Abstract Cancer is a global problem that accounts for almost 13% of deaths worldwide, a number similar to the 7 million deaths each year from HIV/AIDS, TB and malaria combined According to Globocan ...it is estimated that by 2020, there will be between 15 and 17 million new cases of cancer every year, 60% of which will be in developing countries. Moreover, the survival rates in these regions are often half those of developed countries. However, cancer is potentially the most preventable disease; with current resources, one-third of tumors could be preventable, and another one-third of newly diagnosed cancer patients could experience increased survival or early-stage detection. There have been proposed several strategies and programs to ameliorate cancer prevention and treatment in less developed countries. If all these proposed strategies are taken into consideration, worldwide cancer care, control and survival in low-income countries may improve in the years to come.
We evaluated treatment outcomes in a prospective registry of human immunodeficiency virus/hepatitis C virus (HCV)–coinfected patients treated with interferon‐free direct‐acting antiviral agent–based ...therapy in hospitals from the region of Madrid between November 2014 and August 2016. We assessed sustained viral response at 12 weeks after completion of treatment and used multivariable logistic regression to identify predictors of treatment failure. We evaluated 2,369 patients, of whom 59.5% did not have cirrhosis, 33.9% had compensated cirrhosis, and 6.6% had decompensated cirrhosis. The predominant HCV genotypes were 1a (40.9%), 4 (22.4%), 1b (15.1%), and 3 (15.0%). Treatment regimens included sofosbuvir (SOF)/ledipasvir (61.9%), SOF plus daclatasvir (14.6%), dasabuvir plus ombitasvir/paritaprevir/ritonavir (13.2%), and other regimens (10.3%). Ribavirin was used in 30.6% of patients. Less than 1% of patients discontinued therapy owing to adverse events. The frequency of sustained viral response by intention‐to‐treat analysis was 92.0% (95% confidence interval, 90.9%‐93.1%) overall, 93.8% (92.4%‐95.0%) for no cirrhosis, 91.0% (88.8%‐92.9%) for compensated cirrhosis, and 80.8% (73.7%‐86.6%) for decompensated cirrhosis. The factors associated with treatment failure were male sex (adjusted odds ratio, 1.75; 95% confidence interval, 1.14‐2.69), Centers for Diseases Control and Prevention category C (adjusted odds ratio, 1.65; 95% confidence interval, 1.12‐2.41), a baseline cluster of differentiation 4–positive (CD4+) T‐cell count <200/mm3 (adjusted odds ratio, 2.30; 95% confidence interval, 1.35‐3.92), an HCV RNA load ≥800,000 IU/mL (adjusted odds ratio, 1.63; 95% confidence interval, 1.14‐2.36), compensated cirrhosis (adjusted odds ratio, 1.35; 95% confidence interval, 0.96‐1.89), decompensated cirrhosis (adjusted odds ratio, 2.92; 95% confidence interval, 1.76‐4.87), and the use of SOF plus simeprevir, SOF plus ribavirin, and simeprevir plus daclatasvir. Conclusion: In this large real‐world study, direct‐acting antiviral agent–based therapy was safe and highly effective in coinfected patients; predictors of failure included gender, human immunodeficiency virus–related immunosuppression, HCV RNA load, severity of liver disease, and the use of suboptimal direct‐acting antiviral agent–based regimens. (Hepatology 2018;68:32‐47).
The mechanisms underlying neuropathic facial pain syndromes are incompletely understood. We used a unilateral chronic constriction injury of the rat infraorbital nerve (CCI‐IoN) as a facial ...neuropathic model. Pain‐related behavior of the CCI‐IoN animals was tested at 8, 15 and 26 days after surgery (dps). The response threshold to mechanical stimulation with von Frey hairs on the injured side was reduced at 15 and 26 dps, indicating the presence of allodynia. We performed unitary recordings in the caudalis division of the spinal trigeminal nucleus (Sp5C) at 8 or 26 dps, and examined spontaneous activity and responses to mechanical and thermal stimulation of the vibrissal pad. Neurons were identified as wide dynamic range (WDR) or low‐threshold mechanoreceptive (LTM) according to their response to tactile and/or noxious stimulation. Following CCI‐IoN, WDR neurons, but not LTM neurons, increased their spontaneous activity at 8 and 26 dps, and both types of Sp5C neurons increased their responses to tactile stimuli. In addition, the on–off tactile response in neurons recorded after CCI‐IoN was followed by afterdischarges that were not observed in control cases. Compared with controls, the response inhibition observed during paired‐pulse stimulation was reduced after CCI‐IoN. Immunohistochemical studies showed an overall decrease in GAD65 immunoreactivity in Sp5C at 26 dps, most marked in laminae I and II, suggesting that following CCI‐IoN the inhibitory circuits in the sensory trigeminal nuclei are depressed. Consequently, our results strongly suggest that disinhibition of Sp5C neurons plays a relevant role in the appearance of allodynia after CCI‐IoN.
