Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans

The effects of depletion of the serotonin precursor,l-tryptophan, on the threshold and tolerance to cold pressor pain, and the analgesic effect of morphine (10 mg intramuscularly), were tested in a double blind trial on human volunteers. Effects on mood were also assessed using the Profile of Mood States and the Addiction Research Center Inventory (ARCI) Scales. To deplete tryptophan, subjects were fed a tryptophan-deficient amino acid mixture 4.5 h before morphine was administered. Controls received the mixture with tryptophan, which is equivalent to a nutritionally balanced protein. The tryptophan-deficient meal reduced plasma tryptophan more than 70% but had no effect on threshold or tolerance to cold pressor pain. After morphine, tolerance to cold pressor pain increased in controls. Tryptophan depletion abolished this analgesic effect. Pain threshold was not altered by morphine. In subjects with normal tryptophan, the analgesic effect of morphine was predicted by the level of plasma morphine-6-glucuronide, but not by the level of morphine. Morphine increased scores on the LSD scale of the ARCI, but had no effect on other measures of mood. Tryptophan depletion also failed to alter mood in these subjects, who had unusually low depression scores before tryptophan depletion.     

Correlation between Braden Scale and Palliative Performance Scale in advanced illness

This study describes the significant correlation between the Braden Scale (BS) and the Palliative Performance Scale (PPS) in patients with advanced illness that has not been previously reported. The analysis was based on a prospective sequential case series of 664 patients suffering from advanced illness who were referred to a regional palliative medicine programme in Toronto, Canada. Baseline BS and PPS scores assessed within 24 hours of referral were considered for analysis. After controlling for age, gender, consult site and diagnosis (cancer versus non cancer), we observed a significant positive correlation between baseline PPS and BS scores (r = 0·885, P < 0·001). These findings suggest that for patients with advanced illness where BS is not routinely used, PPS could be considered as a proxy for pressure ulcer risk assessment.     

Failure of hepatitis C therapy in HIV-coinfected drug users is not due to a shift in hepatitis C virus genotype

Because most patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are injection drug users (IDUs) who might have been exposed to multiple HCV genotypes while sharing needles, coinfection with distinct HCV genotypes could be frequent in them. Blood samples from 203 coinfected IDUs who did not respond to at least 24 weeks of interferon (IFN)-based therapies were analyzed. At baseline, 131 patients had HCV genotype 1, 4 had HCV genotype 2, 52 had HCV genotype 3, and 16 had HCV genotype 4. Changes in HCV genotype were not found in any patient when samples obtained before and after HCV therapy were compared. HCV therapy did not appear to select for IFN-resistant HCV genotypes that might have been present at baseline. Coinfection with distinct HCV genotypes is unlikely in former IDUs coinfected with HIV and does not explain the lower efficacy of HCV therapy in this population.     

Second line systemic therapies for hepatocellular carcinoma: Reasons for the failure

Hepatocellular carcinoma(HCC) is the main cause of death in patients with cirrhosis, with an increasing incidence worldwide. Sorafenib is the choice therapy for advanced HCC. Over time several randomized phase Ⅲ trials have been performed testing sunitinib, brivanib, linifanib and other molecules in head-tohead comparison with Sorafenib as first-line treatment for advanced-stage HCC, but none of these has so far been registered in this setting. Moreover, another feared vacuum arises from the absence of molecules registered as second-line therapy for patients who have failed Sorafenib, representing an urgent unmet medical need. To date all molecules tested as second-line therapies for advanced hepatocellular carcinoma, failed to demonstrate an increased survival compared to placebo. What are the possible reasons for the failure? What we should expect in the near future?     

Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells

Aims/hypothesis The aim of this study was to determine whether adiponectin elicits glucose uptake via increased GLUT4 translocation and to investigate the metabolic fate of glucose in skeletal muscle cells treated with globular adiponectin.Materials and methods Basal and insulin-stimulated 2-deoxy-d-[³H]glucose uptake, cell surface myc-tagged GLUT4 content, production of ¹⁴CO₂ by oxidation of d-[U-¹⁴C]glucose and [1-¹⁴C]oleate, and incorporation of d-[U-¹⁴C]glucose into glycogen and lactate were measured in the presence and absence of globular adiponectin.Results RT-PCR and Western blot analysis revealed that L6 cells and rat skeletal muscle cells express AdipoR1 mRNA and protein. Globular adiponectin increased both GLUT4 translocation and glucose uptake by increasing the transport V_max of glucose without altering the K_m. Interestingly, the incorporation of d-[U-¹⁴C]glucose into glycogen under basal and insulin-stimulated conditions was significantly decreased by globular adiponectin, whereas lactate production was increased. Furthermore, globular adiponectin did not affect glucose oxidation, but enhanced phosphorylation of AMP kinase and acetyl-CoA carboxylase, and fatty acid oxidation.Conclusions/interpretation The present study is the first to show that globular adiponectin increases glucose uptake in skeletal muscle cells via GLUT4 translocation and subsequently reduces the rate of glycogen synthesis and shifts glucose metabolism toward lactate production. These effects are consistent with the increased phosphorylation of AMP kinase and acetyl-CoA carboxylase and oxidation of fatty acids induced by globular adiponectin.     

