A Brief Screening Tool for Opioid Use Disorder: EMPOWER Study Expert Consensus Protocol.

Growing concerns about the safety of long-term opioid therapy and its uncertain efficacy for non-cancer pain have led to relatively rapid opioid deprescribing in chronic pain patients who have been taking opioid for years. To date, empirically supported processes for safe and effective opioid tapering are lacking. Opioid tapering programs have shown high rates of dropouts and increases in patient distress and suicidal ideation. Therefore, safe strategies for opioid deprescribing that are more likely to succeed are urgently needed. In response to this demand, the EMPOWER study has been launched to examine the effectiveness of behavioral medicine strategies within the context of patient-centered opioid tapering in outpatient settings (https://empower.stanford.edu/). The EMPOWER protocol requires an efficient process for ensuring that collaborative opioid tapering would be offered to the most appropriate patients while identifying patients who should be offered alternate treatment pathways. As a first step, clinicians need a screening tool to identify patients with Opioid Use Disorder (OUD) and to assess for OUD severity. Because such a tool is not available, the study team composed of eight chronic pain and/or addiction experts has extended a validated screening instrument to develop a brief and novel consensus screening tool to identify OUD and assess for OUD severity for treatment stratification. Our screening tool has the potential to assist busy outpatient clinicians to assess OUD among patients receiving long-term opioid therapy for chronic pain.

Vitamin D: in the evolution of human skin colour.

The natural selection hypothesis suggests that lighter skin colour evolved to optimise vitamin D production. Some authors question if vitamin D deficiency leads to sufficient health problems to act as a selection pressure. This paper reviews the numerous effects of vitamin D deficiency on human health and argues that vitamin D deficiency is sufficient to pose as a potent selection pressure for lighter skin colour. Vitamin D deficiency manifesting as rickets and osteomalacia are sufficient to impair reproductive success, but additionally, animal studies and some clinical observations suggest that vitamin D may have more direct impact on human fertility. Vitamin D deficiency may lead to a whole host of clinical conditions which impair health and increase mortality rates: increase susceptibility to bacterial and viral infections; rickets, osteomalacia and osteoporosis, with increased risk of falls and fractures; increased risk of cancers; hypertension and cardiovascular disease; maturity onset diabetes; autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and Type 1 diabetes; and gum disease. We submit that at higher latitudes, lighter skin colour evolved to facilitate vitamin D production under conditions of low ultra-violet B radiation in order to avoid a plethora of ill health, reproductive difficulties and early mortality.

Mechanised nanoparticles for drug delivery.

Time and time again humanity is faced with a unifying global crisis that crosses the many great divides in different societies and serves to bring once segregated communities back together as a collective whole. This global community instinctively turns to science to develop the means of addressing its most pressing problems. More often than not, these forces dictate the direction that scientific research takes. This influence is no more apparent than in the field of supramolecular chemistry where, for decades now, its responsibility to tackle such issues has been put on the back burner as a consequence of a lack of platforms with which to deliver this contemporary brand of chemistry to meaningful applications. However, the tide is slowly turning as new materials emerge from the field of nanotechnology that are poised to host the many attractive attributes that are inherent in the chemistry of these supermolecules and also in the mechanostereochemistry of mechanically interlocked molecules (MIMs), which can be reused as a sequel to supramolecular chemistry. Mesoporous silica nanoparticles (SNPs) have proven to be supremely effective solid supports as their surfaces are easily functionalised with either supermolecules or MIMs. In turn, the blending of supramolecular chemistry and mechanostereochemistry with mesoporous SNPs has led to a new class of materials - namely, mechanised SNPs that are effectively biological nanoscale 'bombs' that have the potential to infiltrate cells and then, upon the pulling of a chemical trigger, explode! The development of these materials has been driven by the need to devise new therapies for the treatment of cancer. Recent progress in research promises not only to control the acuteness of this widespread and insidious disease, but also to make the harsh treatment less debilitating to patients. This global scourge is the unifying force that has brought together supramolecular chemistry, mechanostereochemistry and nanotechnology, uniting these three communities for the common good. At the nanoscale level, the mechanism for the release of cargos from the confines of the nanopores in the SNPs is accomplished by way of mechanical modifications made on the surface of these functionalised supports. These mechanical motions rely on both supramolecular, i.e., host-guest complexes, and mechanostereochemical phenomena (e.g., bistable rotaxanes), which are often stimulated by changes in pH, light and redox potentials, in addition to enzymatic catalysis. The future of this field lies in the development of 'smart bombs' wherein the loaded mechanised SNPs are endocytosed selectively by cancer cells, whereupon an intracellular trigger causes release of a cytotoxin, effectively leading to apoptosis. This review serves to highlight (1) the evolution of surface-functionalisation of SNPs with supermolecules and also with MIMs, (2) the mechanisms through which controlled-release of cargo from mechanised SNPs occurs, and (3) results from the in vitro application of these mechanised SNPs.

