Post-traumatic overload or acute syndrome of the os trigonum: a possible cause of posterior ankle impingement.

The purpose of this paper is to discuss the post-traumatic overload syndrome of the os trigonum as a possible cause of posterior ankle impingement and hindfoot pain. We have reviewed 19 athletes who were referred to our foot unit between 1995 and 2001 because of posterior ankle pain, and in whom a post-traumatic overload syndrome of os trigonum was diagnosed. All these patients were followed up over a period of 2 years. In 11 cases a chronic repetitive movements in forced plantar flexion was found. In the other eight cases the pain appeared to persist after a standard treatment of an ankle sprain in inversion plantar flexion. The diagnosis was based on clinical history, physical examination and X-rays that revealed a non-fused os trigonum. The confirmation of diagnosis was carried-out injecting local anaesthetic under fluoroscopic control. In all cases a corticosteroid injection as first line treatment was performed. In 6 cases a second injection was necessary to alleviate pain because incomplete recovery with the first injection. Three cases (16%) were recalcitrant to this treatment and in these three cases a surgical excision of the os trigonum was carried out. Our conclusion is that after some chronic athletic activity or an acute ankle sprain the os trigonum, if present, may undergo mechanical overload, remain undisrupted and become painful. Treatment by corticosteroid injection often resolves the problem.

The role of teriparatide in sequential and combination therapy of osteoporosis.

Osteoporosis is complicated by the occurrence of fragility fractures. Over past years, various treatment options have become available, mostly potent antiresorptive agents such as bisphosphonates and denosumab. However, antiresorptive therapy cannot fully and rapidly restore bone mass and structure that has been lost because of increased remodelling. Alternatively recombinant human parathyroid hormone (rhPTH) analogues do increase the formation of new bone material. The bone formation stimulated by intermittent PTH analogues not only increases bone mineral density (BMD) and bone mass but also improves the microarchitecture of the skeleton, thereby reducing incidence of vertebral and nonvertebral fractures. Teriparatide, a recombinant human PTH fragment available in Switzerland, is reimbursed as second-line treatment in postmenopausal women and men with increased fracture risk, specifically in patients with incident fractures under antiresorptive therapy or patients with glucocorticoid-induced osteoporosis and intolerance to antiresorptives. This position paper focuses on practical aspects in the management of patients on teriparatide treatment. Potential first-line indications for osteoanabolic treatment as well as the benefits and limitations of sequential and combination therapy with antiresorptive drugs are discussed.

Moeglichkeiten der systemischen Therapie im metastasierten Stadium [Treatment options for chemotherapy in metastatic gastric cancer]

Die Ergebnisse mehrerer, in letzter Zeit publizierter Phase-III-Studien haben die therapeutischen Möglichkeiten in der Behandlung des metastasierten Magenkarzinoms deutlich erweitert. Die Dauerinfusion von 5-Fluorouracil (5-FU) kann ohne Verlust an Wirkung durch Capecitabin ersetzt werden, ebenso wie Cisplatin durch Oxaliplatin. Nach den Ergebnissen der REAL-2-Studie zeigt die Kombination aus Epirubicin, Oxaliplatin und Capecitabin (EOX) eine Verbesserung des Gesamtüberlebens (9,9 vs. 11,2 Monate; HR 0,8) im Vergleich zu Epirubicin, Cisplatin und 5-FU (ECF). Die Frage, ob in der First-Line-Therapie eine Dreifachkombination oder eine Zweifachkombination eingesetzt werden sollte, ist allerdings weiterhin umstritten. Die Kombination aus Irinotecan und 5-FU stellt für solche Patienten, bei denen aufgrund von Komorbiditäten eine platinfreie Therapie bevorzugt wird, eine Alternative zur Kombination Cisplatin/5-FU dar. Docetaxel, 5-FU und Cisplatin (DCF) hat sich bezüglich des Überlebens in einer randomisierten Phase-III-Studie als statistisch signifikant überlegen erwiesen, allerdings besteht eine ausgeprägte hämatologische Toxizität, welche die Anwendbarkeit insbesondere bei den häufig älteren Patienten mit einem Magenkarzinom limitiert. Randomisierte Phase-III-Studien zum Vergleich von DCF mit anderen Dreierkombinationen, wie z. B. EOX, stehen aus. Recently published results from several phase III trials have significantly increased the therapeutic options in the treatment of metastatic stomach cancer: The continuous infusion of 5-FU can be replaced by capecitabine, and cisplatin can be replaced by oxaliplatin in both cases without impairing efficacy. According to the results of the REAL-2 trial, the combination of epirubicin, oxaliplatin and capecitabine (EOX) achieved superior results for overall survival compared to epirubicin, cisplatin und 5-FU (ECF) (9.9 versus 11.2 months, HR 0.8). However, the question of whether an optimal first line therapy should include a triplet regimen or the sequential use of doublets is a matter of debate. The combination of irinotecan and 5-FU may serve as an alternative to platinum-containing regimens in patients where, due to co-morbidity, a platinum-free regimen is preferred. The 3-drug combination of docetaxel, 5-FU and cisplatin (DCF) demonstrated a statistically significant survival benefit compared to the 2-drug combination of 5-FU and cisplatin in a randomized phase III trial, although results were limited by a particularly significant hematological toxicity, which prevents its application in the large group of elderly patients with gastric cancer. Direct randomized phase III comparisons of DCF with other 3-drug combinations, such as EOX are still missing.

