Verification of expected death by district nurses

Pressures on a local out-of-hours GP deputizing service led to lengthy delays before a doctor could visit to verify the (expected) death of patients under the care of the district nursing service. This resulted in distress to the relatives and delayed transfer of the body to a funeral home. This article explores an initiative to enable community nursing staff to verify those expected deaths and to provide more effective support to relatives at a difficult time. The article highlights the benefits of multidisciplinary collaboration in the development of an appropriate protocol and provides an overview of its implementation in one area. The initiative contributes to the Government's agenda to improve access to primary care and to create more patient-friendly services.     

Important effect of food on the bioavailability of oral testosterone undecanoate

STUDY OBJECTIVE: To assess the effects of food on the bioavailability of testosterone undecanoate, testosterone, and 5alpha-dihydrotestosterone (DHT) after administration of a new oral testosterone undecanoate formulation, Andriol Testocaps. DESIGN: Randomized, open-label, crossover study with a 1-week washout period. SETTING: Clinical pharmacology unit. SUBJECTS: Sixteen healthy postmenopausal women. INTERVENTION: Single oral doses of testosterone undecanoate 80 mg were administered either during a fasting period or after consumption of a standardized continental breakfast. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of testosterone undecanoate were assayed by liquid chromatography with mass spectrometry detection; testosterone and DHT were assayed by gas chromatography with mass spectrometry detection. Serum concentrations of testosterone, testosterone undecanoate, and DHT were low to negligible when testosterone undecanoate was administered to subjects in a fasting state; these values were significantly higher when the test drug was coadministered with food. For testosterone, the maximum serum concentration and area under the plasma concentration-time curve were 0.67 ng/ml and 5.37 ng x hr/ml, respectively, in the fasting state, versus 10.7 ng/ml and 56.4 ng x hr/ml, respectively, in the fed state. The same parameters were also significantly higher for testosterone undecanoate and DHT in the fed versus fasting subjects. CONCLUSION: Food increases the bioavailability of testosterone undecanoate, testosterone, and DHT. For proper absorption, Andriol Testocaps must be taken with meals.     

Poly (ADP-ribose) polymerase inhibition prevents spontaneous and recurrent autoimmune diabetes in NOD mice by inducing apoptosis of islet-infiltrating leukocytes

Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. The PARP inhibitor nicotinamide prevents NAD consumption and protects islet beta-cells from chemically induced necrosis but not cytokine-induced apoptosis. Therefore, it is unclear how nicotinamide protects NOD mice from autoimmune diabetes in which apoptosis is the mode of beta-cell death. To investigate the mechanism of diabetes prevention by PARP inhibition, we studied the effects of a novel, potent PARP inhibitor, PJ34, a phenanthridinone derivative, on diabetes development in NOD mice and on diabetes recurrence in diabetic NOD mice transplanted with syngeneic islets. PJ34 administration from age 5 or 15 weeks significantly decreased insulitis, beta-cell destruction and diabetes incidence, and protection from diabetes continued for 12 weeks after PJ34 therapy was stopped. Similarly, syngeneic islet graft survival was prolonged and outlasted therapy in PJ34-treated mice. Immunohistochemical studies revealed significantly fewer leukocytes in islet grafts of PJ34-treated mice, together with increased apoptosis of these cells and decreased expression of the T helper 1-type cytokine interferon (IFN)-gamma. These results suggest that PARP inhibition protects against autoimmune beta-cell destruction in NOD mice by inducing apoptosis of islet-infiltrating leukocytes and decreasing IFN-gamma expression in the islets.     

