Tapering for marathon and cardiac autonomic function.

The purpose of this study was to investigate changes in post-exercise heart rate recovery (HRR) and heart rate variability (HRV) during an overload-tapering paradigm in marathon runners and examine their relationship with running performance. 9 male runners followed a training program composed of 3 weeks of overload followed by 3 weeks of tapering (-33 ± 7%). Before and after overload and during tapering they performed an exhaustive running test (T(lim)). At the end of this test, HRR variables (e.g. HRR during the first 60 s; HRR(60 s)) and vagal-related HRV indices (e.g. RMSSD(5-10 min)) were examined. T(lim) did not change during the overload training phase (603 ± 105 vs. 614 ± 132 s; P = 0.992), but increased (727 ± 185 s; P = 0.035) during the second week of tapering. Compared with overload, RMSSD(5-10 min) (7.6 ± 3.3 vs. 8.6 ± 2.9 ms; P = 0.045) was reduced after the 2(nd) week of tapering. During tapering, the improvements in T(lim) were negatively correlated with the change in HRR(60 s) (r = -0.84; P = 0.005) but not RMSSD(5-10 min) (r = -0.21; P = 0.59). A slower HRR during marathon tapering may be indicative of improved performance. In contrast, the monitoring of changes in HRV as measured in the present study (i.e. after exercise on a single day), may have little or no additive value.

Comparison of DVH data from multiple radiotherapy treatment planning systems.

This study examined the variation of dose-volume histogram (DVH) data sourced from multiple radiotherapy treatment planning systems (TPSs). Treatment plan exports were obtained from 33 Australian and New Zealand centres during a dosimetry study. Plan information, including DVH data, was exported from the TPS at each centre and reviewed in a digital review system (SWAN). The review system was then used to produce an independent calculation of DVH information for each delineated structure. The relationships between DVHs extracted from each TPS and independently calculated were examined, particularly in terms of the influence of CT scan slice and pixel widths, the resolution of dose calculation grids and the TPS manufacturer. Calculation of total volume and DVH data was consistent between SWAN and each TPS, with the small discrepancies found tending to increase with decreasing structure size. This was significantly influenced by the TPS model used to derive the data. For target structures covered with relatively uniform dose distributions, there was a significant difference between the minimum dose in each TPS-exported DVH and that calculated independently.

Mortality and drug exposure in a 5-year cohort of patients with chronic liver disease.

BACKGROUND: Chronic liver diseases are common in the general population. Drug treatment in this group may be challenging, as many drugs are hepatically metabolised and hepatotoxic. OBJECTIVES: We aimed to assess the mortality of patients with chronic liver disease according to specific drug exposures and the three laboratory parameters creatinine, bilirubin and International Normalised Ratio (INR). METHODS: We conducted a multicentre, 5-year retrospective cohort study in two tertiary university referral hospitals and a secondary referral hospital, using a research database to evaluate the crude and adjusted mortality. RESULTS: Of 1159362 individual patients 1.7% (n = 20158) had chronic liver disease and in this group 36.8% had unspecified chronic non-alcoholic liver disease, 30.1% chronic hepatitis C and 11.9% cirrhosis of the liver. 8.4% of patients presented a diagnosis associated with alcohol. The 4-year survival rates were significantly higher in the group with the most normal laboratory values (94.3%) versus 34.5% in the group with elevated parameters (p <0.001). Overall, drug exposure was not associated with higher mortality; in adjusted multivariate analysis the hazard ratio for anti-cancer drugs was 2.69 (95% CI 1.32-5.46). Of individual drugs, mortality hazard ratios for amiodarone, morphine oral, acetazolamide, sirolimus and lamivudine were 2.46 (95% CI 1.68-3.61), 2.26 (95% CI 1.78-2.86), 2.10 (95% CI 1.19-3.70), 1.81 (95% CI 1.02-3.21) and 1.72 (95% CI 1.17-2.53) respectively. CONCLUSIONS: Drug exposure in general was not associated with higher mortality except for a few categories. Mortality in patients with chronic liver disease was high and is associated with simple laboratory values.

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus.

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (C(max)) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUC(sum) (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.

[Somnolence of unknown origin--illness or drug problem?]. / Somnolenz unklarer Provenienz--krankheits- oder medikamentös bedingt?

