Targets of emerging therapies for viral hepatitis B and C

Viral hepatitis B and C, structurally two completely different viruses, commonly infect human hepatocytes and cause similar clinical manifestations. Since their discovery, IFN has been a pillar in the treatment. However, because of the different natures of the viruses, therapeutic approaches diverge and new treatment targets are tailored specifically for each virus. Herein, the authors analyse therapeutic approaches for hepatitis B virus (HBV) and hepatitis C virus (HCV) and focus on emerging concepts that are under clinical evaluation. In particular, promising viral inhibitors for HBV and HCV are reviewed and the current status of research for gene therapy for HCV is described. Immune therapy is a fast-moving field with fascinating results which include therapeutic vaccines and toll-like receptor agonists that could improve tomorrow's treatment approaches.

Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

[Old and new interventional therapies in the treatment of symptomatic benign prostate hyperplasia (BPH)]

Benign Prostatic Hyperplasia is a common entity among the aging male population. Its prevalence is increasing with age and is around 80% in the over 80-years old. The androgen-estrogen ratio changes in favor of the estrogens, which leads to a growth of prostatic tissue, presenting histologically as hyperplasia. BPH can cause irritative or obstructive symptoms or both. Nowadays we speak of bladder storage or bladder voiding symptoms, summarised as LUTS (Lower Urinary Tract Symptoms). LUTS has a structural and a functional component, the structural being caused by the size of the adenoma itself the functional depending on the muscle tone of the bladder neck and the prostatic urethra. To investigate LUTS, we use validated symptom scores, sonography for residual urine and eventually a urodynamic evaluation. There are 3 grades of BPH. The indication for an interventional therapy is relative in BPH II, and absolute in BPH III. Prior to treatment, other diseases mimicking the same symptoms, have to be ruled out and adequatly treated. Electro-resection of the prostate (TUR-P) remains the standard therapy and the benchmark any new technology has to compete with. TUR-P has good short- and longterm results, but can be associated with a considerable perioperative morbidity, and the learning curve for the operator is long. The most promising of the newer techniques is the Holmium-Laser-Enucleation of the prostate (Laser-TUR-P), showing at least identical short- and median-term results, but a lower perioperative morbidity than TUR-P For several minimally-invasive techniques, indications are limited. TUMT TUNA, WIT and laser-coagulation all produce a coagulation necrosis of the prostatic tissue by thermic damage with secondary tissue shrinking. Urodynamic results however, are not comparable to TUR-P or Laser-TUR-P, and significantly more secondary interventions within 2 to 5 years are required. Minimal-invasive techniques present a favorable alternative for younger patients without complications of BPH, and for older patients with relevant comorbidities, and can usually be performed under local anaesthesia. The morbidity is low and further therapies remain possible later, if necessary.

Complementary and conventional medicine in Switzerland: comparing characteristics of general practitioners

OBJECTIVES: Do structural characteristics of general practitioners (GPs) who practice complementary medicine (CAM) differ from those GPs who do not? Assessed characteristics included experience and professional integration of general practitioners (GPs), workload, medical activities, and personal and technical resources of practices. The investigated CAM disciplines were anthroposophic medicine, homoeopathy, traditional Chinese medicine, neural therapy and herbal medicine. MATERIAL AND METHODS: We designed a cross-sectional study with convenience and stratified samples of GPs providing conventional (COM) and/or complementary primary care in Switzerland. The samples were taken from the database of the Swiss medical association (FMH) and from CAM societies. Data were collected using a postal questionnaire. RESULTS: Of the 650 practitioners who were included in the study, 191 were COM, 167 noncertified CAM and 292 certified CAM physicians. The proportion of females was higher in the population of CAM physicians. Gender-adjusted age did not differ between CAM and COM physicians. Nearly twice as many CAM physicians work part-time. Differences were also seen for the majority of structural characteristics such as qualification of physicians, type of practice, type of staff, and presence of technical equipment. CONCLUSION: The study results show that structural characteristics of primary health care do differ between CAM and COM practitioners. We assumed that the activities of GPs are defined essentially by analyzed structures. The results are to be considered for evaluations in primary health care, particularly when quality of health care is assessed.