Summary Objective To explore clinical features of invasive pulmonary aspergillosis (IPA) vs. colonization among hospitalized COPD patients. Methods Records of COPD patients with two respiratory ...cultures yielding Aspergillus were retrospectively reviewed. Cases categorized as proven/probable IPA or colonization was analyzed. Results 118 patients were identified: 70 (59.3%) colonized, 48 (40.7%) with IPA (42 probable, 6 proven). Higher percentage of IPA patients (vs. colonized) presented GOLD III + IV (77.1% vs. 57.1%, p = 0.025). IPA patients presented higher Charlson index (3.5 ± 2.5 vs. 2.6 ± 2.2, p = 0.027), higher rate of ICU admission (27.1% vs. 4.3%, p = 0.001) and worse prognosis (McCabe rapidly fatal category: 31.3% vs. 7.1%, p = 0.001). GOLD-I IPA patients presented risk factors other than COPD. Before hospitalization, 66.7% IPA and 28.6% colonized patients were taking steroids ( p < 0.001). Antifungals were administered to 83.3% IPA and 21.4% colonized patients ( p < 0.001). Mortality was higher among IPA vs. colonized patients, both in global (58.3% vs. 10.0%, p < 0.001), GOLD-I (75.0% vs. 10.0%, p = 0.041), GOLD-II (42.9% vs. 5.0%, p = 0.042) and GOLD-III patients (54.2% vs. 0.0%, p < 0.001), but not in GOLD-IV patients (69.2% vs. 31.3%, p = 0.066). Conclusions IPA should be suspected not only in GOLD-III and GOLD-IV COPD patients, with higher mortality in IPA vs. colonized patients for GOLD-II and -III COPD patients.
The sensory information flow at subcortical relay stations is controlled by the action of topographic connections from the neocortex. To determinate the functional properties of the somatosensory ...corticofugal projections to the principal (Pr5) and caudal spinal (Sp5C) trigeminal nuclei, we performed unitary recordings in anesthetized rats. To examine the effect of these cortical projections we used tactile stimulation of the whisker and electrical stimulation of somatosensory cortices. Corticofugal anatomical projections to Pr5 and Sp5C nuclei were detected by using retrograde fluorescent tracers. Neurons projecting exclusively to Pr5 were located in the cingulate cortex while neurons projecting to both Sp5C and Pr5 nuclei were located in the somatosensory and insular cortices (>75% of neurons). Physiological results indicated that primary somatosensory cortex produced a short-lasting facilitating or inhibiting effects (<5 min) of tactile responses in Pr5 nucleus through activation of NMDA glutamatergic or GABAA receptors since effects were blocked by iontophoretically application of APV and bicuculline, respectively. In contrast, stimulation of secondary somatosensory cortex did not affect most of the Pr5 neurons; however both cortices inhibited the nociceptive responses in the Sp5C nucleus through activation of glycinergic or GABAA receptors because effects were blocked by iontophoretically application of strychnine and bicuculline, respectively. These and anatomical results demonstrated that the somatosensory cortices projects to Pr5 nucleus to modulate tactile responses by excitatory and inhibitory actions, while projections to the Sp5C nucleus control nociceptive sensory transmission by only inhibitory effects. Thus, somatosensory cortices may modulate innocuous and noxious inputs simultaneously, contributing to the perception of specifically tactile or painful sensations.
Since calbindin-D
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(CB-D
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)-positive neurons have been related to nociceptive sensory processing, we have hypothesized that altered CB-D
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expression could alter nociceptive transmission. We ...have used +/+ and −/− knockout (KO) mice for CB-D
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in different behavioral models of pain and sensory responses at the caudalis subdivision of the trigeminal spinal nucleus in order to understand how this protein may participate in nociception. Behavioral responses to formalin injection in the hind paw or at the whisker pad or in the hind paw glutamate or i.p. acetic acid tests showed an increase of the pain threshold in CB-D
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−/− mice. KO mice showed a diminution of the inhibitory activity at Sp5C nucleus and a marked reduction of GABA content. Sp5C neurons from CB-D
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−/− mice did not change their spontaneous activity or tactile response after formalin injection in the whisker pad. In contrast, Sp5C neurons increased their spontaneous firing rate and tactile response after formalin injection in their receptive field in CB-D
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+/+ mice. The results of this study demonstrate the active role played by CB-D
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in nociceptive sensory transmission. The lack of this calcium binding protein, associated to deficient GABAergic neurotransmission, translates into dysfunction of sensory processing of nociceptive stimuli.
