Recovery of adrenal function after chronic secondary adrenal insufficiency in patients with hypopituitarism.

OBJECTIVE: Previous studies have reported recovery of secondary adrenal insufficiency (SAI) in patients with pituitary disorders, generally immediately after pituitary surgery; however, data regarding recovery of long-term SAI are lacking. We conducted a study to assess the longer term recovery rate of SAI in patients with pituitary disorders. METHODS: We identified all SAI patients in the Halifax Neuropituitary Database from 1 November 2005 to 30 September 2014, who had required glucocorticoid therapy for ≥3 months, and had a minimum follow-up of 6 months. Patients with ACTH-secreting adenomas, those receiving glucocorticoids only in the routine peri-operative period for pituitary surgery and those on glucocorticoids for nonpituitary conditions were excluded. SAI was defined as either basal serum cortisol < 130 nm and/or a subnormal cortisol response to ACTH-(1-24) stimulation test or insulin tolerance test response. RESULTS: Fifty-one patients fulfilled the criteria. Nine (17·6%) patients had complete recovery of SAI over a median of 20 months (range: 8-51) after initiating glucocorticoid replacement. Patients with smaller tumour size had increased likelihood of hypothalamic-pituitary-adrenal (HPA) axis recovery, whereas those with secondary hypogonadism or growth hormone deficiency were less likely to recover. Those with initial cortisol >175 nm had an almost one in two chance of recovery. CONCLUSION: Results from our study show that approximately one in six patients with SAI recover adrenal function, even up to 5 years after diagnosis. We recommend that patients with SAI undergo regular testing to assess recovery in order to prevent unnecessary glucocorticoid therapy.

Determinants of hospital costs associated with traumatic brain injury in England and Wales.

Using data from the Trauma Audit Research Network, we investigated the costs of acute care in patients > or = 18 years of age hospitalised for traumatic brain injury between January 2000 and December 2005 in England and Wales. Traumatic brain injury patients were defined and stratified using the Abbreviated Injury Scale. A total of 6484 traumatic brain injury patients were identified; 22.3% had an Abbreviated Injury Scale score of three, 38.0% of four and 39.7% of five. Median age (IQR) was 42 years (28-59) and 76.7% were men. Primary cause of injury was motor vehicle collisions (42.4%) followed by falls (38.0%). In total 23.7% of the patients died before discharge. Hospitalisation costs averaged 15,462 pounds sterling (SD 16,844 pounds sterling). Costs varied significantly by age, Glasgow Coma Score, Injury Severity Score, coexisting injuries of the thorax, spine and lower limb, hospital mortality, availability of neurosurgical services, and specialty of attendants seen in the Accident and Emergency department.

Biphasic insulin aspart 70/30 vs. insulin glargine in insulin naïve type 2 diabetes patients: modelling the long-term health economic implications in a Swedish setting.

OBJECTIVES: To evaluate the long-term clinical and economic outcomes of biphasic insulin aspart 70/30 (BIAsp 70/30) treatment vs. insulin glargine in insulin naïve, type 2 diabetes patients failing oral antidiabetic drugs in a Swedish setting. METHODS: A published and validated computer simulation model (the CORE Diabetes Model) was used to project life expectancy, quality-adjusted life expectancy (QALE) and costs over patient lifetimes. Cohort characteristics [54.5% male, mean age 52.4 years, 9 years mean diabetes duration, mean glycosylated haemoglobin (HbA1c) 9.77%] and treatment effects were based on results from the Initiate Insulin by Aggressive Titration and Education (INITIATE) clinical trial. Direct medical costs were accounted in 2006 Swedish Kronor (SEK) and economic and clinical benefits were discounted at 3% per annum. RESULTS: Biphasic insulin aspart 70/30 treatment when compared with insulin glargine treatment was associated with improvements in discounted life expectancy of 0.21 years (13.10 vs. 12.89 years) and QALE of 0.21 quality-adjusted life years (QALYs) (9.16 vs. 8.96 QALYs). Reductions in the incidence of diabetes-related complications in the BIAsp 70/30 treatment arm led to reduced total costs of SEK 10,367 when compared with insulin glargine (SEK 396,475 vs. SEK 406,842) over patient lifetimes. BIAsp 70/30 treatment was projected to be dominant (cost and lifesaving) when compared with insulin glargine in the base case analysis. CONCLUSIONS: Biphasic insulin aspart 70/30 treatment was associated with improved clinical outcomes and reduced costs compared with insulin glargine treatment over patient lifetimes. These results were driven by improved HbA1c levels associated with BIAsp 70/30 compared with insulin glargine and the accompanying reduction in diabetes-related complications despite increases in body mass index.

