Insulin-induced desensitization at the receptor and postreceptor level in mitogen-activated human T-lymphocytes

Human T-lymphocytes activated by phytohemagglutin acquire insulin receptors in culture. Saturation analysis of insulin-binding activity in the presence of competing ligand revealed curvilinear Scatchard plots. Insulin receptors were not regulated by insulin before mitogen activation and culture of T-lymphocytes. However, insulin-induced downregulation of insulin receptors was: (1) demonstrable in receptor-positive cells, (2) dependent on insulin concentration, (3) temporally unrelated to insulin internalization, and (4) prevented by culture at 4 degrees C but not by cycloheximide at 37 degrees C. Recovery of insulin receptors required further culture of cells in media depleted of insulin for 24 h. Scatchard analysis revealed loss of receptor number without changes in receptor affinity. Insulin-induced increases in glucose transport and oxidation were demonstrable in receptor-positive cells but not in receptor-negative cells. However, these effects were extremely time-dependent. After a 2-h exposure of cells to 10(-8) M insulin, increases in glucose transport were no longer demonstrable. Elution of bound insulin from these cells followed by re-exposure to insulin depressed glucose transport in them. Recovery from this hyporesponsive, desensitized state required a 6-h culture in insulin-depleted media. Glucose oxidation of desensitized cells could be stimulated by spermine but not by insulin. These studies demonstrate the activated human T-lymphocyte is an insulin-sensitive tissue that is capable of limiting its physiologic response to insulin by receptor- and postreceptor-mediated mechanisms.     

Anticholinergic burden and functional status in older people with cognitive impairment: Results from the ReGAl project

Objective

The use of drugs with intrinsic anticholinergic properties is widespread among old age persons. A growing body of evidences suggest that a high anticholinergic burden is associated with physical and cognitive impairment. However, the association between anticholinergic drug use and functional status is still poorly investigated, particularly among subjects with initial cognitive impairment.

Design

Cross-sectional study examining the association between drug-related anticholinergic burden and functional status in cognitively healthy (CH) (n=691), mild cognitive impairment (MCI) (n=541) or mild Alzheimer’s diseases (AD) (n=1127) subjects.

Setting

Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer’s disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG).

Participants

2359 outpatients, older than 65 years, admitted to memory clinics. The total sample size, estimated according to a global effect size of 25% with type I error of 0.05 and a power of 95% is 2010 subjects.

Measurement

Functional status was evaluated by the Katz Index of Independence in Activities of Daily Living (ADL) and the Lawton-Brody Instrumental Activities of Daily Living (IADL) scales. The drug-related anticholinergic burden was estimated by the Anticholinergic Risk Scale (ARS).

Results

The 15.9 % (n=375) of total population used at least one drug with anticholinergic properties. Such a drug use was associated with partially dependence in ADL (OR:1.42, CI95%: 1.10-1.83; p=0.006), independently of gender, number of drugs, comorbidity index, presence of clinically relevant neuropsychiatric symptoms and adjusted MMSE. Anticholinergic drug use was associated with un-ability at each IADL task only in male MCI subjects, with significant impairment in shopping (p=0.011), and drug management (p=0.05).

Conclusions

The use of medications with anticholinergic properties is common among older persons cognitively health as well as with cognitive impairment. Our results suggest that the use of anticholinergic drugs is associated with functional impairment, especially in old age subjects with initial cognitive impairment. Minimizing anticholinergic burden should result in maintaining daily functioning, especially in a vulnerable population, such as MCI and mild AD.

     

Simultaneous bilateral laparoscopic adrenalectomy is safe for synchronous large adrenal tumors.

Laparoscopy is now considered the gold standard for treating benign monolateral adrenal lesions. We present the case of a patient affected by Cushing's syndrome due to large bilateral adrenal adenomas (7.5 cm) who underwent simultaneous laparoscopic bilateral adrenalectomy. An anterior, lateral transperitoneal approach was used. Operative time was 200 minutes, and blood loss was 200 mL. No intraoperative complications were encountered. The postoperative course was uneventful, and the patient was discharged after 3 days. Laparoscopic bilateral adrenalectomy is a safe, effective procedure when performed by experienced hands and may be an alternative treatment for large adrenal lesions.     

Revisiting the role of pathological analysis in transarterial chemoembolization-treated hepatocellular carcinoma after transplantation