A 64 year old female patient with previously known temporal lobe epilepsy (TLE) was admitted to the emergency department (ED) for further investigation of somnolence of unknown origin. Differential diagnosis remained puzzling after exclusion of an intracranial process and status epilepticus. Quantitative and qualitative fluctuations of consciousness are well known to take place in TLE as well as that these patients often are receiving several drugs for their illness. Drug history and measuring serum drug levels are helpful. Adverse Drug Events (ADE) are not rare in EDs: approximately 5% of ED patients are suffering an ADE and about 3% of patients admitted to hospitals are admitted because of an ADE. It is important to realize that three out of four ADEs are estimated to be preventable.

[Nosocomial urinary tract infection in adults]. / Nosokomiale Harnwegsinfektionen des Erwachsenen.

Urinary tract infection (UTI) is the most common infection in hospitalized adults. Nosocomial UTIs are mainly associated with the use of urinary catheters. Thus, the decision for catheterization should be made carefully and catheters removed in time. In order to prevent unnecessary antibiotic use in patients with urinary catheters correct diagnosis is crucial. Chinolones, broad-spectrum penicillins and third-generation cephalosporins are the mainstay of therapy. Comorbidities should be considered and potential obstructions of urinary flow removed. Economically important are the normally higher prices of i.v. antibiotics compared to oral use.

[Atypical erythema induratum Bazin with tuberculous osteomyelitis]. / Atypisches erythema induratum Bazin bei tuberkulöser osteomyelitis.

Diagnosis of all types of cutaneous tuberculosis is challenging because the clinical picture of these diseases is highly variable. We describe the case of a 79-year old woman with an atypical presentation of Erythema induratum Bazin (EIB) on the chest and left arm in association with a tuberculous osteomyelitis of the left olecranon. Surprisingly, M. tuberculosis grew also from biopsies of the EIB-lesions. This contradicts the conventional view that considers EIB (a tuberculid) to be caused by a hypersensitivity reaction to mycobacteria. The presented case supports the hypothesis that EIB may also be caused by hematogenous or lymphatic spread of viable M. tuberculosis.

[Wound botulism after drug injection]. / Wundbotulismus nach Drogeninjektion.

CLINICAL PRESENTATION: A 32-year old male drug user presented with diplopia, ataxia and general weakness. The patient had abscesses on arms and legs at injection sites, bilateral ptosis, a bifacial weakness, nasal speech, severely reduced ability to raise his arms and a positive Trendelelenburg sign with normal motor neuron reflexes and normal sensation. CLINICAL AND LABORATORY TESTS: The haematological values indicated a hypochromic, microcytic anaemia (12,1 mg/dl), a slight leuko (10,8 G/L) - and thrombocytosis (582G/l) with elevated erythrocyte sedimentation rate (74 mm/h), and a reduced prothrombin time (67%). The HIV test was negative. The MRI scan of the brain and the bacterial, serological and cytological results of a lumbar puncture were normal. In the bloodculture no bacterial growth and no botulinum toxin was found. In a culture of the wound material grew coagulase-negative staphylococcus and Clostridium perfringens, diagnosed with PCR. The serum anti-acethylcholine antibodies were negative. The motor-nerve conduction test with repetitive stimulation of the ulnari nerve with a 3 Hz trigger showed no change in the amplitude, while a 20 Hz trigger showed an increment up to 160 %. DIAGNOSIS, TREATMENT AND RESPONSE TO THERAPY: Another possible diagnosis was excluded through MRI, CSF and serum examination. The typical presentation of a rapidly progressive descending paralysis without loss of sensation and the typical motor-nerve conduction disorder of a presynaptic block established the diagnosis of wound botulism. This was treated immediately by surgical removal of wound debris, antitoxin- and penicillin therapy. After 28 days the patient left the hospital with slight residual problems. He had been admitted to the intensive care unit for a short period only and intubation was not necessary at any time. CONCLUSION: After exclusion of any other possible diagnosis, it is possible to establish an early diagnosis of injection related wound botulism by its typical symptoms and signs. These are presented as wound abcesses at intramuscular drug injection sites together with rapidly progressive descending paralysis with preserved sensation. Treatment consists of surgical excision of wound debris combined with antitoxin and penicillin administration in order to prevent a possible build-up of residues. Early diagnosis and associated therapy overcome the necessity of intubation and prolonged intensive care.