Peripheral Frequency of CD4+ CD28? Cells in Acute Ischemic Stroke: Relationship With Stroke Subtype and Severity Markers

CD4+ CD28− T cells also called CD28 null cells have been reported as increased in the clinical setting of acute coronary syndrome. Only 2 studies previously analyzed peripheral frequency of CD28 null cells in subjects with acute ischemic stroke but, to our knowledge, peripheral frequency of CD28 null cells in each TOAST subtype of ischemic stroke has never been evaluated. We hypothesized that CD4+ cells and, in particular, the CD28 null cell subset could show a different degree of peripheral percentage in subjects with acute ischemic stroke in relation to clinical subtype and severity of ischemic stroke.The aim of our study was to analyze peripheral frequency of CD28 null cells in subjects with acute ischemic stroke in relation to TOAST diagnostic subtype, and to evaluate their relationship with scores of clinical severity of acute ischemic stroke, and their predictive role in the diagnosis of acute ischemic stroke and diagnostic subtypeWe enrolled 98 consecutive subjects admitted to our recruitment wards with a diagnosis of ischemic stroke. As controls we enrolled 66 hospitalized patients without a diagnosis of acute ischemic stroke. Peripheral frequency of CD4+ and CD28 null cells has been evaluated with a FACS Calibur flow cytometer.Subjects with acute ischemic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to control subjects without acute ischemic stroke. Subjects with cardioembolic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to subjects with other TOAST subtypes. We observed a significant relationship between CD28 null cells peripheral percentage and Scandinavian Stroke Scale and NIHSS scores. ROC curve analysis showed that CD28 null cell percentage may be useful to differentiate between stroke subtypes.These findings seem suggest a possible role for a T-cell component also in acute ischemic stroke clinical setting showing a different peripheral frequency of CD28 null cells in relation of each TOAST subtype of stroke.     

Early outcomes of colon laparoscopic resection in the elderly patients compared with the younger

Background

The aim of this study was to define any benefits in terms of early outcome for laparoscopic colectomy in patients over 75 years old (OP) compared with the outcomes of a younger populations (YP).

Methods

Forty elderly patients undergoing laparoscopic colectomy for colorectal cancer between 2007-2011 were studied, the patients are divided for gender, age, year of surgery, site of cancer, and comorbidity on admission and compared with 40 younger patients.

Results and discussion

Mean (standard deviation) age was 81.3 in OP and 68.3 YP Conversion rate was the same between the two groups. There was no difference in operative mean time . The overall mortality rate was 0% percent. The surgical morbidity rate was the same but there was an increased in cardiologic e bronchopneumonia complications in older population. Patients treated with laparoscopic approach had a faster recovery of bowel function and a significant reduction of the mean length of hospital stay not age related. Laparoscopy allowed a better preservation of postoperative independence status.

Conclusions

Laparoscopic colectomy for cancer in elderly patients is safe and beneficial including preservation of postoperative independence and a reduction of length of hospital stay.

     

Natural history of untreatable hepatocellular carcinoma: A retrospective cohort study

AIM:To investigate the clinical course of untreatable hepatocellular carcinoma(HCC) identified at any stage and to identify factors associated with mortality.METHODS:From January 1999 to December 2010,320 out of 825 consecutive patients with a diagnosis of HCC and not appropriate for curative or palliative treatments were followed and managed with supportive therapy.Cirrhosis was diagnosed by histological or clinical features and liver function was evaluated according to Child-Pugh score.The diagnosis of HCC was performed by Ultra-Sound guided biopsy or by multiphasic contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging.Data were collected for each patient including all clinical,laboratory and imaging variables necessary for the outcome prediction staging systems considered.HCC staging was performed according Barcelona Clinic Liver Cancer(BCLC) and Cancer of the Liver Italian Program scores.Follow-up time was defined as the number of months from the diagnosis of HCC to death.Prognostic baseline variables were analyzed by multivariate Cox analysis to identify the independent predictors of survival.RESULTS:Seventy-five per cent of patients had hepatitis C.Ascites was present in 169 patients(53%),while hepatic encephalopathy was present in 49 patients(15%).The Child-Pugh score was class A in 105 patients(33%),class B in 142 patients(44%),and class C in 73 patients(23%).One hundred patients(31%) had macroscopic vascular invasion and/or extrahepatic spread of the tumor.A single lesion 10 cm was observed in 34 patients(11%),while multinodular HCC was present in 189 patients(59%).Thirty nine patients(12%) were BCLC early(A) stage,55(17%) were BCLC intermediate(B) stage,124(39%) were BCLC advanced(C) stage,and 102(32%) were endstage BCLC(D).At the time of this analysis(July 2011),28(9%) patients were still alive.Six(2%) patients who were lost during follow-up were censored at the last visit.The overall median survival was 6.8 mo,and the 1-year survival was 32%.The 1-year survival according to BCLC classes was 100%,79%,12% and 0%,for BCLC A,B,C and D,respectively.There was a significant difference in survival between each BCLC class.The median survival of patients of BCLC stages A,B,C and D was 33,17.4,6.9,and 1.8 mo,respectively(P 0.05 for comparison between stages).The median survival of Child-Pugh A,B and C classes were 9.8 mo(range 6.4-13),6.1(range 4.9-7.3),and 3.7(range 1.5-6),respectively(P 0.05 for comparison between stages).By univariate analysis,the variables significantly associated to an increased liklihood of mortality were Eastern Cooperative Oncology Group performance status(PS),presence of ascites,low level of albumin,elevated level of bilirubin,international normalized ratio(INR) and Log-[(α fetoprotein(AFP)].At multivariate analysis,mortality was independently predicted by bad PS(P 0.0001),high INR values(P = 0.0001) and elevated Log-(AFP) levels(P = 0.009).CONCLUSION:This study confirms the heterogeneous behavior of untreated HCC.BCLC staging remains an important prognostic guide and may be important in decision-making for palliative treatment.