Chronic stress induces wide-spread hyperalgesia: The involvement of spinal CCK1 receptors.

Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.

Case series: O-arm navigation assisted by the Wiltse approach improves the accuracy of pedicle screw placement in ankylosing spondylitis combined with thoracolumbar fractures.

Here we assessed the accuracy of O-arm navigation assisted by Wiltse approach to improve based pedicle screw insertion in ankylosing spondylitis combined with thoracolumbar fractures. We then compared it with the freehand pedicle screw insertion technique. The study sample included 32 patients with ankylosing spondylitis combined with thoracolumbar fractures. Pedicle screw reduction and internal fixation was performed under an O-arm navigation system assisted by a Wiltse approach-combined osteotomy ("navigation group," n = 17) and posterior pedicle screw reduction and internal fixation was performed using freehand technique combined osteotomy ("freehand group," n = 15). We then compared the operation time and bleeding volume between the 2 groups. The visual analog scale (VAS) and Oswestry disability index (ODI) were then used to evaluate the clinical efficacy and the kyphosis Cobb angle was used to evaluate the radiological efficacy before operation, 3 days after operation and after the last follow-up. All complications were noted when detected. Finally, classification of screw positions as proposed by Neo et al was used to evaluate the relationship of the position between the screw, the bone cortex, and the incidence of screw penetration. All patients were followed up for 18 to 36 months (i.e., 24.2 ±â€…3.5 months). The operation time and intraoperative bleeding volume of the navigation group were significantly shorter (lower) than those of the freehand group (P < .05). In addition, Both groups showed significantly decreased VAS, ODI, and Cobb angle 3 days after the operation and at the last follow-up when compared to values recorded pre-operation. However, we found no significant difference in VAS, ODI, and Cobb angle between the 2 groups (P > .05). We identified no complications (e.g., infection, VTE/PE, or nerve injury). Moreover, the pedicle screw placement position of the navigation group was better than that of the freehand group (P < .05), and the screw cortical penetration rate was lower than the freehand group (P < .05). During the process of posterior pedicle screw placement, O-arm navigation assisted by the Wiltse approach can significantly reduce operation time, minimize the amount of bleeding volume, and enhance the accuracy of pedicle screw implantation.

PD-1/PD-L1 inhibitor monotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck: a meta-analysis.

PURPOSE: To evaluate the efficacy and safety of programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy compared to the standard of care in the first-line setting for recurrent or metastatic head and neck squamous cell carcinoma. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane Library databases were searched for relevant randomized controlled trials. The clinical outcomes of overall survival, progression-free survival, objective response rates, and grade 3 or higher adverse events were analyzed using Stata SE 15 software with a significance level set to 0.05. RESULTS: We identified four randomized controlled trials (1 nivolumab, 2 pembrolizumab, and 1 durvalumab), including a total of 2474 patients. The results of the meta-analysis showed pooled hazard ratios of overall and progression-free survival for programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy of 0.82 (95% CI: 0.73-0.91, p < 0.001) and 0.96 (95%CI: 0.84-1.07, p < 0.001) and pooled odds ratios of objective response rates and grade 3 or higher adverse events of 1.04 (95%CI: 0.46-2.37; p = 0.926) and 0.28 (95%CI: 0.22-0.35, p < 0.001), respectively. Subgroup analysis showed that inhibitors for both programmed cell death-1 (nivolumab and pembrolizumab) and programmed cell death-ligand 1 (durvalumab) were associated with significantly longer overall survival (HR = 0.80, 95% CI: 0.70-0.90, p < 0.001 and HR = 0.88, 95%CI: 0.70-1.06, p < 0.001, respectively). CONCLUSIONS: Programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy showed more clinical benefit versus the standard of care in patients with recurrent or metastatic head and neck squamous cell carcinoma, with an acceptable safety profile.

Efficacy and safety of weekly versus triweekly cisplatin concurrent with radiotherapy in nasopharyngeal carcinoma: A meta-analysis.

BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is a standard of care for locally advanced nasopharyngeal carcinoma (NPC), and weekly and triweekly cisplatin are both alternative regimens based on the results of squamous cell carcinoma of the head and neck. However, there is a lack of direct evidence on the efficacy and safety of weekly versus triweekly cisplatin concurrent with radiotherapy in NPC alone. This meta-analysis aimed to identify which regimen is more superior between weekly and triweekly cisplatin in patients with NPC treated with concurrent chemoradiotherapy. METHODS: The PubMed, Embase, and Cochrane Library were searched for eligible literatures. Clinical outcome measures including 1-year overall survival (OS), 3-year OS, 5-year OS, 5-year loco-regional failure-free survival, 5-year distant metastasis-free survial and the most common 3 grade or higher acute toxicities (hematological toxicity, mucositis and nausea and vomiting) were analyzed by RevMan 5.4 software; significance level was 0.05. RESULTS: Seven clinical controlled studies with 1795 patients were included in the meta-analysis. There were no significant differences between weekly and triweekly cisplatin in 1-year OS, 3-year OS, 5-year OS, 5-year loco-regional failure-free survival, and 5-year distant metastasis-free survial) (all P > .05). Grade 3 or higher mucositis and nausea and vomiting showed similar between the 2 arms. However, grade 3 or higher hematological toxicity of weekly cisplatin was significantly higher than that of triweekly cisplatin (1.55; 95% CI, 1.22-1.98, P = .0004). CONCLUSIONS: Weekly cisplatin resulted in similar survival benifit as triweekly cisplatin, but with higher hematological toxicity.

The efficacy of N-acetylcysteine plus sodium bicarbonate in the prevention of contrast-induced nephropathy after cardiac catheterization and percutaneous coronary intervention: A meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of combining use of N-acetylcysteine (NAC) and sodium bicarbonate (SOB) in the prevention of contrast-induced nephropathy (CIN) after cardiac catheterization and percutaneous coronary intervention (PCI) is unclear. METHODS: All relevant studies that compared the effect of combining the use of NAC and SOB with individual use on CIN in patients undergoing cardiac catheterization and PCI were identified by searching the databases including Pubmed, Embase, Cochrane Library, and Web of Science without time and language limitation. Only randomized controlled trials (RCTs) with full-text published were considered. RESULTS: Sixteen RCTs involving 4432 cases were included into this meta-analysis. The results showed there were no additional benefit in reduction of CIN in COM group (COM versus NAC: RR 0.85, 95% CI 0.70-1.03, P=0.103; COM versus SOB: RR 0.91, 95% CI 0.71-1.16, P=0.449), even in patients with diabetes mellitus (COM versus NAC: RR 1.11, 95% CI 0.71-1.75, P=0.646; COM versus SOB: RR 1.06, 95% CI 0.45-2.47, P=0.893), undergoing PCI procedure (COM versus NAC: RR0.76, 95% CI 0.39-1.47, P=0.411; COM versus SOB: RR0.96, 95% CI 0.65-1.40, P=0.814), or with baseline renal dysfunction (COM versus NAC: RR 0.89, 95% CI 0.70-1.14, P=0.366; COM versus SOB: RR 0.95, 95% CI 0.67-1.36, P=0.788). CONCLUSIONS: The present study demonstrated combining use of NAC and SOB was not significantly superior to individual use method in the prevention of CIN after cardiac catheterization and PCI.

Overexpression of tomato enhancer of SOS3-1 (LeENH1) in tobacco enhanced salinity tolerance by excluding Na+ from the cytosol.

The salt overly sensitive pathway has an important function in plant salinity tolerance. The enhancer of SOS3-1 (ENH1) participates in a new salinity stress pathway with SOS2 but without SOS3. To investigate the physiological effects and functional mechanism of ENH1 under salt stress, ENH1 was isolated from tomato and overexpressed in tobacco. Under salt stress, the sprouting percentage, fresh weight, and dry weight of transgenic plants were higher than those of wild-type (WT) plants. Under salt stress, the chlorophyll content, net photosynthetic rate, and maximal photochemical efficiency of PSII in transgenic plants decreased more slowly than those in WT plants. The overexpression of LeENH1 in tobacco excluded Na(+) from the cytosol and retained high K(+) levels in the cytosol to reestablish ion homeostasis. Higher thylakoid-bound ascorbate peroxidase activity and lower reactive oxygen species levels were found in transgenic plants under salt stress.

Overexpression and suppression of violaxanthin de-epoxidase affects the sensitivity of photosystem II photoinhibition to high light and chilling stress in transgenic tobacco.

