Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4

Background and Purpose

Previous work in our laboratory showed opioid agents inhibit cytokine expression in astrocytes. Recently, Watkins and colleagues hypothesized that opioid agonists activate toll-like receptor 4 (TLR4) signalling, which leads to neuroinflammation. To test this hypothesis, we characterized LPS and opioid effects on TLR4 signalling in reporter cells.

Experimental Approach

NF-κB reporter cells expressing high levels of TLR4 were used to compare LPS and opioid effects on NF-κB activation, a pathway activated by TLR4 stimulation.

Key Results

LPS increased TLR4 signalling in a concentration-dependent manner and was antagonized by LPS antagonist (LPS-RS, from Rhodobacter sphaeroides). A concentration ratio analysis showed that LPS-RS was a competitive antagonist. The opioid agonists, morphine and fentanyl, produced minor activation of TLR4 signalling when given alone. When tested following LPS stimulation, opioid agonists inhibited NF-κB activation but this inhibition was not blocked by the general opioid antagonist, naloxone, nor by the selective μ opioid receptor antagonist, β-FNA. Indeed, both naloxone and β-FNA also inhibited NF-κB activation in reporter cells. Further examination of fentanyl and β-FNA effects revealed that both opioid agents inhibited LPS signalling in a non-competitive fashion.

Conclusions and Implications

These results show that LPS-RS is a competitive antagonist at the TLR4 complex, and that both opioid agonists and antagonists inhibit LPS signalling in a non-competitive fashion through a non-GPCR, opioid site(s) in the TLR4 signalling pathway. If confirmed, existing opioid agents or other drug molecules more selective at this novel site may provide a new therapeutic approach to the treatment of neuroinflammation.     

Secrets,shame and guilt: HIV disclosure in rural Chinese families from the perspective of caregivers

This in-depth ethnographic study examines the processes, barriers and impacts experienced by Mainland Chinese caregivers residing in rural Yunnan for disclosing HIV status to their adolescents born with the infection and other community members. In particular, highlighted are their associated personal, social, relational and cultural vulnerabilities. A purposeful sample of 13 pairs of HIV-born adolescents between the ages of 11–19 years and their primary caregivers were recruited in December 2014. The Conceptual Model Sexual Health Disclosure (CMSHD) was modified with Chinese culturally specific adaptation to guide the exploration of the complex aspects of the adolescents and caregiver’s relationships. All interviews were audiotaped, transcribed verbatim and then translated into English.

Complex sociocultural interactions emerging in these dyadic interviews included guilt, shame, unintended disclosure, the need for secrecy, perceived stigma, ‘loss of face’, protection of parents, inability to support their families and deep concerns over lineage and future marriage prospects amongst the parents, which had significant psychosocial and even physical impacts for these adolescents born with HIV and their families. Frontline health-care workers and HIV peer support programs are recommended to counteract China’s current top-down biomedical disease-related approach to health services. It is crucial to provide instrumental avenues of confidential psychosocial support including disclosure approaches for caregivers of HIV positive adolescents within a uniquely Chinese cultural context.     

Resection of hepatocellular carcinoma in cirrhotic patients: longterm results of a prospective study.

BACKGROUND: Surgical resection of hepatocellular carcinoma in cirrhotic patients remains controversial because of a high reported recurrence rate. To assess the longterm results of resection, 37 patients included in a prospective study were followed for more than 5 years, with special interest in early detection of recurrence. STUDY DESIGN: Resection was performed from 1986 to 1991 with the goal of sparing the functional liver parenchyma. The mean tumor diameter was 5.3 +/- 2.6 cm (range 2 to 11 cm). Nineteen patients had tumors smaller than 5 cm. No additional perioperative therapy was performed. RESULTS: Evidence of intrahepatic recurrence was demonstrated in 26 of the 33 patients surviving the operation. Eight recurrences (31%) were diagnosed from the third to the fifth postoperative years. The recurrence-free survival rates at 1, 2, 3, 4, and 5 years were 68%, 40%, 26%, 13%, and 9%, respectively. Only 2 patients (7%) were alive and free of recurrence at 5 years. Some long survivals were observed after treatment of recurrence. The overall survival rates at 3 and 5 years were 35% and 24%, respectively. Tumor cell differentiation was the only significant prognostic factor for both recurrence and survival. Multifocal tumors were associated with a higher recurrence rate. Patients with good liver function had longer survivals that reached 38% in those with small solitary tumors. Study of the other dinicopathologic factors failed to demonstrate any prognostic value. CONCLUSIONS: Only a few patients are alive and free of recurrence 5 years after resection. Some long survival can be observed after treatment. Assessment of prognostic factors remains difficult, but the best results of resection are obtained in patients with small solitary hepatocellular carcinoma function.     