Familial melanoma: a complex disorder leading to controversy on DNA testing

The initial enthusiasm generated by the discovery of the first susceptibility gene found for melanoma has slightly dampened over recent years. For the majority of melanoma families the underlying gene defect is still not known, so the search for other melanoma genes is continuing. Also, the increased risk of melanoma does not seem to be restricted to mutation carriers, but is present even in non-mutation carriers in melanoma families. The underlying defect of familial melanoma is less straightforward than previously thought; both environmental and hereditary risk modifiers intermingle in a perplexing way. This makes familial melanoma a complex disorder which deserves the close attention of both clinicians and researchers, especially as the opinion on gene testing in familial melanoma has not yet achieved consensus. On the one hand, there is a rising demand from families for genetic testing; on the other hand, there is the clinicians' concern about the value of such testing. This revised version was published online in August 2006 with corrections to the Cover Date.     

Epidemiological validation of pulsed-field gel electrophoresis patterns for methicillin-resistant Staphylococcus aureus

To determine the stability of pulsed-field gel electrophoresis (PFGE) patterns of methicillin-resistant Staphylococcus aureus in the nosocomial setting, we analyzed isolates from long-term carriers (>1 month) and from patients involved in well-defined nosocomial epidemics. The number of fragment differences between the first isolate and subsequent isolates in long-term carriers showed a bimodal distribution, with one group having 0 to 6 fragment differences and the other group having 14 to 24 fragment differences. The PFGE patterns of isolates involved in epidemics also presented a similar bimodal distribution of the number of fragment differences. Typing these isolates with another molecular method (inter-IS256 PCR) showed that isolates of the first group (i.e., with 1 to 6 fragment differences) were clonally related, whereas the second group (with 14 to 24 fragment differences) could be considered genetically different. Among long-term carriers with clonally related isolates, 74 of 84 (88%) of consecutive isolates showed indistinguishable patterns, whereas 10 of 84 (12%) showed related patterns differing by one to six fragments. Moreover, the frequency of apparition of related patterns is higher when the time between the first and the subsequent isolate is longer. During seven nosocomial epidemics lasting from 1 to 15 months, only 2 of 120 isolates (1.7%) showed a pattern which was different, although related, from the predominant one involved in each of these outbreaks.     

Effects of long-term Irbesartan in reducing portal pressure in cirrhotic patients: comparison with propranolol in a randomised controlled study

BACKGROUND/AIMS: The role of angiotensin II (AT-II) type I receptor antagonists in the treatment of portal hypertension remains controversial. We tested the efficacy of Irbesartan (Irb) vs. Propranolol (Pro) in reducing portal pressure and evaluated its systemic haemodynamic effects. METHODS: Thirty-four patients were randomly assigned to receive either Irb 300 mg/day (19 patients) or Pro 40-120 mg/day (15 patients) for 2 months. RESULTS: Irb was discontinued in five patients (26%). No major side effect occurred in the Pro group. On an average, the portal pressure gradient decreased significantly more in the Pro than in the Irb group (median -19.5%, range -11/-31% vs. -4.8%, +2.5/-10%, P<0.001). A clinically significant decrease was seen in one (7%) of the patients given Irb vs. five (33%) given Pro (P<0.02). The fall in mean arterial pressure was significantly higher with Irb than with Pro (median -29%, range -15/-45% vs. -4.9%, +8/-19%, P<0.02). Irb significantly modified the blood creatinine clearance (median -29 ml/m, range +9/-61 ml/m, -30, -24/-35% P<0.0001 vs. basal). CONCLUSIONS: Irb offers no advantage over Pro in the control of portal hypertension. Moreover, its therapeutic profile is limited by important side effects.     

Detrimental Immunologic Effects of Preoperative Chemoradiotherapy in Advanced Rectal Cancer