Physicians' philosophy of care: a comparison of complementary and conventional medicine

BACKGROUND: This project is part of an evaluation of complementary and alternative medicine (CAM) aimed at providing a scientific basis for the Swiss Government to include 5 CAM methods in basic health coverage: anthroposophic medicine, homeopathy, neural therapy, phytotherapy and Traditional Chinese Medicine (TCM). OBJECTIVES: The objective was to explore the philosophy of care (convictions and values, priorities in medical activity, motivation for CAM, criteria for the practice of CAM, limits of the used methods) of conventional and CAM general practitioners (GPs) and to determine differences between both groups. MATERIALS AND METHODS: This study was a cross-sectional survey of a representative sample of 623 GPs who provide complementary or conventional primary care. A mailed questionnaire with open-ended questions focusing on the philosophy of care was used for data collection. An appropriate methodology using a combination of quantitative and qualitative approaches was developed. RESULTS: Significant differences between both groups include philosophy of care (holistic versus positivistic approaches), motivation for CAM (intrinsic versus extrinsic) and priorities in medical activity. Both groups seem to be aware of limitations of the therapeutic methods used. The study reveals that conventional physicians are also using complementary medicine. DISCUSSION: Our study provides a wealth of data documenting several aspects of physicians' philosophy of care as well as differences and similarities between conventional and complementary care. Implications of the study with regard to quality of care as well as ethical and health policy issues should be investigated further.

Health status and health care utilisation of patients in complementary and conventional primary care in Switzerland--an observational study

BACKGROUND: The study is part of a nationwide evaluation of complementary and alternative medicine (CAM) in primary care in Switzerland. OBJECTIVES: Patient health status with respect to demographic attributes such as gender, age, and health care utilisation pattern was studied and compared with conventional primary care. METHODS: The study was performed as a cross-sectional survey including 11932 adult patients seeking complementary or conventional primary care. Patients were asked to document their self-perceived health status by completing a questionnaire in the waiting room. Physicians were performing conventional medicine and/or various forms of complementary primary care such as homeopathy, anthroposophic medicine, neural therapy, herbal medicine, or traditional Chinese medicine. Additional information on patient demographics and yearly consultation rates for participating physicians was obtained from the data pool of all Swiss health insurers. These data were used to confirm the survey results. RESULTS: We observed considerable and significant differences in demographic attributes of patients seeking complementary and conventional care. Patients seeking complementary care documented longer lasting and more severe main health problems than patients in conventional care. The number of previous physician visits differed between patient groups, which indicates higher consumption of medical resources by CAM patients. CONCLUSIONS: The study supports the hypothesis of differences in socio-demographic and behavioural attributes of patients seeking conventional medicine or CAM in primary care. The study provides empirical evidence that CAM users are requiring more physician-based medical services in primary care than users of conventional medicine.

The supply of complementary and alternative medicine in Swiss hospitals

OBJECTIVES: Over the past few years, a considerable increase in complementary and alternative medicine (CAM) has been observed, particularly in primary care. In contrast little is known about the supply of CAM in Swiss hospitals. This study aims at the investigation of amount and structure of CAM activities of Swiss hospitals. MATERIALS AND METHODS: We designed a cross-sectional survey using a 2-step, questionnaire- based approach acquiring overview information form hospital managers in a first questionnaire leading to detailed information on CAM usage at medical department level (head of department). This second questionnaire provides data of physician-based and non-physician-based CAM supply. RESULTS: The size of hospitals was significantly associated with the provision of CAM. 33% of the hospital managers indicated 1 or more medical doctor (MD) using CAM in their hospital compared to 37% of confirmation on department level (Kappa value 0.5). Mostly different CAM methods were applied. Acupuncture was used most frequently. However only 13 hospitals (11%) occupied more than 3 CAM MDs and only 5 hospitals had more than 2 full-time equivalents for MDs. Furthermore, 74.7% of these personnel resources were dedicated for outpatient care. In terms of CAM methods anthroposophic medicine accounted for more than half of the total personnel costs. On the other hand usage of non-physician based CAM accounted for 41% according to hospital managers compared to 64% of CAM usage according to medical departments (Kappa values 0.31). Reflexology of the foot was used most frequently. CONCLUSION: Total supply of CAM in Swiss hospitals is low and concentrates on few hospitals. Acupuncture is the widest spread discipline but anthroposophic medicine spends the most resources. The study shows that a high patient demand for CAM faces low supply in hospitals.

