Upper gastrointestinal haemorrhage in the elderly: a record of 92 patients in a joint geriatric/surgical unit

Ninety-two consecutive elderly patients suffering from acute gastrointestinal bleeding were studied over a 3-year period. All were admitted to a specially designated Geriatric/Surgical Ward under the care of consultant physicians in geriatric medicine. The nurses were trained to look after acute surgical and geriatric patients. Patients were aged between 65 and 93 years. All were managed jointly by the surgeons and physicians. Only 13 needed emergency surgery which was preceded by urgent endoscopy. The rest were managed conservatively with intravenous cimetidine and blood transfusions as required. The overall mortality was low at 5.4%. It is concluded that in a series of elderly patients with acute gastrointestinal bleeding the mortality was not high in a unit where the management was conservative and there was joint care between geriatricians and surgeons.     

The Influence of refractoriness upon comprehension of non-verbal auditory stimuli

An investigation of non-verbal auditory comprehension in two patients with global aphasia following stroke is reported. The primary aim of the investigation was to establish whether refractory access disorders can affect non-verbal input modalities. All previous reports of refractoriness, a cognitive syndrome characterized by response inconsistency, sensitivity to temporal factors and insensitivity to item frequency, have involved comprehension tasks which have a verbal component. Two main experiments are described. The first consists of a novel sound-to-picture and sound-to-word matching task in which comprehension of environmental sounds is probed under conditions of semantic relatedness and semantic unrelatedness. In addition to the two stroke patients, the performance of a group of 10 control patients with non-vascular pathology is reported, along with evidence of semantic relatedness effects in sound comprehension. The second experiment examines environmental sound comprehension within a repetitive probing paradigm which affords assessment of the effects of semantic relatedness, response consistency and presentation rate. It is demonstrated that the two stroke patients show a significant increase in error rate across multiple probes of the same set of sound stimuli, indicating the presence of refractoriness within this non-verbal domain. The implications of the results are discussed with reference to our current understanding of the mechanisms of refractoriness.     

Low rate of active treatment of patients with hilar cholangiocarcinoma

Introduction

The results of surgical resection and palliative chemotherapy use in hilar cholangiocarcinoma (HC) have been well publicised but the proportion of patients able to undergo these treatments and the comparative outcomes in a population of patients with HC are less well known.

Methods

Patients with HC were identified by review of all patients undergoing percutaneous cholangiography over a nine-year period (2002–2010) in a tertiary facility. The treatment undertaken and outcomes were recorded.

Results

Overall, 68 patients were identified (37 female) with a median age of 70 years. Forty-five (66%) were treated solely by insertion of a metal stent (median survival 4.73 months) and nine (13%) also received palliative chemotherapy (median survival 13.7 months). Persisting jaundice after stent insertion was noted in 18 of 35 patients (51%) tested within one month of death. Fourteen patients (21%) underwent surgical resection (median survival 20.2 months).

Conclusions

Patients undergoing surgical resection had significantly longer survival than those receiving only a palliative stent but not compared with those also receiving palliative chemotherapy, with short-term follow-up. Only a third of patients, however, receive active treatment (surgery or chemotherapy) and improvements in long-term biliary palliation are needed.     

Human class I major histocompatibility complex alleles determine central nervous system injury versus repair

Background

We investigated the role of human HLA class I molecules in persistent central nervous system (CNS) injury versus repair following virus infection of the CNS.

Methods

Human class I A11⁺ and B27⁺ transgenic human beta-2 microglobulin positive (Hβ2m⁺) mice of the H-2 ^b background were generated on a combined class I-deficient (mouse beta-2 microglobulin deficient, β2m⁰) and class II-deficient (mouse Aβ⁰) phenotype. Intracranial infection with Theiler’s murine encephalomyelitis virus (TMEV) in susceptible SJL mice results in acute encephalitis with prominent injury in the hippocampus, striatum, and cortex.

Results

Following infection with TMEV, a picornavirus, the Aβ⁰.β2m⁰ mice lacking active immune responses died within 18 to 21 days post-infection. These mice showed severe encephalomyelitis due to rapid replication of the viral genome. In contrast, transgenic Hβ2m mice with insertion of a single human class I MHC gene in the absence of human or mouse class II survived the acute infection. Both A11⁺ and B27⁺ mice significantly controlled virus RNA expression by 45 days and did not develop late-onset spinal cord demyelination. By 45 days post-infection (DPI), B27⁺ transgenic mice showed almost complete repair of the virus-induced brain injury, but A11⁺ mice conversely showed persistent severe hippocampal and cortical injury.

Conclusions

The findings support the hypothesis that the expression of a single human class I MHC molecule, independent of persistent virus infection, influences the extent of sub frequent chronic neuronal injury or repair in the absence of a class II MHC immune response.

     

Tolerability,pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor,in healthy subjects

Aims

Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Methods

Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18–55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18–55 years), 25, 50, 100 and 150 mg (Japanese males, 18–55 years). Study 2: Caucasian males (18–55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21–28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests.

Results

Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92–99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated.

Conclusions

TA-8995 is a potent CETP inhibitor and warrants further investigation.