PURPOSE: Preoperative chemoradiotherapy for advanced rectal cancer has been an important therapeutic tool to improve the long-term results of curative resection. It is not known whether preoperative chemoradiotherapy for advanced rectal cancer influences the perioperative course of immune parameters. METHODS: Thirty patients with rectal cancer underwent surgery with (study group, n = 15) or without (control group, n = 15) preoperative chemoradiotherapy (2 cycles of 5-fluorouracil, 45 Gy). Blood samples were taken before neoadjuvant therapy, preoperatively, and on Days 1, 2, and 5 after surgery. Cell numbers of lymphocyte subpopulations, granulocytes, monocytes, and natural killer cells were determined by flow cytometry; tumor necrosis factor- and interleukin-6 serum levels were measured with enzyme-linked immunosorbent assay. RESULTS: Significant differences between study and control patients (P < 0.05) were detected regarding circulating interleukin-6 and tumor necrosis factor- levels, with depression of the proinflammatory response to surgery in study patients. Similarly, granulocytosis and monocytosis after surgery were significantly lower in patients after neoadjuvant therapy. Furthermore, cell counts of total T lymphocytes, T helper cells, B lymphocytes, and natural killer cells were significantly reduced after preoperative chemoradiotherapy. This depression of cell-mediated immunity in study patients was even more pronounced after surgery. CONCLUSIONS: Preoperative chemoradiotherapy for advanced rectal cancer results in a significant preoperative and postoperative immune dysfunction as indicated by depression of lymphocyte subpopulations, monocytes, granulocytes, and proinflammatory cytokine release. These findings are of importance because increased perioperative morbidity and mortality rates have been observed after preoperative chemoradiotherapy.     

No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the beta-cleaved C-terminal APP fragment

Previous studies in the literature have resulted in conflicting reports on the potential neurotoxicity of the beta-cleaved Alzheimer's disease C-terminal fragment (beta-CTF) of beta-amyloid precursor protein in vivo. To readdress this question by rigorous quantitative methods, we analyzed transgenic mice expressing human beta-CTF with the I45F mutation (SPA4CT) under control of the prion protein promoter by stereological techniques. The transgene was expressed in hippocampus and cortex in large pyramidal neurons and in dentate gyrus granule cells. Proteolytic processing of beta-CTF released Abeta. However, most of it remained uncleaved. Neurodegeneration was evaluated by investigating the numbers of hippocampal pyramidal and granule neurons, as well as the number of synaptophysin-immunopositive presynaptic boutons in the hippocampus of 15-month-old SPA4CT mice with design-based stereological techniques. The analyses showed that a fourfold higher expression of the transgene compared to murine APP levels had no effect on the numbers of both neurons and synaptophysin-immunopositive presynaptic boutons. These data implicate that expression of beta-CTF per se is not neurotoxic, and that other mechanisms are responsible for the neurotoxic events in Alzheimer's disease brain.     

The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys

Absence of a common diagnostic interview has hampered cross-national syntheses of epidemiological evidence on major depressive episodes (MDE). Community epidemiological surveys using the World Health Organization Composite International Diagnostic Interview administered face-to-face were carried out in 10 countries in North America (Canada and the US), Latin America (Brazil, Chile, and Mexico), Europe (Czech Republic, Germany, the Netherlands, and Turkey), and Asia (Japan). The total sample size was more than 37,000. Lifetime prevalence estimates of hierarchy-free DSM-III-R/DSM-IV MDE varied widely, from 3% in Japan to 16.9% in the US, with the majority in the range of 8% to 12%. The 12-month/lifetime prevalence ratio was in the range 40% to 55%, the 30-day/12-month prevalence ratio in the range 45% to 65%, and median age of onset in the range 20 to 25 in most countries. Consistent socio-demographic correlates included being female and unmarried. Respondents in recent cohorts reported higher lifetime prevalence, but lower persistence than those in earlier cohorts. Major depressive episodes were found to be strongly co-morbid with, and temporally secondary to, anxiety disorders in all countries, with primary panic and generalized anxiety disorders the most powerful predictors of the first onset of secondary MDE. Major depressive episodes are a commonly occurring disorder that usually has a chronic-intermittent course. Effectiveness trials are needed to evaluate the impact of early detection and treatment on the course of MDE as well as to evaluate whether timely treatment of primary anxiety disorders would reduce the subsequent onset, persistence, and severity of secondary MDE.