Four cancer cases after esophageal atresia repair: Time to start screening the upper gastrointestinal tract

Esophageal atresia(EA) is one of the most common congenital digestive malformations and requires surgical correction early in life. Dedicated centers have reported survival rates up to 95%. The most frequent comorbidities after EA repair are dysphagia(72%) and gastroesophageal reflux(GER)(67%). Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma. Several long-term follow-up studies found an increased risk of Barrett's esophagus and esophageal carcinoma in EA patients, both at a relatively young age. Given these findings, the recent ESPGHAN-NASPGHAN guideline recommends routine endoscopy in adults born with EA. We report a series of four EA patients who developed a carcinoma of the gastrointestinal tract: three esophageal carcinoma and one colorectal carcinoma in a colonic interposition. These cases emphasize the importance of lifelong screening of the upper gastrointestinal tract in EA patients.     

Effects of Erxian decoction, a Chinese medicinal formulation, on serum lipid profile in a rat model of menopause

Background

Infantile colic is a common painful clinical condition associated with signs of distended intestines and an increase in colon peristalsis. However, clinical documentation of observed gastrointestinal functions in the condition is still lacking. Even though the ailment is common, no clear treatment guidelines exist. While acupuncture with minimal stimulation has been shown to be effective in reducing crying behaviour of infants suffering from colic, the documented effect of acupuncture on gastrointestinal function in children with infantile colic is scarce. This case series study aims to document the symptoms of routinely rated gastrointestinal function and the changes in these symptoms after minimal acupuncture in a larger group of children with infantile colic.

Methods

This study included 913 infants with normal weights, and lengths at birth. The infants' mean age was 5.4 weeks when the observations started, and had colic symptoms since two weeks after birth. Light needling stimulation of the acupuncture point LI4 was performed for 10-20 seconds bilaterally on a daily basis for a mean of 6.2 consecutive days. A questionnaire with verbal rating scales for the parents' evaluation was used before and after the treatment period.

Results

Before treatment the infants were assessed by the parents in terms of 'often have inflated stomachs' (99%) and 'seldom drool' (76%), 'regurgitate' (53%) and 'belch' (62%). Moreover, the reported frequency of defecation was 5-8 times per day (64%), with a yellowish-green colour (61%) and with a water-thin consistency (74%). After treatment, the variables of inflated stomachs, drooling and regurgitating were systematically changed, and rated by the parents as occurring 'sometimes' while belching was rated as occurring 'often' and the frequency of defecation was reduced to 1-4 times/day with a mustard yellow colour and a gruel-like consistency. The parents also rated their impression of the infants' general colic symptoms including crying behaviour as much ameliorated in 76% of the cases.

Conclusion

The results of the present study show that minimal acupuncture at LI4 in infantile colic is an effective and easy treatment procedure that, furthermore, is reported to be without serious side effects.     