Pharmacological inhibition of AMP-deaminase in rat cardiac myocytes.

Because mutation of AMP deaminase 1 gene leading to reduced AMP deaminase activity may result in protection of cardiac function in patients with heart disease, inhibitors of AMP deaminase (AMPD) may have therapeutic applications. This study evaluated the effect of a specific inhibitor of AMP deaminase 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo [4,5-d][1,3]diazepin-8-ol (AMPDI) on the isolated human enzyme and on nucleotide catabolism in rat cardiomyocytes. AMPDI effectively inhibited isolated human AMPD with an IC(50) = 0.5 micro M. AMPDI was much less effective with isolated cardiomyocytes (IC(50) = 0.5 mM). AMPDI is a very effective inhibitor of AMPD that despite lower efficiency in the cell system examined could be useful for in vivo studies.

Differences in activities of the enzymes of nucleotide metabolism and its implications for cardiac xenotransplantation.

Xenotransplantation is one be possible solution for a severe shortage of human organs available for transplantation. However, only a few studies addressed metabolic compatibility of transplanted animal organs. Our aim was to compare activities of adenosine metabolizing enzymes in the heart of different species that are relevant to clinical or experimental xenotransplantation. We noted fundamental differences: ecto-5' nucleotidease (E5' N) activity was 4-fold lower in pig and baboon hearts compared to the human hearts while mouse activity was compatible with human and rat activity was three times higher than human. There also were significant differences in AMP-deaminase (AMPD), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) activities. We conclude that differences in nucleotide metabolism may contribute to organ dysfunction after xenotransplantation.

Molecular and cytogenetic changes involved in the immortalization of nasopharyngeal epithelial cells by telomerase.

Nasopharyngeal carcinoma (NPC) is a common disease in Hong Kong and southern provinces of China. EBV infection is believed to play a critical role in the development of NPC. Previous studies on the transformation mechanism of EBV genes were mostly performed in either NPC or nonnasopharyngeal epithelial cells which may not be representative of premalignant nasopharyngeal epithelial cells. Establishment of a representative cell system would greatly facilitate the elucidation of the role of EBV infection in the development of NPC. Using telomerase alone, we were able to establish an immortalized nasopharyngeal epithelial cell line from primary nonmalignant nasopharyngeal biopsies. The telomerase-immortalized nasopharyngeal epithelial cells are largely diploid in karyotype. Interestingly, this newly immortalized nasopharyngeal epithelial cell line, referred as NP460hTert, harbors genetic alterations previously identified in premalignant and malignant nasopharyngeal epithelial cells. These include inactivation of p16 by homozygous deletion of the p16(INK4A) locus and downregulation of RASSF1A expression. The deletion of the p16(INK4A) locus appears to be the most crucial event for the immortalization of nasopharyngeal epithelial cells by telomerase and precedes RASSF1A downregulation. In addition, detailed analysis of the cytogenetic changes by conventional cytogenetics, spectral karyotyping (SKY) and array-based CGH revealed a gain of a 17q21-q25 fragment on 11p15 chromosome in all NP460hTert cells which occurred before deletion of the p16(INK4A) locus. Gain of 17q has been previously reported in NPC. In addition, activation of NF-kappaB was observed in immortalized NP460hTert cells at the later population doublings, and may play a role in the survival of immortalized NP epithelial cells. Id1 which is commonly expressed in various human cancers, including NPC, was also upregulated in the immortalized NP460hTert cells. Thus, the establishment of an immortalized nasopharyngeal epithelial cell line harboring common genetic alterations present in premalignant and cancerous nasopharyngeal epithelial cells may provide a valuable cell system to examine for early events involved in NPC carcinogenesis, particularly in elucidating the role of EBV infection in NPC development.

Abductor pollicis longus tendon rupture in De Quervain's disease.

De Quervain's disease is a stenosing tenovaginitis involving the first extensor compartment of the wrist. The similarity of its symptomatology to a number of other conditions and its controversial aetiology are only a few of the barriers which often delay its diagnosis and treatment. We report the first two cases in the literature of abductor pollicus longus tendon rupture in patients with De Quervain's disease who had been treated with conservative methods. The relevant literature is reviewed.