Failure of voriconazole to cure disseminated zygomycosis in an immunocompromised child.

Voriconazole is increasingly used as a first-line agent for empirical antifungal therapy of prolonged febrile neutropenia in paediatric cancer patients. We describe the case of a 9-year-old patient with stage IV Burkitt lymphoma, who developed pulmonary and splenic zygomycosis while receiving voriconazole for persistent febrile neutropenia. The causative agent, Absidia corymbifera, was identified by broad-range fungal PCR in a lung biopsy sample. The patient was successfully treated with a combination of partial resection of the left upper lobe and antifungal therapy with high-dose liposomal amphotericin B followed by oral itraconazole as demonstrated by resolving pulmonary infiltrates on serial high resolution CT scans. CONCLUSION: This case emphasises that the lack of in vitro activity of voriconazole against zygomycetes is clinically relevant. Failure of voriconazole in suspected fungal infection should be investigated for the possibility of zygomycosis. Broad-range polymerase chain reaction may be able to identify the causative organism when cultures remain sterile.

No longitudinal mitochondrial DNA sequence changes in HIV-infected individuals with and without lipoatrophy.

The potential for mitochondrial (mt) DNA mutation accumulation during antiretroviral therapy (ART), and preferential accumulation in patients with lipoatrophy compared with control participants, remains controversial. We sequenced the entire mitochondrial genome, both before ART and after ART exposure, in 29 human immunodeficiency virus (HIV)-infected Swiss HIV Cohort Study participants initiating a first-line thymidine analogue-containing ART regimen. No accumulation of mtDNA mutations or deletions was detected in 13 participants who developed lipoatrophy or in 16 control participants after significant and comparable ART exposure (median duration, 3.3 and 3.7 years, respectively). In HIV-infected persons, the development of lipoatrophy is unlikely to be associated with accumulation of mtDNA mutations detectable in peripheral blood.

Minor protease inhibitor mutations at baseline do not increase the risk for a virological failure in HIV-1 subtype B infected patients.

BACKGROUND: Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naïve patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential. METHODS: To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥ 1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs. RESULTS: We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥ 4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥ 1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0-1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5-1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome. CONCLUSIONS: The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals.

Transient suppression of Shigella flexneri type 3 secretion by a protective O-antigen-specific monoclonal IgA.

Mucosal immunity to the enteric pathogen Shigella flexneri is mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag of S. flexneri serotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary for S. flexneri to gain entry into intestinal epithelial cells. IgAC5's effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5's effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag of S. flexneri partially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells. IMPORTANCE: Secretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by "immune exclusion," a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S-IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells.

Economic evaluation of the levonorgestrel-releasing intrauterine system for the treatment of dysfunctional uterine bleeding in Spain

To compare the cost and effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus combined oral contraception (COC) and progestogens (PROG) in first-line treatment of dysfunctional uterine bleeding (DUB) in Spain. STUDY DESIGN: A cost-effectiveness and cost-utility analysis of LNG-IUS, COC and PROG was carried out using a Markov model based on clinical data from the literature and expert opinion. The population studied were women with a previous diagnosis of idiopathic heavy menstrual bleeding. The analysis was performed from the National Health System perspective, discounting both costs and future effects at 3%. In addition, a sensitivity analysis (univariate and probabilistic) was conducted. RESULTS: The results show that the greater efficacy of LNG-IUS translates into a gain of 1.92 and 3.89 symptom-free months (SFM) after six months of treatment versus COC and PROG, respectively (which represents an increase of 33% and 60% of symptom-free time). Regarding costs, LNG-IUS produces savings of 174.2-309.95 and 230.54-577.61 versus COC and PROG, respectively, after 6 months-5 years. Apart from cost savings and gains in SFM, quality-adjusted life months (QALM) are also favourable to LNG-IUS in all scenarios, with a range of gains between 1 and 2 QALM compared to COC and PROG. CONCLUSIONS: The results indicate that first-line use of the LNG-IUS is the dominant therapeutic option (less costly and more effective) in comparison with first-line use of COC or PROG for the treatment of DUB in Spain. LNG-IUS as first line is also the option that provides greatest health-related quality of life to patients.

ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir.

BACKGROUND: An ADME (absorption, distribution, metabolism and excretion)-pharmacogenetics association study may identify functional variants relevant to the pharmacokinetics of lopinavir co-formulated with ritonavir (LPV/r), a first-line anti-HIV agent. METHODS: An extensive search of literature and web resources helped select ADME genes and single nucleotide polymorphisms (SNPs, functional and HapMap tagging SNPs) with a proven or potentially relevant role in LPV/r pharmacokinetics. The study followed a two-stage design. Stage 1 (discovery) considered a Caucasian population (n=638) receiving LPV/r, where we selected 117 individuals with low LPV clearance (cases) and 90 individuals with high clearance (controls). Genotyping was performed by a 1536-SNP customized GoldenGate Illumina BeadArray. Stage 2 (confirmation) represented a replication study of candidate SNPs from the stage 1 in 148 individuals receiving LPV/r. The analysis led to formal population pharmacokinetic-pharmacogenetic modeling of demographic, environmental and candidate SNP effects. RESULTS: One thousand three hundred and eighty SNPs were successfully genotyped. Nine SNPs prioritized by the stage 1 analysis were brought to replication. Stage 2 confirmed the contribution of two functional SNPs in SLCO1B1, one functional SNP in ABCC2 and a tag SNP of the CYP3A locus in addition to body weight effect and ritonavir coadministration. According to the population pharmacokinetic-pharmacogenetic model, genetic variants explained 5% of LPV variability. Individuals homozygous rs11045819 (SLCO1B1*4) had a clearance of 12.6 l/h, compared with 5.4 l/h in the reference group, and 3.9 l/h in individuals with two or more variant alleles of rs4149056 (SLCO1B1*5), rs717620 (ABCC2) or rs6945984 (CYP3A). A subanalysis confirmed that although a significant part of the variance in LPV clearance was attributed to fluctuation in ritonavir levels, genetic variants had an additional effect on LPV clearance. CONCLUSION: The two-stage strategy successfully identified genetic variants affecting LPV/r pharmacokinetics. Such a general approach of ADME pharmacogenetics should be generalized to other drugs.

Molecular predictors of gemcitabine response in pancreatic cancer.

Gemcitabine is one of the most used anti-neoplastic drugs with documented activity in almost all major localizations of cancer. In pancreatic cancer treatment, gemcitabine occupies a prominent place as a first line chemotherapy, partly because of the paucity of other efficacious chemotherapy options. In fact, only a minority of pancreatic cancer patients display a response or even stability of disease with the drug. There are currently no clinically applicable means of predicting which patient will derive a clinical benefit from gemcitabine although several proposed markers have been studied. These markers are proteins involved in drug up-take, activation and catabolism or proteins that define the ability of the cell to undergo apoptosis in response to the drug. Several of these markers are reviewed in this paper. We also briefly discuss the possible role of stem cells in drug resistance to gemcitabine.

The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

Vitamin B12 Deficiency in the aged: Laboratory Diagnosis, Prevalence and Clinical Profile