Vascular dendritic cells and atherosclerosis.

CD1a positive cells of dendritic shape were detected in the intima of human arteries by immunohistochemical investigation. Analysis of contiguous parallel sections showed that the CD1a positive cells also stained with S-100 and expressed HLA-DR. The CD1a+/S-100+/HLA-DR+ vascular dendritic cell is a type of dendritic cell which participates in atherosclerotic lesion formation. This finding has important implications for understanding atherogenesis and offers a link between immune mechanisms and atherosclerotic lesion formation.

VCAM-1 expression and network of VCAM-1 positive vascular dendritic cells in advanced atherosclerotic lesions of carotid arteries and aortas.

This study was undertaken to determine whether vascular dendritic cells (VDCs) display VCAM-1 in atherosclerotic lesions. Specimens of carotid artery and aorta were obtained at operation. All the plaques contained VCAM-1+ cells, but VCAM-1 immunoreactivity was irregularly distributed being mainly associated with the zones of neovascularisation in the base of the atherosclerotic plaques. Vascular dendritic cells were identified with DAKO-CD1 a. Alternative parallel sections were stained with either anti-CD1 a or anti-VCAM-1. By comparison of consecutive parallel sections the CD1a+ vascular dendritic cells were located separate from other intimal cells. In some areas networks formed by VCAM-1+ vascular dendritic cells were observed suggesting that cellular networks may mediate a local immune response in atherosclerotic lesions. We speculate that VCAM-1 is involved in the formation of cell-to-cell contacts of vascular dendritic cells in atherogenesis.

Cost-effectiveness analysis for statin therapies in the primary prevention of coronary heart disease in Italy.

OBJECTIVE: The objective of this analysis was to compare the costs, benefits and cost effectiveness of two dosage regimens of cerivastatin (0.2 and 0.4 mg/day) with Italian National Health Service (NHS) reimbursed comparative statins in the primary prevention of coronary heart disease in Italy. This study is part of a broader analysis undertaken in five European countries. DESIGN AND SETTING: A cost-effectiveness analysis (CEA) was performed, as the interventions have the same treatment objectives but vary in terms of magnitude of effectiveness. This CEA compared alternative treatments both in the NHS and from societal perspectives. PATIENTS: A coronary heart disease risk assessment model, based on intervention study data from the Lipid Research Clinics Coronary Primary Prevention Trial, was used. This was augmented with demographic, disease, life expectancy, pharmacological and economic data for patients with coronary heart disease in Italy. RESULTS: In terms of average cost effectiveness, our analysis showed that cerivastatin 0.2 mg/day compared favourably with pravastatin 20 mg/day, and compared similarly with simvastatin 20 mg/day in all age groups studied. The study also demonstrated that cerivastatin 0.4 mg/day compared favourably with both simvastatin 40 mg/day and pravastatin 20 mg/day. These results were consistent for both the NHS and societal perspective.The incremental cost per life-year gained [in 1998 Italian lire (L)] of simvastatin versus cerivastatin ranged from about L40 million [or Euro (Eur)20 658] to greater than L650 million (or Eur335 697). Cerivastatin 0.2 mg/day was more cost-effective than pravastatin 20 mg/day, while the incremental cost per life-year gained for cerivastatin 0.4 mg/day versus pravastatin 20 mg/day ranged from L11.1 million (or Eur5733) to L31.8 million (or Eur16 423) in the three age groups (35 to 39 years, 50 to 54 years and 65 to 69 years) for both perspectives. CONCLUSIONS: The results of this study showed that in primary prevention, average cost-effectiveness ratios of cerivastatin compared favourably with those of the other pharmacological interventions available on the Italian market.

Square pegs in round holes: the dilemma of conjoined twins and individual rights.