Purine metabolism in pigs and humans and its implications for xenotransplantation.

We compared concentrations of nucleotide substrates and activities of enzymes of nucleotide metabolism in pig and human blood, heart, and kidney. The most important difference was lower ecto-5-nucleotidase (ESN) activity in both pig hearts and kidney. Furthermore, higher hypoxanthine, inosine, adenine, and uracil, but lower uridine and uric acid concentrations were observed in pig blood as compared to human. A twofold increase in UTP concentration has been observed in pig hearts following 4 h perfusion with human blood. Purine metabolism is an important target for genetic and pharmacological manipulation during xenotransplantations.

Exposure to human blood inactivates swine endothelial ecto-5'-nucleotidase.

Ecto-5'-nucleotidase (E5'N) is an extracellular enzyme forming anti-inflammatory and immunosuppressive adenosine. We evaluated whether confrontation of pig heart and endothelial cells with human blood changes the activity of E5'N. Pig hearts were perfused ex vivo with fresh human blood for 4 h. Pig aortic endothelial cells (PAEC) were incubated in vitro with human plasma for 3 h. Ex vivo perfusion of pig heart with fresh human blood resulted in a decrease in E5'N activity to 62% and 61% of initial in wild-type and transgenic pig hearts, respectively. PAEC activity of E5'N decreased to 71% and 50% of initial after 3 h exposure to heat-inactivated and active complement human plasma, respectively, while it remained constant in controls. Pig heart activity of E5'N decreased following exposure to human blood, which may affect adenosine production and exacerbate hyperacute and vascular rejection.

Prevention of adriamycin induced heart failure by an increase in endogenous adenosine production.

Adenosine (Ado) triggers several protective mechanisms that may attenuate development of heart failure, both locally and systemically. We developed a procedure allowing sustained increase in endogenous Ado production by the combined application of Ado metabolism inhibitors and nucleotide precursors. We found that our procedure attenuate the development of heart failure induced by adriamycin.

AMPD1 C34T mutation selectively affects AMP-deaminase activity in the human heart.

Possession of the nonsense mutation in AMPD 1 C34T gene has been linked to improved survival in patients with heart failure, possibly by promoting the formation of adenosine. This mutation is known to decrease the activity of AMP-deaminase in skeletal muscle. We have found that the AMPD1 mutation decreases the activity of AMP-deaminase in the heart without changing the activity of any other enzymes of adenine nucleotide metabolism. Protective mechanism of this mutation may be thus induced by local cardiac metabolic changes.

Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma.

AIMS: We evaluated the clinicopathologic relevance of plasma osteopontin (OPN) level in nasopharyngeal carcinoma patients. METHODS: Seventy-two plasma samples were collected from patients with undifferentiated nasopharyngeal carcinoma (NPC) before radiotherapy. Plasma OPN level was determined by quantitative sandwich enzyme immunoassay. The plasma OPN level was evaluated for its clinicopathologic relevance. RESULTS: The mean plasma OPN level was significantly higher in NPC patients than in normal controls (184.66 vs 75.89 ng/ml, p<0.001). In addition, high OPN level was found in the patients with advanced cancer and was correlated with neck node metastasis (p<0.05). CONCLUSIONS: Our findings indicated a potential role of OPN in the pathogenesis and nodal metastasis of undifferentiated NPC.

Laparoscopic surgery for common surgical emergencies: a population-based study.

BACKGROUND: Despite being controversial in the past, many reports on the safe use of laparoscopic surgery in emergency settings have been published. The aim of this study was to investigate the diffusion of laparoscopic surgery in three common surgical emergency operations, namely, appendectomy, cholecystectomy, and simple repair of perforated peptic ulcer (PPU), in a stable population. METHODS: This was a retrospective analysis of the central database of the Hospital Authority (HA) in Hong Kong. Data for patients managed in 14 HA hospitals from 1998 to 2002 were studied. The operation record and discharge record of each patient were also investigated to verify the data. RESULTS: A total of 12,708 patients underwent appendectomy, 2631 patients underwent cholecystectomy, and 2260 patients had simple repair of PPU performed. During the study period, 37.2% of appendectomies, 46.5% of cholecystectomies, and 23.1% of simple repairs of PPU were performed laparoscopically. More than a two-fold increase in the proportion of laparoscopic surgery was observed in each of these three operations. By the end of 2002, the percentage of laparoscopic surgery had increased to 53.5% for appendectomies, 61.3% for cholecystectomies, and 32.9% for simple repairs of PPU. Significantly lower hospital mortality rates and shorter postoperative hospital stay were consistenty observed in patients with laparoscopic surgery of the three emergencies. A wide variation in the use of laparoscopic surgery, ranging from 3.7% to 73.1%, was observed among the 14 HA hospitals. However, there was no correlation in the use of laparoscopic surgery with the volume of operation performed in each hospital (p = 0.933). CONCLUSION: A high diffusion rate on the use of laparoscopic surgery for common surgical emergency was observed in Hong Kong. However, there was also a wide variation in the diffusion rate among the 14 HA hospitals. Efforts to reduce hospital variation for the better dissemination of safe laparoscopic technique may be warranted.