Isolation of Aspergillus from lower respiratory samples is associated with colonisation in high percentage of cases, making it of unclear significance. This study explored factors associated with ...diagnosis (infection vs. colonisation), treatment (administration or not of antifungals) and prognosis (mortality) in non-transplant/non-neutropenic patients showing repeated isolation of Aspergillus from lower respiratory samples.
Records of adult patients (29 Spanish hospitals) presenting ≥ 2 respiratory cultures yielding Aspergillus were retrospectively reviewed and categorised as proven (histopathological confirmation) or probable aspergillosis (new respiratory signs/symptoms with suggestive chest imaging) or colonisation (symptoms not attributable to Aspergillus without dyspnoea exacerbation, bronchospasm or new infiltrates). Logistic regression models (step-wise) were performed using Aspergillosis (probable + proven), antifungal treatment and mortality as dependent variables. Significant (p < 0.001) models showing the highest R2 were considered.
A total of 245 patients were identified, 139 (56.7%) with Aspergillosis. Aspergillosis was associated (R2 = 0.291) with ICU admission (OR = 2.82), congestive heart failure (OR = 2.39) and steroids pre-admission (OR = 2.19) as well as with cavitations in X-ray/CT scan (OR = 10.68), radiological worsening (OR = 5.22) and COPD exacerbations/need for O2 interaction (OR = 3.52). Antifungals were administered to 79.1% patients with Aspergillosis (100% proven, 76.8% probable) and 29.2% colonised, with 69.5% patients receiving voriconazole alone or in combination. In colonised patients, administration of antifungals was associated with ICU admission at hospitalisation (OR = 12.38). In Aspergillosis patients its administration was positively associated (R(2) = 0.312) with bronchospasm (OR = 9.21) and days in ICU (OR = 1.82) and negatively with Gold III + IV (OR = 0.26), stroke (OR = 0.024) and quinolone treatment (OR = 0.29). Mortality was 78.6% in proven, 41.6% in probable and 12.3% in colonised patients, and was positively associated in Aspergillosis patients (R2 = 0.290) with radiological worsening (OR = 3.04), APACHE-II (OR = 1.09) and number of antibiotics for treatment (OR = 1.51) and negatively with species other than A. fumigatus (OR = 0.14) and aspergillar tracheobronchitis (OR = 0.27).
Administration of antifungals was not always closely linked to the diagnostic categorisation (colonisation vs. Aspergillosis), being negatively associated with severe COPD (GOLD III + IV) and concomitant treatment with quinolones in patients with Aspergillosis, probably due to the similarity of signs/symptoms between this entity and pulmonary bacterial infections.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Corticofugal influences from the primary somatosensory cortex to the gracilis nuclei were studied with single unit recordings performed in urethane‐anaesthetized rats. Two types of neurons were ...identified: low firing rate (LF) neurons, which could be activated antidromically by medial lemniscus stimulation; and high firing rate (HF) neurons. The effects of electrically stimulating the contralateral primary somatosensory cortex were studied in two situations: when the stimulated cortical area and specific gracilis cells had overlapping receptive fields and when the receptive fields of the cells and primary somatosensory cortex did not overlap. Cortical stimulation facilitated cortical and tactile responses in most gracilis neurons (68% and 58% for LF and HF neurons, respectively) with overlapping receptive fields. When receptive fields were different, cortical stimulation inhibited tactile response in most LF neurons (58%) and some HF neurons (20%). Trains of cortical shocks during sensory stimulation demonstrated that the facilitatory and inhibitory effects outlasted the stimulation period by 5 min. The facilitatory effect was decreased by iontophoretic application of the N‐methyl‐D‐aspartate (NMDA) receptor antagonist APV (50 mm). However, APV did not modify the intensity of the tactile response inhibition in cells with nonoverlapping receptive fields, although, its duration was decreased (<5 min). Iontophoretic application of the γ‐aminobutyric acid (GABA)A antagonist bicuculline (20 mm) blocked the cortically evoked inhibition in cells with nonoverlapping receptive fields. The results indicate that the somatosensory cortex precisely controls somatosensory transmission throughout the gracilis nucleus by means of NMDA and GABAA receptor activation.
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