The judgment in the English Court of Appeal case of Re A (Conjoined Twins: Surgical Separation) highlights forcefully the highly individualistic and abstract assumptions that commonly shape the deployment of rights discourse in liberal legal adjudication. Forced by the all-or-nothing nature of this discourse into a dilemma between perceiving of the twins as separate right-bearers or perceiving of the stronger twin, Jodie, as the singular right-bearer and of Mary, her weaker sibling, as a non-legal entity, the court chose the former option. Perceiving of the twins as distinct and equal legal persons forced the court to employ a balancing of incommensurate interests, implicitly accepting a utilitarian analysis within the strongly deontological confines of law and medicine. The implications of this turn towards utilitarianism are significant. Within the confines of this article, it will be argued, however, that these implications are avoidable if the law concedes a more flexible approach to the dominant notion of the distinct and autonomous right-bearer.

Nasal carriage of pathogenic bacteria in Kalauna Village, Goodenough Island.

Nasal swabs from 62 villagers of Kalauna, Goodenough Island were cultured. Streptococcus pneumoniae was isolated from 16 of 25 adults (64%) and 36 of 37 children (97%). Significant regional clustering of prevalent pneumococcal serotypes were seen among families in core hamlets. Five of 20 adults (20%) and 30 of 37 children (81%) grew Haemophilus influenzae all of which were biotypable. A variety of faecal Gram negative bacilli comprising enterobacteria, Alcaligenes species and an aeromonad were isolated from 30 of 62 (48%) swabs.

Cost-effectiveness of insulin aspart compared to human insulin in pregnant women with type 1 diabetes in the UK.

OBJECTIVES: In women with type 1 diabetes, poor glycaemic control during pregnancy is associated with high risk of pre-term delivery, perinatal mortality and morbidity. This economic analysis utilises clinical effectiveness data from the Insulin Aspart Pregnancy Study Group Trial to assess costs and outcomes associated with insulin aspart (IAsp) and human insulin (HI) as part of a basal-bolus insulin regimen in pregnant women with type 1 diabetes in the UK. RESEARCH DESIGN AND METHODS: Women with type 1 diabetes were enrolled if or=37 weeks' gestation). We considered costs of insulin, adverse events, delivery, and neonatal care for pre-term infants. Expected need for neonatal care was estimated from gestational age, using data from the literature and a large UK hospital. Costs were calculated from the perspective of the UK National Health Service. RESULTS: A total of 322 pregnant women were enrolled in the study and the outcome of pregnancy was known for 302, 151 in each arm. More women experienced a live birth at term with IAsp (72.8%) than with HI (60.9%), difference 11.9% (95% CI 2.0%, 22.5%, p = 0.028). Mean cost per woman was 3222 pounds for IAsp and 3539 pounds for HI, difference--318 pounds (95% CI--1353 pounds, 576 pounds; p = 0.49). CONCLUSIONS: Compared with HI, the use of IAsp in pregnant women with type 1 diabetes resulted in more live births at term, without increasing total costs of treatment. A prospectively defined study is required to confirm these conclusions.

Cost effectiveness of recombinant activated factor VII for the control of bleeding in patients with severe blunt trauma injuries in the United Kingdom.

The aim of this study was to assess the lifetime cost effectiveness of recombinant activated factor VII vs placebo as adjunctive therapy for control of bleeding in patients with severe blunt trauma in the UK. We developed a cost-effectiveness model based on patient level data from a 30-day international, randomised, placebo-controlled Phase II trial. The data were supplemented with secondary data from UK sources to estimate lifetime costs and benefits. The model produced a baseline estimate of the incremental cost per life year gained with recombinant activated factor VII relative to placebo of 12 613 UK pounds. The incremental cost per quality adjusted life year gained was 18 825 UK pounds. These estimates are sensitive to the choice of discount rate and health state utility values used. Preliminary results suggest that relative to placebo, recombinant activated factor VII may be a cost-effective therapy to the UK National Health Service.

The effectiveness of 50% lactose-reduced milk in alleviating milk intolerance.