Gallbladder cancer presenting with acute cholecystitis: a population-based study.

BACKGROUND: The role of laparoscopic cholecystectomy (LC) in acute cholecystitis remains controversial. The aim of the present study was to determine the incidence, clinicopathological characteristics, and outcome of patients with gallbladder cancer presenting with acute cholecystitis. METHODS: We performed a retrospective analysis of patients with gallbladder cancer who presented with acute cholecystitis and were treated at the public hospitals in Hong Kong between 1998 and 2002. RESULTS: Among 2,700 patients with acute cholecystitis managed with cholecystectomy (1,347 open and 1,353 LC), 63 patients (2.3%) were found to have gallbladder cancer. There were 44 women and 19 men with a mean age of 74.7 (+/-12.8) years. Adenocarcinoma (90.5%) was the most common cancer. The overall median survival was 5 months (95% CI = 2.6-7.4). The 5-year survival rate was 20.8%. Laparoscopic cholecystectomy was attempted in 11 patients and was completed successfully in six of them. There was no difference between the LC and open groups in the complication rate, hospital mortality rate, or survival rate. CONCLUSIONS: In the ethnic Chinese population of Hong Kong, the incidence of gallbladder cancer presenting with acute cholecystitis is higher than the same finding in patients undergoing elective cholecystectomy for cholelithiasis. Long-term survival is possible because such patients may be diagnosed at an early stage of the disease.

Nonhematologic malignancies after allogeneic hematopoietic stem cell transplantation: incidence and molecular monitoring.

Survivors of allogeneic hematopoietic stem cell transplantation (HSCT) are at a life-long increased risk of secondary nonhematologic malignancies. In 615 adult Chinese allogeneic HSCT patients, nine developed nonhematologic malignancies. The 5-year cumulative incidence was 6.1%, 4.5 times the background cancer incidence. Early-onset (within first 6 months) and late-onset (>3 years) subtypes were observed. Secondary cancers included hepatocellular carcinoma, oral and esophageal squamous cell tumors and lung adenocarcinoma in a female nonsmoker. The spectrum reflected local cancer epidemiology, which was different from Western populations. The pathogenesis might be related to acceleration of pre-existing cancers (early-onset type), or prolonged immunosuppression (late-onset type). DNA chimerism studies showed that all tumors were recipient-derived. In the plasma, DNA in all cases was apparently donor-derived, although aberrantly methylated p15 was detectable in a patient with a p15-methylated secondary cancer, implying that minute quantities of tumor (and therefore recipient) derived DNA might be present.

Clinicopathologic significance of plasma matrix metalloproteinase-2 and -9 levels in patients with undifferentiated nasopharyngeal carcinoma.

UNLABELLED: Increased in plasma pro-MMP2 and pro-MMP9 levels in patients with advanced stage NPC were observed. Plasma pro-MMP2 is a significant independent prognostic marker for undifferentiated NPC. AIM: Upregulation of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) expression is observed in many cancers and high level of these proteins are found in peripheral blood of many cancer patients. In this study, we aimed at evaluating the plasma pro-MMP2 and pro-MMP9 pro-enzymes (pro-MMP2 and pro-MMP9) levels and their clinical significances in patients with undifferentiated nasopharyngeal carcinoma (NPC). METHODS: The plasma pro-MMP2 and pro-MMP9 levels were measured in 40 NPC patients and 40 normal individuals by enzyme linked immunosorbant assay. RESULTS: By using the Cox-regression model, a high pro-MMP2 level was found to be significantly correlated with poorer survival. Patients with plasma pro-MMP2 below 650 ng/ml had higher 5-year survival rate of 89%, compared with 50% for patients with plasma pro-MMP2 above 650 ng/ml. CONCLUSIONS: A high level of plasma pro-MMP2 was associated with poor survival of NPC patients independent of sex, age and stage.

Validation of POSSUM scoring systems for audit of major hepatectomy.

