Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Weight-bearing osteochondral lesions of the lateral femoral condyle following patellar dislocation in adolescent athletes

In patients with patellar dislocation, osteochondral injury is often an indication for early surgical intervention. However, no studies have identified a relationship between injury to the weight-bearing surface of the lateral femoral condyle following a patellar dislocation and the eventual need for surgical treatment. The authors hypothesized that a significant number of patients sustain injury to the weight-bearing surface of the lateral femoral condyle following an acute patellar dislocation.Radiographs and magnetic resonance images were retrospectively reviewed and the patterns of injury were evaluated for 80 patients with a diagnosis of acute patellar dislocation, including the presence of osteochondral damage, the location of the medial patellofemoral ligament injury, and concomitant meniscal pathology. Magnetic resonance imaging identified a 27.5% incidence of osteochondral injury involving the articular, weight-bearing region of the lateral femoral condyle following an acute lateral patellar dislocation. Surgical intervention was performed in more than 60% of these injuries, and most were not identified with plain radiographs. Injury to the weight-bearing surface of the lateral femoral condyle following patellar dislocation was 3.6 times more common in boys in the current study population.Osteochondral injury to the weight-bearing surface of the lateral femoral condyle may occur in a high percentage of patients following a lateral patellar dislocation and in a higher percentage of boys than girls. Patients with tenderness over the lateral femoral condyle following an acute lateral patellar dislocation should undergo magnetic resonance imaging.     

Simultaneous measurement of gallbladder emptying with cholescintigraphy and US during infusion of physiologic doses of cholecystokinin: a comparison

Both ultrasonography (US) and cholescintigraphy are used to study gallbladder dynamics. The present study was undertaken to determine whether the two methods provide the same or different information relating to gallbladder emptying. Emptying was simultaneously studied with both methods during infusion of graded physiologic doses of cholecystokinin (CCK) in six healthy subjects. Infusion of stepwise increasing doses of CCK, ranging from 0.03 to 0.5 Ivy dog units per kilogram of body weight per hour (IDU/kg.h), induced significant dose-related increases in plasma CCK, decreases in gallbladder volume assessed with US, and gallbladder emptying assessed with cholescintigraphy. The threshold dose for inducing significant gallbladder emptying was 0.13 IDU/kg.h, as determined with both techniques, indicating similar detection limits. There was a highly significant correlation between decreases in gallbladder volume and decreases in radioactive counts over the gallbladder region, with a tendency toward greater gallbladder responses at sonography during the early phase of gallbladder contraction and toward greater responses at cholescintigraphy during the later phase of gallbladder contraction. It is concluded that these methods can be used interchangeably for the quantitation of gallbladder emptying.     

Major motor atrophic patterns in the face and neck: CT evaluation

Cranial nerve deficits from various pathologic processes of the head and neck may result in characteristic patterns of denervation muscular atrophy. Such atrophic patterns may be clues to the location and extent of the lesion, particularly when cranial nerves are involved early in the course of the disease process. Thirty-six patients with computed tomographic (CT) evidence of muscular atrophy secondary to pathologic conditions involving the motor division of cranial nerves were examined. Five characteristic denervation muscular atrophy patterns seen on CT scans were identified. In several patients, identification of the muscular atrophy pattern was the only clue to the presence of a pathologic condition. Recognition of these atrophic patterns can prevent misinterpretation of their CT appearance and direct the CT examination to the course of the compromised cranial nerve from the brainstem to its peripheral innervation.     

脐部给药的多塞平栓研制及应用

目的：研制透皮制剂多塞平栓,考察其治疗各型急、慢性荨麻疹的临床疗效。方法：多塞平以甘油明胶为质,氮酮为促透剂,制成栓剂,经脐部给药,观察５０个病例,与口服多塞平片作对照,观察临床疗效。结果：多塞平栓治疗各型急、慢性荨麻疹,总有效率为９４．０％,经统计学分析,Ｐ〈０．０５,差异具显著性。结论：本品制备工艺可行,疗效确切,用药剂量小,无副作用,具有进一步研究、开发的价值。     

N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类的合成及抗真菌活性

根据氮唑类和烯丙胺类抗真菌化合物的构效关系、作用机理。设计合成了30个N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类化合物。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物Ⅰ_1a的真菌活性大致与克霉唑相当,对白念珠菌的活性明显高于naftifine和terbinafine,但对其它七种菌株的活性均不及naftifine和terbinafine;化合物Ⅲ_1a对八种试验菌株的活性均与terbinafine相当。     

Chronic naltrexone infusion: effects on innervation of rat neurointermediate lobe

The rat pituitary neurointermediate lobe contains nerve fibers which are sensitive to the neurotoxic effects of 6-hydroxydopamine and to acute injections of the opiate antagonist, naltrexone. In the present study, naltrexone hydrochloride was administered to adult male Sprague-Dawley rats in a chronic infusion over a period of one week, using Alza osmotic pumps to determine whether a low (10(-5)M) dose could, over a longer period, also induce toxic effects on pituitary innervation. Electron microscopy of pituitary intermediate lobe fibers revealed swollen neurovesicles and membranous structures in nerve terminals, and significantly fewer normal-appearing nerve terminals, after drug infusion. Light microscopic immunostaining of paraffin sections of pituitary glands illustrated some diminution of serotonin (5-HT)-immunofluorescence in the intermediate lobe after naltrexone treatment. Immunostaining of sections from the same animals for tyrosine hydroxylase (TH) revealed intensified fiber staining in the intermediate lobe, with some regions of terminals having a swollen appearance. High pressure liquid chromatographic-electrochemical detection (HPLC-EC) analysis of neurotransmitters in selected brain areas and pituitary indicated a significant increase in norepinephrine levels in the hypothalamus. The observations suggest that intermediate lobe innervation is sensitive to low, continuously infused doses of naltrexone, which acts as a neurotoxin to produce degenerative changes in nerve terminals. The changes appear to be reflected in alterations in staining patterns of neurotransmitters, and may also affect transmitter uptake in damaged terminals.