The level of lactose reduction in milk necessary to alleviate the signs and symptoms of lactose intolerance has received little study. The purpose of this study was to determine whether 50% lactose-reduction in milk is adequate to alleviate the signs and symptoms of lactose maldigestion. even when large amounts of milk are consumed. Seven healthy subjects with proven lactose maldigestion consumed graded doses of whole cow's milk and 50% lactose reduced (LR) whole milk to determine the amount which could be consumed before breath hydrogen rose >20 ppm. This threshold was exceeded on average with 500 ml of 50% LR milk and 200 ml of whole milk. Whole milk produced significantly more breath hydrogen (P<0.05) and maldigestion symptoms (P<0.05) at all levels than the 50% LR milk. These results suggest that milk with as little as 50% lactose reduction can play a major role in the diet of individuals with lactase deficiency.

Perforation of a gastric ulcer into the pericardium: a case report.

This report describes a patient in whom a gastric ulcer arising in a surgically transposed thoracic stomach perforated into the pericardial sac.

Pseudoscleroderma secondary to phytomenadione (vitamin K1) injections: Texier's disease.

Cutaneous reactions to vitamin K1 (phytomenadione) are uncommon. They can present as acute eczematous reactions or late reactions that resemble localized scleroderma after vitamin K1 injections. A case is reported here of a patient who developed bilateral sclerodermoid plaques in a cowboy's holster pattern, which persisted for more than 10 years after subcutaneous vitamin K1 injections. Positive intradermal test with vitamin K1 that persisted as an erythematous indurated plaque at the test site for more than 5 months confirmed marked cutaneous hypersensitivity to vitamin K1 in this patient. Serial biopsies of the erythematous plaque at the test site showed transition from spongiotic eczematous features initially to inflammatory morphoea-like histology over a 5 month period. Possible pathogenic mechanisms for phytomenadione-induced pseudoscleroderma are discussed.

The annual cost of blood transfusions in the United Kingdom.

This study estimated the annual cost of blood transfusions in the UK during 1994/1995. The analysis was based on published data, information derived from interviews with relevant NHS personnel and a purpose-designed structured questionnaire of blood donors. The cost to the UKs blood transfusion services of providing blood and blood products for transfusion was 165.5 Pounds million in 1994/1995. During this period, 2.75 million conventional donations of whole blood and 144,000 apheresis donations of platelets and plasma were collected: 2.58 million units of red blood cells were issued, resulting in approximately 866,000 red blood cell transfusions; 334,000 units of fresh frozen plasma and 1.16 million units of platelets were issued, resulting in approximately 17,000 and 188,000 isolated plasma and platelet transfusions, respectively. Hospital resource use attributable to providing blood transfusions during 1994/1995 cost the NHS 52.6 Pounds million. In total, blood transfusions cost the NHS 218.2 Pounds million during 1994/1995. Of this, red blood cell transfusions accounted for 76% of the annual cost, isolated platelet transfusions 16%, isolated plasma transfusions 1% and other products 7%. Donors incurred direct costs of 3.1 Pounds million and indirect costs of 11.2 Pounds million were accrued due to lost productivity. Additionally, blood donors gave up 2.5 million hours of their leisure time donating blood.

Mononuclear cell subpopulations in the skin defined by monoclonal antibodies after HLA-identical sibling marrow transplantation.

Mononuclear cell subpopulations present in the skin of 36 recipients of HLA-identical sibling marrow transplants were defined by immunoperoxidase using a battery of monoclonal antibodies to cell surface differentiation antigens. The T4-positive (T4+) (helper-inducer T cells), T8+ (cytotoxic-suppressor T cells) and the T6+ (Langerhans cells) decreased in number early post transplant and returned towards normal numbers from day 42 onwards. There was no evidence that either the T4+ or the T8+ subset was involved in cell-to-cell contact damage in acute graft-versus-host disease (GVHD). The paucity of lymphoid cell infiltration of the epidermis in acute GVHD suggested the possibility of a soluble factor being responsible for basal layer damage. In patients with chronic GVHD there was no evidence of T4+ lymphocyte involvement, but T8+ lymphocytes were present in increased numbers, suggesting a role for the T8+ population in the skin lesions of chronic GVHD, or possibly a reflection of the pattern of T4+ and T8+ cell reconstitution in the blood post-transplant. Finally, our study provided no evidence that BI+ (B cells), Leu 7+ (natural killer cells), OKMI+ (histiocytes) or OKT1O+ cells were involved in cell-to-cell contact damage in either acute or chronic GVHD.