Oligomerization of ETO is obligatory for corepressor interaction.

Nearly 40% of cases of acute myelogenous leukemia (AML) of the M2 subtype are due to a chromosomal translocation that combines a sequence-specific DNA binding protein, AML1, with a potent transcriptional repressor, ETO. ETO interacts with nuclear receptor corepressors SMRT and N-CoR, which recruit histone deacetylase to the AML1-ETO oncoprotein. SMRT-N-CoR interaction requires each of two zinc fingers contained in C-terminal Nervy homology region 4 (NHR4) of ETO. However, here we show that polypeptides containing NHR4 are insufficient for interaction with SMRT. NHR2 is also required for SMRT interaction and repression by ETO, as well as for inhibition of hematopoietic differentiation by AML1-ETO. NHR2 mediates oligomerization of ETO as well as AML1-ETO. Fusion of NHR4 polypeptide to a heterologous dimerization domain allows strong interaction with SMRT in vitro. These data support a model in which NHR2 and NHR4 have complementary functions in repression by ETO. NHR2 functions as an oligomerization domain bringing together NHR4 polypeptides that together form the surface required for high-affinity interaction with corepressors. As nuclear receptors also interact with corepressors as dimers, oligomerization may be a common mechanism regulating corepressor interactions.

A year's review of bacterial pneumonia at the central hospital of Lucerne, Switzerland.

Community acquired pneumonia (CAP) remains an important cause of substantial morbidity and mortality in inhospital patients. We conducted a retrospective study of all patients hospitalised at our hospital with the diagnosis of bacterial pneumonia according to ICD-10 within one year. Of 360 identified charts, 335 met the requirements and were reviewed regarding risk factors, diagnosis, treatment, and overall mortality. The typical patient hospitalised with pneumonia was elderly (mean 68 years), male (60%), and suffered from comorbidities or predisposing factors (96.4%). A total of 72.8% of pneumonias were localized in the inferior lobes, and 21.1% had bilateral infiltrates. Etiologic agents were searched for in 297/335 patients (87.5%) and were found positive in 33.4%: of 169 blood cultures 9.5% were positive, of 150 sputum cultures taken 46.6% were positive, of 17 serologies taken 58.8% were positive, and of 9 pleural effusions analysed 22.2% were positive. Encapsulated bacteria were the most common found bacterial etiologies, namely Streptococcus pneumoniae (S. pneumoniae) in 30.9% of patients with known bacterial etiology, Haemophilus in 24.7%, and Klebsiella in 12.4%. Methicillin-resistant S. aureus was not found. The three most commonly used antibiotics were amoxicillin/clavulanic acid used in 77.3% of patients, clarithromycin (41.2%), and ceftriaxone (16.6%). Mean duration of treatment was 12.1 days. 245/335 (73.1%) patients had a favourable outcome, 16.7% (56/335) of patients had a protracted illness with delayed resolution (i.e. prolonged hospital stay, need for intensive care, intubation or several of these complications). Overall mortality in our unit was 8.6%.

Independent formation of DnaseI hypersensitive sites in the murine beta-globin locus control region.

Mammalian beta-globin loci are composed of multiple orthologous genes whose expression is erythroid specific and developmentally regulated. The expression of these genes both from the endogenous locus and from transgenes is strongly influenced by a linked 15-kilobase region of clustered DNaseI hypersensitive sites (HSs) known as the locus control region (LCR). The LCR encompasses 5 major HSs, each of which is highly homologous among humans, mice, and other mammals. To analyze the function of individual HSs in the endogenous murine beta-globin LCR, we have used homologous recombination in embryonic stem cells to produce 5 mouse lines, each of which is deficient for 1 of these major HSs. In this report, we demonstrate that deletion of the conserved region of 5'HS 1, 2, 3, 4, or 5/6 abolishes HS formation at the deletion site but has no influence on the formation of the remaining HSs in the LCR. Therefore, in the endogenous murine locus, there is no dominant or initiating site whose formation must precede the formation of the other HSs. This is consistent with the idea that HSs form autonomously. We discuss the implications of these findings for current models of beta-globin regulation.

