda quad-core Tegra K1), l’efficienza di ogni paradigma in funzione della velocità di calcolo e dell’energia impiegata. La soluzione da noi proposta prevede la combinazione del porting in OpenMP e di quello in CUDA C. Tre core CPU vengono riservati per l'esecuzione del codice in OpenMP, il quarto per gestire la GPU usando il porting in CUDA C. Questa doppia parallelizzazione ha la massima efficienza in funzione della potenza e dell’energia, mentre il cluster HPC ha la massima efficienza in velocità di calcolo. Il metodo proposto quindi permetterebbe di sfruttare quasi completamente le potenzialità della CPU e GPU con un costo molto contenuto. Una possibile ottimizzazione futura potrebbe prevedere la ricostruzione di due slice contemporaneamente sulla GPU, raddoppiando circa la velocità totale e sfruttando al meglio l’hardware. Questo studio ha dato risultati molto soddisfacenti, infatti, è possibile con solo tre schede TK1 eguagliare e forse a superare, in seguito, la potenza di calcolo di un server tradizionale con il vantaggio aggiunto di avere un sistema portatile, a basso consumo e costo. Questa ricerca si va a porre nell’ambito del computing come uno tra i primi studi effettivi su architetture SoC low-power e sul loro impiego in ambito scientifico, con risultati molto promettenti.

Comparison of low-strength compression stockings with bandages for the treatment of recalcitrant venous ulcers

OBJECTIVE: To compare the proportion and rate of healing, pain, and quality of life of low-strength medical compression stockings (MCS) with traditional bandages applied for the treatment of recalcitrant venous leg ulcers. METHODS: A single-center, randomized, open-label study was performed with consecutive patients. Sigvaris prototype MCS providing 15 mm Hg-25 mm Hg at the ankle were compared with multi-layer short-stretch bandages. In both groups, pads were placed above incompetent perforating veins in the ulcer area. The initial static pressure between the dressing-covered ulcer and the pad was 29 mm Hg and 49 mm Hg with MCS and bandages, respectively. Dynamic pressure measurements showed no difference. Compression was maintained day and night and changed every week. The primary endpoint was healing within 90 days. Secondary endpoints were healing within 180 days, time to healing, pain (weekly Likert scales), and monthly quality of life (ChronIc Venous Insufficiency Quality of Life [CIVIQ] questionnaire). RESULTS: Of 74 patients screened, 60 fulfilled the selection criteria and 55 completed the study; 28 in the MCS and 27 in the bandage group. Ulcers were recurrent (48%), long lasting (mean, 27 months), and large (mean, 13 cm2). All but one patient had deep venous reflux and/or incompetent perforating veins in addition to trunk varices. Characteristics of patients and ulcers were evenly distributed (exception: more edema in the MCS group; P = .019). Healing within 90 days was observed in 36% with MCS and in 48% with bandages (P = .350). Healing within 180 days was documented in 50% with MCS and in 67% with bandages (P = .210). Time to healing was identical. Pain scored 44 and 46 initially (on a scale in which 100 referred to maximum and 0 to no pain) and decreased within the first week to 20 and 28 in the MCS and bandage groups, respectively (P < .001 vs .010). Quality of life showed no difference between the treatment groups. In both groups, pain at 90 days had decreased by half, independent of completion of healing. Physical, social, and psychic impairment improved significantly in patients with healed ulcers only. CONCLUSION: Our study illustrates the difficulty of bringing large and long-standing venous ulcers to heal. The effect of compression with MCS was not different from that of compression with bandages. Both treatments alleviated pain promptly. Quality of life was improved only in patients whose ulcers had healed.

Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers

The experiment investigated the impact of sleep restriction on pain perception and related evoked potential correlates (laser-evoked potentials, LEPs). Ten healthy subjects with good sleep quality were investigated in the morning twice, once after habitual sleep and once after partial sleep restriction. Additionally, we studied the impact of attentional focussing on pain and LEPs by directing attention to (intensity discrimination) or away from the stimulus (mental arithmetic). Laser stimuli directed to the hand dorsum were rated as 30% more painful after sleep restriction (49+/-7 mm) than after a night of habitual sleep (38+/-7 mm). A significant interaction between attentional focus and sleep condition suggested that attentional focusing was less distinctive under sleep restriction. Intensity discrimination was preserved. In contrast, the amplitude of the early parasylvian N1 of LEPs was significantly smaller after a night of partial sleep restriction (-36%, p<0.05). Likewise, the amplitude of the vertex N2-P2 was significantly reduced (-34%, p<0.01); also attentional modulation of the N2-P2 was reduced. Thus, objective (LEPs) and subjective (pain ratings) parameters of nociceptive processing were differentially modulated by partial sleep restriction. We propose, that sleep reduction leads to an impairment of activation in the ascending pathway (leading to reduced LEPs). In contradistinction, pain perception was boosted, which we attribute to lack of pain control distinct from classical descending inhibition, and thus not affecting the projection pathway. Sleep-restricted subjects exhibit reduced attentional modulation of pain stimuli and may thus have difficulties to readily attend to or disengage from pain.

Ignoring non-specific abdominal pain in emergency department patients may be related to decreased quality of life. A follow up of an underestimated problem

Patients suffering from chronic pain have a high prevalence of depression, resulting in a significant impact on overall quality of life. Our aim was to investigate how long term acute non-specific abdominal pain (NSAP) affected overall physical and mental well-being in patients admitted to our emergency department (ED).