Tobacco (Nicotiana tabacum) transformed with the sense and antisense constructs of tomato (Lycopersicon esculentum) violaxanthin de-epoxidase gene (LeVDE) was obtained under the control of the cauliflower mosaic virus 35S promoter (35S-CaMV). Reverse transcription-polymerase chain reaction and western blot analysis demonstrated that the exogenous gene was integrated into the tobacco genome. Wild type (WT), the sense-transgenic line T(1)-24(+) and the antisense-transgenic line T(1)-17(-) were used for physiological measurement. The ratio of (A+Z)/(V+A+Z) and non-photochemical quenching in WT were lower than that in sense plants and higher than that in antisense ones under high light and chilling stress with low irradiance. The maximal photochemical efficiency of photosystem II (PSII) (Fv/Fm) and the net photosynthetic rate (Pn) in the sense line decreased less, while Fv/Fm and Pn in the antisense line decreased most obviously among all lines. These results suggest that the expression of the violaxanthin de-epoxidase gene in transgenic plants affects the sensitivity of PSII photoinhibition to high light and chilling stress.

Overexpression of sweet pepper glycerol-3-phosphate acyltransferase gene enhanced thermotolerance of photosynthetic apparatus in transgenic tobacco.

In order to investigate the relationship between the lipid composition in thylakoid membrane and thermostability of photosynthetic apparatus, tobacco transformed with sweet pepper sense glycerol-3-phosphate acyltransferase (GPAT) gene were used to analyze the lipid composition in thylakoid membrane, the net photosynthetic rate and chlorophyll fluorescence parameters under high temperature stress. The results showed that the saturated extent of monogalactosyldiacylglycerol (MGDG), sulfoquinovosyldiacylglycerol, digalactosyldiacylglycerol and phosphatidylglycerol in thylakoid membrane of transgenic tobacco T(1) lines increased generally. Particularly, the saturated extent in MGDG increased obviously by 16.2% and 12.0% in T(1)-2 and T(1)-1, respectively. With stress temperature elevating, the maximum efficiency of photosystem II (PSII) photochemistry (Fv/Fm), actual photochemical efficiency of PSII in the light (Phi(PSII)) and net photosynthetic rate (Pn) of the two lines and wild type tobacco plants decreased gradually, but those parameters decreased much less in transgenic plants. Even though the recovery process appeared differently in the donor and acceptor side of PSII in transgenic tobacco compared with wild-type plants, the entire capability of PSII recovered faster in transgenic tobacco, which was shown in the parameters of PI, Fv/Fm and Phi(PSII), as a result, the recovery of Pn was accelerated. Conclusively, we proposed that the increase in saturated extent of thylakoid membrane lipids in transgenic plants enhanced the stability of photosynthetic apparatus under high temperature stress.

The function of chloroplastic NAD(P)H dehydrogenase in tobacco during chilling stress under low irradiance.

The function of chloroplastic NAD(P)H dehydrogenase (NDH) was examined by comparing a tobacco transformant (DeltandhB) in which the ndhB gene had been disrupted with its wild type, upon exposure to chilling temperature (4 degrees C) under low irradiance (100 micro mol m(-2) s(-1) PFD). During the chilling stress, the maximum photochemical efficiency of PSII (F(v)/F(m)) decreased markedly in both the wild type and DeltandhB. However, both F(v)/F(m) and P700(+), as well as the PSII-driven electron transport rate (ETR), in DeltandhB were lower than that in the wild type, implying that NDH-dependent cyclic electron flow around PSI functioned to protect the photosynthetic apparatus from chilling stress under low irradiance. Under the stress, non-photochemical quenching (NPQ), particularly the fast relaxing NPQ component (qf) and the de-epoxidized ratio of the xanthophyll cycle pigments, (A+Z)/(V+A+Z), were distinguishable in DeltandhB from those in the wild type. The lower NPQ in DeltandhB might be related to an inefficient proton gradient across thylakoid membranes (DeltapH) because of lacking an NDH-dependent cyclic electron flow around PSI at chilling temperature under low irradiance.

[Role of recombinant human bone morphogenetic protein 2/collagen as an onlay bone graft on adult rat calvarial bone].

OBJECTIVE: To evaluate the bone regenerative potential of recombinant human bone morphogenetic protein 2(rhBMP-2)/collagen on adult rat calvarial bone. METHODS: A tight subperiosteal pocket was produced under both sides of the temporal muscle in rats. rhBMP-2/collagen was implanted in one side and collagen alone was implanted in the other side as control. The rats were sacrificed 2, 4 and 8 weeks after operation. The specimen was harvested and examined histologically. For morphometric analysis, the thickness of the temporal bone of both sides was measured and compared. RESULTS: The rhBMP-2/collagen onlay implant resulted in active bone formation and the augmented bone was connected directly with the original bone, whereas the collagen alone resulted in neither bone nor cartilage production. The ossification process in the rhBMP-2/collagen occurred directly through bone formation, similar to intramembranous ossification. CONCLUSION: rhBMP-2/collagen is an effective material as a biological onlay implant.