BACKGROUND: The aim of the study was to validate the use of Physiological and Operative Severity Score in the enUmeration of Mortality and morbidity (POSSUM) and Portsmouth (P) POSSUM scoring systems to predict postoperative mortality in a group of Chinese patients who had a major hepatectomy for hepatocellular carcinoma. METHODS: A retrospective analysis was performed on data collected prospectively over a 6-year interval from January 1997 to December 2002. The mortality risks were calculated using both the POSSUM and the P-POSSUM equations. RESULTS: Two hundred and fifty-nine patients underwent major hepatectomy; there were 17 (6.6 per cent) postoperative deaths. Of 32 preoperative and intraoperative variables studied, age, smoking habit, serum creatinine concentration, American Society of Anesthesiologists grade, and physiological and operative severity scores were found to be significant factors predicting mortality. On multivariate analysis only the physiological and operative severity scores were independent variables. The POSSUM system overpredicted mortality risk (14.2 per cent) and there was a significant lack of fit in these patients (chi(2) = 14.1, 3 d.f., P = 0.003). The mortality rate predicted by P-POSSUM was 4.2 per cent and showed no significant lack of fit (chi(2) = 7.6, 3 d.f., P = 0.055), indicating that it predicted outcome effectively. A new logistic equation was derived from the present patient data set that requires testing prospectively. CONCLUSION: P-POSSUM significantly predicted outcome in Chinese patients who had major hepatectomy for hepatocellular carcinoma. A modified disease-specific equation requires further testing.

The study of p16 and p15 gene methylation in head and neck squamous cell carcinoma and their quantitative evaluation in plasma by real-time PCR.

Epigenetic silencing of the p16 and p15 genes by promoter methylation are commonly observed in human epithelial malignancies, including head and neck squamous cell carcinomas (HNSCC). In this study, a methylation-specific polymerase chain reaction (MSP) was used to evaluate the methylation status of the p16 and p15 genes in 73 HNSCC surgical specimens. p16 and p15 gene methylation was also examined in 29 paired metastatic lymph nodes and 29 paired histologically, normal resection margin mucosae. The quantity of cell-free methylated p16 and p15 DNA in the plasma samples of 20 HNSCC patients and 24 healthy controls was also examined using a fluorescence-based real-time PCR assay. The frequencies of p16 and p15 methylation in the primary tumour were 49% and 60%, respectively. Concordant methylation of p16 and p15 in tumour samples and metastatic lymph nodes was found in 59 and 38% of cases, respectively. A significantly higher prevalence of p15 methylation was found in histologically-normal surgical margin epithelia of HNSCC patients with chronic smoking and drinking habits compared with non-smokers and non-drinkers. In addition, methylated p16 and p15 DNA levels were significantly higher in the plasma of HNSCC patients (mean 56 copies/ml plasma and 65 copies/ml plasma, respectively) compared with normal controls (mean 6 copies/ml plasma and 16 copies/ml plasma, respectively). In conclusion, promoter methylation of the p16 and p15 genes is involved in the pathogenesis of HNSCC and may be related to chronic smoking and drinking. The differential levels of methylated p16 and p15 DNA in plasma might be potential useful markers in screening high-risk populations for early HNSCC and monitoring their treatment response.

Ontogeny and specificities of mucosal and blood human immunodeficiency virus type 1-specific CD8(+) cytotoxic T lymphocytes.

Induction of adaptive immunity to human immunodeficiency virus type 1 (HIV-1) at the mucosal site of transmission is poorly understood but crucial in devising strategies to control and prevent infection. To gain further understanding of HIV-1-specific T-cell mucosal immunity, we established HIV-1-specific CD8(+) cytotoxic T-lymphocyte (CTL) cell lines and clones from the blood, cervix, rectum, and semen of 12 HIV-1-infected individuals and compared their specificities, cytolytic function, and T-cell receptor (TCR) clonotypes. Blood and mucosal CD8(+) CTL had common HIV-1 epitope specificities and major histocompatibility complex restriction patterns. Moreover, both systemic and mucosal CTL lysed targets with similar efficiency, primarily through the perforin-dependent pathway in in vitro studies. Sequence analysis of the TCRbeta VDJ region revealed in some cases identical HIV-1-specific CTL clones in different compartments in the same HIV-1-infected individual. These results clearly establish that a subset of blood and mucosal HIV-1-specific CTL can have a common origin and can traffic between anatomically distinct compartments. Thus, these effectors can provide immune surveillance at the mucosa, where rapid responses are needed to contain HIV-1 infection.