Immunohistological assessment of cutaneous drug hypersensitivity in patients with HIV infection.

The pathogenesis of drug hypersensitivity in patients with HIV infection is unknown. To study further the nature of hypersensitivity, the histopathological features of morbilliform drug hypersensitivity reactions were examined in a group of HIV-infected patients. Skin sections from 23 HIV-infected subjects with morbilliform drug hypersensitivity reactions were examined by light microscopy, direct immunofluorescence and immunohistochemistry, to determine the nature of the inflammatory infiltrate and the role of immunoglobulin, complement and cytokines. The principal light microscopic findings were spongiosis, hydropic generation of the basal layer, civatte bodies, an epidermal lymphocytic infiltrate (48%), and a perivascular dermal infiltrate of lymphocytes (87%) and macrophages (52%). Two patients had findings consistent with toxic epidermal necrolysis. Immunohistochemistry demonstrated that the lymphocytic infiltrate consisted of CD8+, HLA-DR+ T lymphocytes (some of which also stained for CD38), a marked depletion of epidermal Langerhans cells (90%), and strong cytoplasmic staining of keratinocytes for IL-6 (60%), IL-1 beta (50%), tumour necrosis factor-alpha (TNF-alpha) (45%) and to a lesser degree, interferon-gamma (IFN-gamma) (35%). Immunofluorescence did not demonstrate any significant deposition of immunoglobulin or complement. The histological findings were independent of the responsible drug, the duration of either therapy or the rash, and of peripheral blood CD4+ and CD8+ cell counts. These findings suggest that activated CD8+ lymphocytes and perhaps epidermal production of cytokines are involved in the pathogenesis of cutaneous drug hypersensitivity in HIV-infected patients. The common histological features, regardless of the causative drug, suggest a common pathogenesis.

The effects of water soluble contrast agents on the respiratory tract.

The water soluble contrast agents Gastrografin (Sodium diatrizoate and meglumine diatrizoate, Schering, Berlin), Iopamiro 300 (Iopamidol, Schering, Berlin), and Dionosil Aqueous (propyliodone BP, Glaxo, England) were instilled into the tracheobronchial tree of rats in doses of either 0.1 ml and 0.25 ml. Rats being used as controls, underwent sham operations with the instillation of air instead of contrast agent. In all, 85 rats were used. All rats that had not already died from the effects of contrast agent were sacrificed 30 minutes after instillation. The relative effects of the contrast agents were measured by comparing: 1. survival time; 2. radiographic effects of the contrast agents on the lungs and; 3. pathological changes as estimated by post mortem lung section and microscopy. The least toxic agent was the one with the lowest osmotic activity, namely Aqueous Dionosil. It is therefore recommended that Aqueous Dionosil be used in preference to Gastrografin or Iopamidol for studies of the oesophagus whenever there is a danger of aspiration of contrast agent into the tracheobronchial tree.

Pulmonary manifestations of the acquired immunodeficiency syndrome.

Between 1983 and 1985, 71 patients with the acquired immunodeficiency syndrome (AIDS) were evaluated. Pulmonary manifestations were present in 42 patients (59%). Pneumocystis carinii pneumonia (PCP) was the most common pulmonary manifestation, present in 32 patients (45%). Other pulmonary findings were cytomegalovirus pneumonia (one patient), Candida pneumonia (one patient), cryptococcal pneumonia (one patient), bacterial pneumonia (three patients), nonspecific pneumonitis (three patients), Kaposi's sarcoma (one patient), and non-Hodgkin's lymphoma (one patient). The presenting features of PCP were reviewed and in seven patients the chest X-ray and blood gases were normal at the time of diagnosis of PCP. Bronchoscopy was a safe and useful technique for obtaining specimens for diagnosis promptly, and a combination of samples obtained by bronchial washings/brushings and transbronchial biopsy was found to give a higher diagnostic yield than any single sample. Drug side-effects were common during therapy, requiring change of therapy in 16 patients. At one month after diagnosis 16% of patients with PCP had died. PCP is a common pulmonary manifestation in patients with AIDS which is treatable and has an initially favourable outcome.