Quality of life after total mesorectal excision for rectal cancer

BACKGROUND: After total mesorectal excision for rectal cancer, many surgeons try to avoid an abdominoperineal resection (APR) by performing a transanally double stapled low colo-rectal anastomosis (LRA), frequently without a pouch. This policy is mainly based on the assumption that the quality of life after such LRA is higher than after APR. It has been suggested that a better functional outcome and therefore a higher quality of life might be achieved by a colo-anal J-pouch anastomosis (CPA). The aim of this study was to assess quality of life among disease-free survivors after APR, LRA and CPA. METHODS: The charts of 301 consecutive patients who had undergone surgery for cancer in the middle or lower third of the rectum were analysed. Two hundred four patients were eligible for inclusion. The quality of life among these patients was assessed using one generic (EQ-5D) and two disease-specific questionnaires (EORTC QLQ-C30 and EORTC QLQ-CR38). RESULTS: The response rate was 82%. The median follow-up was 31 months. Overall, quality of life was good but CPA patients had better quality of life scores than APR and LRA patients. This difference was not only due to the better functional outcome but also to the lower incidence of disturbed micturition and sexual problems in the CPA group. CONCLUSION: The quality of life after colo-anal J-pouch anastomosis is better than after abdominoperineal resection (APR) and low colo-rectal anastomosis (LRA). The quality of life after APR is similar to that after LRA.     

Inhibition of N-, P/Q- and other types of Ca channels in rat hippocampal nerve terminals by the adenosine A1 receptor

The effects of the adenosine A₁ receptor agonist, N⁶-cyclopentyladenosine (CPA), on both the increase in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) and on the release of endogenous glutamate in rat hippocampal synaptosomes were studied. The inhibitory effect of CPA on the increase in [Ca²⁺]_i stimulated with 4-aminopyridine was neutralized by the adenosine A₁ receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). The inhibitory effect of CPA was greater in synaptosomes from the CA1 subregion than in whole hippocampal synaptosomes. The inhibitory effects of both CPA and of the Ca²⁺ channel blockers, ω-conotoxin GVIA, ω-conotoxin MVIIC or ω-conotoxin GVIA plus ω-conotoxin MVIIC, were greater than those caused by the Ca²⁺ channel blockers. The release of endogenous glutamate was inhibited by 41% by CPA. The inhibition observed when CPA and ω-conotoxin GVIA or CPA and ω-conotoxin MVIIC were present was also greater than the inhibition by the Ca²⁺ channel blockers alone. The presence of both ω-conotoxin GVIA and ω-conotoxin MVIIC did not completely inhibit the release of glutamate, and CPA significantly enhanced this inhibition. The membrane potential and the accumulation of [

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]tetraphenylphosphonium of polarized or depolarized synaptosomes was not affected by CPA, suggesting that adenosine did not increase potassium conductances. The present results suggest that, in hippocampal glutamatergic nerve terminals, adenosine A₁ receptor activation partly inhibits P/Q- and other non-identified types of Ca²⁺ channels.     

Structural difference between the two forms of guinea-pig beta 2-microglobulin and their occurrence in inbred guinea-pig strains

The structural difference between two forms (basic and acidic) of guinea-pig beta 2-microglobulin (beta 2m) has been established. Both forms are present in urine from inbred guinea-pig strains. The beta 2m forms were each digested with carboxypeptidase Y and carboxypeptidase A contaminated with carboxypeptidase B. Released amino acids were separated from remaining protein, dansylated and analysed by 2-dimensional TLC on polyamide layer sheets. From the results it was concluded that the basic beta 2m form has lysine and the acidic beta 2m form has asparagine as their respective C-terminal amino acids. The acidic form is also 1 amino acid (lysine) shorter than the basic form, which is supported by electrophoretic studies on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The presence of the 2 forms of beta 2m in urine from inbred guinea-pig strains 2 and 13, shown by gel filtration and ion exchange chromatography, makes it unlikely that the 2 forms are a result of genetic polymorphism.     

固相萃取HPLC法测定豆芽中4-氯苯氧乙酸钠

目的:建立固相萃取HPLC法测定豆芽中4-氯苯氧乙酸钠残留的检测方法。方法:豆芽样品经稀碱提取后,用50%的H3PO4溶液调至酸性,经OasisR○HLB柱富集,甲醇洗脱。以甲醇+0.01 mol/L磷酸盐缓冲液(40+60)为流动相,采用ZORBAX SB C18柱(250 mm×4.6 mm×5μm)分离,UV 228 nm检测,外标法定量。结果:豆芽中4-氯苯氧乙酸钠的线性范围在0.20~6.0 mg/L,回收率在92.0%~95.0%,RSD均小于6%,最低定量检出限为0.04 mg/kg。结论:该方法具有快速、灵敏、简便、准确等优点,能满足实际工作的需要。     

Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide

Glioblastoma (GBM) causes poor survival in patients even when applying aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment, but resistance always ensues. In previous years, efforts have focused on new therapeutic regimens with conventional drugs to activate immune responses that may enhance tumor regression and prevent regrowth, for example the “metronomic” approaches. In metronomic scheduling studies, cyclophosphamide (CPA) in GL261 GBM growing subcutaneously in C57BL/6 mice was shown not only to activate antitumor CD8⁺ T‐cell response, but also to induce long‐term specific T‐cell tumor memory. Accordingly, we have evaluated whether metronomic CPA or TMZ administration could increase survival in orthotopic GL261 in C57BL/6 mice, an immunocompetent model. Longitudinal in vivo studies with CPA (140 mg/kg) or TMZ (range 140–240 mg/kg) metronomic administration (every 6 days) were performed in tumor‐bearing mice. Tumor evolution was monitored at 7 T with MRI (T₂‐weighted, diffusion‐weighted imaging) and MRSI‐based nosological images of response to therapy. Obtained results demonstrated that both treatments resulted in increased survival (38.6 ± 21.0 days, n = 30) compared with control (19.4 ± 2.4 days, n = 18). Best results were obtained with 140 mg/kg TMZ (treated, 44.9 ± 29.0 days, n = 12, versus control, 19.3 ± 2.3 days, n = 12), achieving a longer survival rate than previous group work using three cycles of TMZ therapy at 60 mg/kg (33.9 ± 11.7 days, n = 38). Additional interesting findings were, first, clear edema appearance during chemotherapeutic treatment, second, the ability to apply the semi‐supervised source analysis previously developed in our group for non‐invasive TMZ therapy response monitoring to detect CPA‐induced response, and third, the necropsy findings in mice cured from GBM after high TMZ cumulative dosage (980–1400 mg/kg), which demonstrated lymphoma incidence. In summary, every 6 day administration schedule of TMZ or CPA improves survival in orthotopic GL261 GBM with respect to controls or non‐metronomic therapy, in partial agreement with previous work on subcutaneous GL261.     

Serum Carboxypeptidase Activity and Genotype-Stratified CA19-9 to Detect Early-Stage Pancreatic Cancer

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Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.     

Glutamate receptors and the regulation of steroidogenesis in the human adrenal gland: The metabotropic pathway

Background

l-glutamate is a major excitatory neurotransmitter in the mammalian brain. Glutamate receptors have been reported in the rat adrenal cortex and in human aldosterone-producing adenomas (APA). However, details regarding the expression levels and functions of these receptors in human adrenocortical tissues remain unknown.

Methods

The mRNA levels of glutamate receptors were evaluated by qPCR in: 12 normal adrenal cortex (NAC), 11 APA, and 12 cortisol-producing adenoma (CPA) tissues. Protein localization was evaluated by immunohistochemistry for 15 NAC, 5 idiopathic hyperaldosteronism cases, 15 APA and 15 CPA. H295R cells were treated with angiotensin-II or forskolin alone or combined with the GRM2/3 agonist LY354740.

Results

The level of GRM3 mRNA was higher in APA than in CPA (P = 0.0086) or NAC (P = 0.0022). GRM1, IGLUR2, and IGLUR3 were also detected in adrenocortical tissues. When added to angiotensin-II/forskolin treatments, LY354740 decreased aldosterone and cortisol production in H295R cells.

Conclusions

GRM3 is considered to regulate steroidogenesis in adrenocortical tissues.     

Crystallization of Cyclophosphamide Monohydrate During Lyophilization

The purpose of this study was to investigate the phase behavior of cyclophosphamide (CPA) during various stages of lyophilization, with special emphasis on obtaining crystalline CPA monohydrate (CPA-MH) in the lyophilized product. Subambient differential scanning calorimetry and low-temperature X-ray diffractometry (LTXRD) were used to study the phase behavior of CPA solution (3.7% w/v). In situ lyophilization in LTXRD chamber was used to monitor the phase transitions occurring during the drying stages. Finally, the implications of these findings were confirmed by freeze-drying the aqueous solution in a laboratory-scale freeze-dryer. The results suggested that CPA remains amorphous during freeze concentration, with a T_g' of ?50°C. However, its crystallization as CPA-MH can be induced by annealing the frozen solution between ?5°C and ?10°C. In situ lyophilization in LTXRD showed that the CPA-MH crystallized during annealing, rapidly dehydrated during primary drying, thereby causing structural collapse. The dehydration of CPA-MH can be prevented by lowering the escaping tendency of water molecules from the crystal lattice of CPA-MH by maintaining the chamber pressure to 300, 400, or 500 mTorr. This study highlights the relationship of process parameters used during lyophilization with the solid form of lyophilized CPA.