AIM: To define the histopathological features predictive of post-transplant hepatocellular carcinoma (HCC) recurrence after transarterial chemoembolization, applicable for recipient risk stratification.METHODS: We retrospectively reviewed the specimens of all suspicious nodules (total 275) from 101 consecutive liver transplant recipients which came to our Pathology Unit over a 6-year period. All nodules were sampled and analyzed, and follow-up data were collected. We finally considered 11 histological variables for each patient: total number of nodules, number of viable nodules, size of the major nodule, size of the major viable nodule, occurrence of microscopic vascular invasion, maximum Edmondson''s grade, clear cell/sarcomatous changes, and the residual neoplastic volume. Survival data were computed by means of the Kaplan-Meier procedure and analyzed by means of the Cox proportional hazards model. The multivariate linear regression and a k-means cluster analysis were also used in order to compute the standardized histological score.RESULTS: The total number of nodules, the residual neoplastic volume (the total volume of all evaluated nodules minus the necrotic portion) and the microvascular invasion entered the Cox multivariate hazard model with HCC recurrence as dependent variable. The histological score was therefore computed and a cluster analysis sorted recipients into 3 risk groups, with 3.3%, 18.5% and 53.8% respectively of tumor recurrence rates and 1.6%, 11.1% and 38.5% of tumor-related mortality respectively at the end of follow-up.CONCLUSION: The histological score allows a reliable stratification of HCC recurrence risk, especially in those recipients found out to be beyond the Milan criteria after orthotopic liver transplantation (OLT).     

Kidney Preservation: Review of Present and Future Perspective

One of the main problems in transplant surgery is the preservation of the organ during the cold ischemic time. The interrupted blood supply triggers a cascade of biological modifications resulting in cell death, which predisposes to discharge of a large quantity of toxic metabolites at the moment of organ reperfusion. Many approaches have been studied to prevent the toxic processes. Immediately after procurement, kidneys are flushed with these solutions. Two main: techniques of organ preservation are cold static storage and hypothermic machine perfusion (HMP). Based on age and comorbidities, individuals can be generally divided into 2 groups: ideal and marginal donors. Characteristics of organs from marginal donors are associated with an increased rate of delayed graft function and primary graft nonfunction (PNF), which reduce transplant survival and increase the acute rejection risk. In the last 20 years, the United Network of Organ Sharing has reported a 170% increase in deceased donors older than 50 years of age. Techniques of perfusion have been demonstrated to play a pivotal role in graft function after transplantation. Some studies suggest that HMP may improve outcomes after transplantation.     

Contributions of cell kill and posttreatment tumor growth rates to the repopulation of intracerebral 9L tumors after chemotherapy: An MRI study

The drought of progress in clinical brain tumor therapy provides an impetus for developing new treatments as well as methods for testing therapeutics in animal models. The inability of traditional assays to simultaneously measure tumor size, location, growth kinetics, and cell kill achieved by a treatment complicates the interpretation of therapy experiments in animal models. To address these issues, tumor volume measurements obtained from serial magnetic resonance images were used to noninvasively estimate cell kill values in individual rats with intracerebral 9L tumors after treatment with 0.5, 1, or 2 × LD₁₀ doses of 1,3-bis(2-chloroethyl)-1-nitrosourea. The calculated cell kill values were consistently lower than those reported using traditional assays. A dose-dependent increase in 9L tumor doubling time after treatment was observed that significantly contributed to the time required for surviving cells to repopulate the tumor mass. This study reveals that increases in animal survival are not exclusively attributable to the fraction of tumor cells killed but rather are a function of the cell kill and repopulation kinetics, both of which vary with treatment dose.     

Daclizumab and Alemtuzumab as induction agents in adult intestinal and multivisceral transplantation: A comparison of two different regimens on 29 recipients during the early post-operative period

INTRODUCTION: Induction therapy has been recently adopted for intestinal transplant. PATIENTS AND METHODS: We compared during first 30 days post-transplantation 29 recipients, allocated in two groups, treated with Daclizumab (Zenapax) or Alemtuzumab (Campath-1H). RESULTS: During first month, 45% of Daclizumab recipients experienced six acute cellular rejections (ACRs) of mild degree, while 63% of them developed an infection requiring treatment. We found three acute cellular rejections in 17.6% of Alemtuzumab recipients, two with moderate degree; 64.7% of them required treatment for infection. DISCUSSION AND CONCLUSIONS: Graft and patient 3-years cumulative survival rate were not significantly different between groups. Alemtuzumab seems to offer a better immunosuppression during first month.     

Splenoadrenal shunt. An original portosystemic decompressive technique

Management of gastrointestinal hemorrhage from rupture of esophageal and gastric varices due to portal hypertension remains a debated question. In patients with sclerotherapy-resistant esophagogastric varices, and preserved hepatic function, a surgical shunt is considered the treatment of choice. A 63-year-old male was admitted in our Department with a diagnosis of idiopathic fibrosis of the liver, portal hypertension, esophageal and gastric varices and previous history of variceal bleeding. A distal splenorenal shunt was planned. During the isolation, a large diameter left adrenal vein was identified. An end-to-end anastomosis utilizing the distal splenic vein and the proximal adrenal stump was performed. The procedure was uneventful. An ultrasound color-Doppler on the 3rd postoperative day, showed normal intrasplenic resistance index, demonstrating the efficacy of the shunt. A splenic angiography carried out on the 8th postoperative day showed the complete patency of the splenoadrenal shunt. At the 15th postoperative day, the patient was discharged. In patients with portal hypertension, sclerotherapy-resistant esophagogastric varices and preserved hepatic function, a surgical portosystemic shunt is mandatory. Splenoadrenal shunt, utilizing a left adrenal vein represent an excellent option in selected cases.