B₁₂-vitamiinin puute iäkkäillä: laboratoriodiagnostiikka, yleisyys ja yhteys sairastavuuteen Tausta: B12-vitamiinin puute on yleistä iäkkäillä ja se tulisi todeta riittävän varhaisessa vaiheessa palautumattomien vaurioiden estämiseksi. On epäselvää pitäisikö diagnostiikka kohdistaa tiettyihin riskiryhmiin vai mahdollisesti seuloa valikoimatonta vanhusväestöä. Myöskään yksimielisyyttä laboratoriotutkimusten valinnasta ei ole. Tavoitteet: Tutkimuksen tarkoituksena oli evaluoida uutta HoloTC RIA menetelmää ja tuottaa viitearvot sille, selvittää B12-vitamiinin puutteen yleisyys, yhteys sairastavuuteen ja mahdolliset riskitekijät suomalaisessa vanhusväestössä, arvioida munuaisfunktion vaikusta B12-vitamiinin puutteen laboratoriotutkimuksiin ja näiden perusteella ehdottaa suomalaiseen terveydenhuoltoon sopivaa laboratoriotutkimusstrategiaa. Aineisto ja menetelmät: Liedon iäkkäät -tutkimuksen vanhusaineisto on edustava otos yhden kunnan yli 65-vuotiaasta väestöstä, yhteensä 1260 henkilöä. Tutkittavat kävivät lääkärintarkastuksessa, ja heistä on käytettävissä runsaasti laboratoriotutkimuksia sekä tiedot sairauksista, ruokavaliosta, lääkkeiden ja vitamiinivalmisteiden käytöstä, dementiaseula ja depressiokysely. Viitearvoaineistoa varten kerättiin näytteet 84 vapaaehtoisesta terveestä aikuisesta ja menetelmäevaluaatiota varten 107 sairaalapotilaasta. Tulokset: HoloTC RIA menetelmän toistettavuus oli hyvä manuaalimenetelmäksi. 95%:n viiteväli holotranskobalamiinille oli 37-171 pmol/l. Kaikilla tutkittavilla, joilla oli muilla laboratoriotutkimuksilla osoitettu todennäköinen B12-vitamiinin puute, myös holotranskobalamiini oli viitealueen alarajaa pienempi. Suurentuneella kystatiini C-pitoisuudella osoitettu munuaisten vajaatoiminta korreloi voimakkaasti homokysteiinin (rs=0.53, p<0.001) ja metyylimalonihapon (rs=0.27, p<0.001) pitoisuuksiin, mutta ei kokonais-B12-vitamiinin (rs=- 0.04, p=0.227) tai holotranskobamiinin (rs=-0.01, p=0.817) pitoisuuksiin. Suomalaisessa vanhusväestössä B12-vitamiinin puutteen prevalenssi oli 12%. Kokonais- B12-vitamiinin pitoisuus oli matala (<150 pmol/l) 6%:lla. Miessukupuoli (OR 1.9, 95% CI 1.2-2.9), ikä ≥75 (OR 2.2, 95% CI 1.4-3.4) ja maitotuotteiden välttäminen (OR 2.3, 95% CI 1.2-4.4) lisäsivät B12-vitamiinin puutteen riskiä, mutta anemia (OR 1.3, 95% CI 0.7-2.3) tai makrosytoosi (OR 1.2, 95% CI 0.6-2.7) eivät. Päätelmät: Diagnosoimaton B12-vitamiinin puute on yleistä iäkkäillä, mutta kliinisesti merkityksellistä spesifistä riskiryhmää ei löydy. Koska anemian ja makrosytoosin puuttuminen ei poissulje B12-vitamiinin puutetta ja munuaisten vajaatoiminta heikentää metabolisten merkkiaineiden käyttökelpoisuutta, kokonais-B12-vitamiinia suositellaan ensisijaiseksi laboratoriotutkimukseksi epäiltäessä B12-vitamiinin puutetta ja tarvittaessa varmentavina tutkimuksina käytetään homokysteiiniä ja holotranskobalamiinia.

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Argemone mexicana decoction versus artesunate-amodiaquine for the management of malaria in Mali: policy and public-health implications.

A classic way of delaying drug resistance is to use an alternative when possible. We tested the malaria treatment Argemone mexicana decoction (AM), a validated self-prepared traditional medicine made with one widely available plant and safe across wide dose variations. In an attempt to reflect the real situation in the home-based management of malaria in a remote Malian village, 301 patients with presumed uncomplicated malaria (median age 5 years) were randomly assigned to receive AM or artesunate-amodiaquine [artemisinin combination therapy (ACT)] as first-line treatment. Both treatments were well tolerated. Over 28 days, second-line treatment was not required for 89% (95% CI 84.1-93.2) of patients on AM, versus 95% (95% CI 88.8-98.3) on ACT. Deterioration to severe malaria was 1.9% in both groups in children aged </=5 years (there were no cases in patients aged >5 years) and 0% had coma/convulsions. AM, now government-approved in Mali, could be tested as a first-line complement to standard modern drugs in high-transmission areas, in order to reduce the drug pressure for development of resistance to ACT, in the management of malaria. In view of the low rate of severe malaria and good tolerability, AM may also constitute a first-aid treatment when access to other antimalarials is delayed.

Amoebal pathogens as emerging causal agents of pneumonia.

Despite using modern microbiological diagnostic approaches, the aetiological agents of pneumonia remain unidentified in about 50% of cases. Some bacteria that grow poorly or not at all in axenic media used in routine clinical bacteriology laboratory but which can develop inside amoebae may be the agents of these lower respiratory tract infections (RTIs) of unexplained aetiology. Such amoebae-resisting bacteria, which coevolved with amoebae to resist their microbicidal machinery, may have developed virulence traits that help them survive within human macrophages, i.e. the first line of innate immune defence in the lung. We review here the current evidence for the emerging pathogenic role of various amoebae-resisting microorganisms as agents of RTIs in humans. Specifically, we discuss the emerging pathogenic roles of Legionella-like amoebal pathogens, novel Chlamydiae (Parachlamydia acanthamoebae, Simkania negevensis), waterborne mycobacteria and Bradyrhizobiaceae (Bosea and Afipia spp.).