Microduplication of Xp11.23p11.3 with effects on cognition,behavior, and craniofacial development

El‐Hattab AW, Bournat J, Eng PA, Wu JBS, Walker BA, Stankiewicz P, Cheung SW, Brown CW. Microduplication of Xp11.23p11.3 with effects on cognition, behavior, and craniofacial development. We report an ～1.3 Mb tandem duplication at Xp11.23p11.3 in an 11‐year‐old boy with pleasant personality, hyperactivity, learning and visual‐spatial difficulties, relative microcephaly, long face, stellate iris pattern, and periorbital fullness. This clinical presentation is milder and distinct from that of patients with partially overlapping Xp11.22p11.23 duplications which have been described in males and females with intellectual disability, language delay, autistic behaviors, and seizures. The duplicated region harbors three known X‐linked mental retardation genes: FTSJ1, ZNF81, and SYN1. Quantitative polymerase chain reaction from whole blood total RNA showed increased expression of three genes located in the duplicated region: EBP, WDR13, and ZNF81. Thus, over‐expression of genes in the interval may contribute to the observed phenotype. Many of the features seen in this patient are present in individuals with Williams‐Beuren syndrome (WBS). Interestingly, the SYN1 gene within the duplicated interval, as well as the STX1A gene, within the WBS critical region, co‐localize to presynaptic active zones, and play important roles in neurotransmitter release.     

Evaluation of arterial grafts prior to coronary bypass in pseudoxanthoma elasticum

Pseudoxanthoma elasticum is a rare, inherited connective tissue disorder associated with coronary and peripheral arterial disease and accelerated atherosclerosis in medium sized arteries. We describe 110-month symptom-free survival in a patient with pseudoxanthoma elasticum who underwent coronary bypass using the left internal mammary artery at 56 years of age. The vessel was evaluated pre-operatively with angiography to determine suitability, and he has not required further investigation or intervention due to lack of symptoms.     

Genome‐wide transcriptome analyses reveal p53 inactivation mediated loss of miR‐34a expression in malignant peripheral nerve sheath tumours

Malignant peripheral nerve sheath tumours (MPNSTs) are aggressive soft tissue tumours that occur either sporadically or in patients with neurofibromatosis type 1. The malignant transformation of the benign neurofibroma to MPNST is incompletely understood at the molecular level. We have determined the gene expression signature for benign and malignant PNSTs and found that the major trend in malignant transformation from neurofibroma to MPNST consists of the loss of expression of a large number of genes, rather than widespread increase in gene expression. Relatively few genes are expressed at higher levels in MPNSTs and these include genes involved in cell proliferation and genes implicated in tumour metastasis. In addition, a gene expression signature indicating p53 inactivation is seen in the majority of MPNSTs. Subsequent microRNA profiling of benign and malignant PNSTs indicated a relative down‐regulation of miR‐34a in most MPNSTs compared to neurofibromas. In vitro studies using the cell lines MPNST‐14 (NF1 mutant) and MPNST‐724 (from a non‐NF1 individual) show that exogenous expression of p53 or miR‐34a promotes apoptotic cell death. In addition, exogenous expression of p53 in MPNST cells induces miR‐34a and other miRNAs. Our data show that p53 inactivation and subsequent loss of expression of miR‐34a may significantly contribute to the MPNST development. Collectively, our findings suggest that deregulation of miRNAs has a potential role in the malignant transformation process in peripheral nerve sheath tumours. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Genetics of cardiovascular and renal complications in diabetes

The development of debilitating complications represents a major heathcare burden associated with the treatment of diabetes. Despite advances in new therapies for controlling hyperglycemia, the burden associated with diabetic complications remains high, especially in relation to cardiovascular and renal complications. Furthermore, an increasing proportion of patients develop type 2 diabetes at a younger age, putting them at higher risk of developing complications as a result of the increased exposure to hyperglycemia. Diabetes has become the main contributing cause to end‐stage renal disease in most countries. Although there has been important breakthroughs in our understanding of the genetics of type 1 and type 2 diabetes, bringing important insights towards the pathogenesis of diabetes, there has been comparatively less progress in our understanding of the genetic basis of diabetic complications. Genome‐wide association studies are beginning to expand our understanding of the genetic architecture relating to diabetic complications. Improved understanding of the genetic basis of diabetic cardiorenal complications might provide an opportunity for improved risk prediction, as well as the development of new therapies.