Deletions within the mouse beta-globin locus control region preferentially reduce beta(min) globin gene expression.

The mouse beta-globin gene cluster is regulated, at least in part, by a locus control region (LCR) composed of several developmentally stable DNase I hypersensitive sites located upstream of the genes. In this report, we examine the level of expression of the beta(min) and beta(maj) genes in adult mice in which HS2, HS3, or HS5,6 has been either deleted or replaced by a selectable marker via homologous recombination in ES cells. Primer extension analysis of RNA extracted from circulating reticulocytes and HPLC analysis of globin chains from peripheral red blood cells revealed that all mutations that reduce the overall output of the locus preferentially decrease beta(min) expression over beta(maj). The implications of these findings for the mechanism by which the LCR controls expression of the beta(maj) and beta(min) promoters are discussed.

Treatment for human immunodeficiency virus with indinavir may cause relevant urological side-effects, effectively treatable by rehydration.

OBJECTIVE: To explore the occurrence of, and diagnostic and therapeutic procedures for urological side-effects (e.g. micro- and macrohaematuria, and kidney stone formation) in individuals treated with indinavir for the human immunodeficiency virus (HIV). PATIENTS AND METHODS: The study comprised a retrospective follow-up of 74 individuals infected with HIV-1 and who were treated with indinavir orally at a daily dose of 2.4 g. Data were collected at the outpatient department of our institution between March 1996 and November 1997. RESULTS: Of the 74 individuals treated with indinavir, 15 (20%) had indinavir-related urological side-effects (19 episodes), most commonly dull flank pain and dysuria. Microhaematuria occurred in 16 of the 19 episodes. Four patients showed urinary tract distension ultrasonographically as a possible indirect sign of urolithiasis and one patient passed a kidney stone. In four patients treatment had to be stopped permanently, but in the remaining 11 patients treatment was continued. Some patients required dose reduction and/or interruption of treatment; only conservative therapeutic measures were required, consisting of rehydration (fluid intake >1.5 L/day) and analgesics. CONCLUSIONS: Urological side-effects of indinavir may be apparent in 20% of patients so treated; some (5%) may require permanent withdrawal. In addition to a history and clinical examination, urine analysis and ultrasonography were the only diagnostic procedures required. Therapy is mainly conservative, using rehydration, analgesics and a brief discontinuation of therapy, according to the severity of the symptoms.

[Anti-retroviral therapy and antiepileptics. Case report and discussion]. / Antiretrovirale Therapie und Antiepileptika. Fallbeispiel und Diskussion.

Therapy of HIV infection is changing rapidly as new drugs are introduced. Many patients with HIV infection require anticonvulsants for therapy or prophylaxis of seizures. Antiretroviral drugs, above all protease inhibitors, and anticonvulsants may cause interactions since they are metabolised through common hepatic pathways and may substantially modulate the activity of numerous cytochrome P450 isoenzymes. We describe known interactions between anticonvulsants and antiretroviral drugs and advise on possible combinations.

Reduced beta-globin gene expression in adult mice containing deletions of locus control region 5' HS-2 or 5' HS-3.

To gain insights into the functions of individual DNA'se hypersensitive sites within the beta globin locus control region (LCR), we deleted the endogenous 5' HS-2 and HS-3 regions from the mouse germline using homologous recombination techniques. We demonstrated that the deletion of either murine 5' HS-2 or 5' HS-3 reduced the expression of the embryonic epsilon y and beta h1 globin genes minimally in yolk sac-derived erythrocytes, but that both knockouts reduced the output of the adult beta (beta-Major + beta-Minor) globin genes by approximately 30% in adult erythrocytes. When the selectable marker PGK-Neo cassette was retained within either the HS-2 or HS-3 region, a much more severe reduction in globin gene expression was observed at all developmental stages. PGK-Neo was shown to be expressed in an erythroid-specific fashion when it was retained in the HS-3 position. These results show that neither 5' HS-2 nor HS-3 is required for the activity of embryonic globin genes, nor are these sites required for correct developmental switching. However, each site is required for approximately 30% of the total LCR activity associated with adult beta-globin gene expression in adult red blood cells. Each site therefore contains some non-redundant information that contributes to adult globin gene function.