Extent and structure of health insurance expenditures for complementary and alternative medicine in Swiss primary care

BACKGROUND: The study is part of a nationwide evaluation of complementary and alternative medicine (CAM) in primary care in Switzerland. The goal was to evaluate the extent and structure of basic health insurance expenditures for complementary and alternative medicine in Swiss primary care. METHODS: The study was designed as a cross-sectional evaluation of Swiss primary care providers and included 262 certified CAM physicians, 151 noncertified CAM physicians and 172 conventional physicians. The study was based on data from a mailed questionnaire and on reimbursement information obtained from health insurers. It was therefore purely observational, without interference into diagnostic and therapeutic procedures applied or prescribed by physicians. Main outcome measures included average reimbursed costs per patient, structured into consultation- and medication-related costs, and referred costs. RESULTS: Total average reimbursed cost per patient did not differ between CAM physicians and conventional practitioners, but considerable differences were observed in cost structure. The proportions of reimbursed costs for consultation time were 56% for certified CAM, 41% for noncertified CAM physicians and 40% for conventional physicians; medication costs--including expenditures for prescriptions and directly dispensed drugs--respectively accounted for 35%, 18%, and 51% of costs. CONCLUSION: The results indicate no significant difference for overall treatment cost per patient between CAM and COM primary care in Switzerland. However, CAM physicians treat lower numbers of patients and a more cost-favourable patient population than conventional physicians. Differences in cost structure reflect more patient-centred and individualized treatment modalities of CAM physicians.

Seasonal variation in orthopedic health services utilization in Switzerland: the impact of winter sport tourism

BACKGROUND: Climate- or holiday-related seasonality in hospital admission rates is well known for many diseases. However, little research has addressed the impact of tourism on seasonality in admission rates. We therefore investigated the influence of tourism on emergency admission rates in Switzerland, where winter and summer leisure sport activities in large mountain regions can generate orthopedic injuries. METHODS: Using small area analysis, orthopedic hospital service areas (HSAo) were evaluated for seasonality in emergency admission rates. Winter sport areas were defined using guest bed accommodation rate patterns of guest houses and hotels located above 1000 meters altitude that show clear winter and summer peak seasons. Emergency admissions (years 2000-2002, n = 135'460) of local and nonlocal HSAo residents were evaluated. HSAo were grouped according to their area type (regular or winter sport area) and monthly analyses of admission rates were performed. RESULTS: Of HSAo within the defined winter sport areas 70.8% show a seasonal, summer-winter peak hospital admission rate pattern and only 1 HSAo outside the defined winter sport areas shows such a pattern. Seasonal hospital admission rates in HSAo in winter sport areas can be up to 4 times higher in winter than the intermediate seasons, and they are almost entirely due to admissions of nonlocal residents. These nonlocal residents are in general -and especially in winter- younger than local residents, and nonlocal residents have a shorter length of stay in winter sport than in regular areas. The overall geographic distribution of nonlocal residents admitted for emergencies shows highest rates during the winter as well as the summer in the winter sport areas. CONCLUSION: Small area analysis using orthopedic hospital service areas is a reliable method for the evaluation of seasonality in hospital admission rates. In Switzerland, HSAo defined as winter sport areas show a clear seasonal fluctuation in admission rates of only nonlocal residents, whereas HSAo defined as regular, non-winter sport areas do not show such seasonality. We conclude that leisure sport, and especially ski/snowboard tourism demands great flexibility in hospital beds, staff and resource planning in these areas.

Heavy use of acute in-patient psychiatric services: the challenge to translate a utilization pattern into service provision

There is an inequality in resource utilization among acute psychiatric in-patients. About 20-30% of them absorb 60-80% of the total resources allocated to this form of treatment. This study intends to summarize findings related to heavy in-patient service use and to illustrate them by means of utilization data for acute psychiatric wards.

Palliative in-patient cancer treatment in an anthroposophic hospital: I. Treatment patterns and compliance with anthroposophic medicine

BACKGROUND: Complementary and alternative medicine (CAM) and most of all anthroposophic medicine (AM) are important features of cancer treatment in Switzerland. While the number of epidemiological investigations into the use of such therapies is increasing, there is a distinct lack of reports regarding the combination of conventional and CAM methods. PATIENTS AND METHODS: 144 in-patients with advanced epithelial cancers were enrolled in a prospective quality-of-life (QoL) study at the Lukas Klinik (LK), Arlesheim, Switzerland. Tumor-related treatment was assessed 4 months prior to admission, during hospitalization and 4 months after baseline. OBJECTIVE: We aimed at giving a detailed account of conventional, AM and CAM treatment patterns in palliative care, before, during and after hospitalization, with emphasis on compliance with AM after discharge. RESULTS: Certain conventional treatments featured less during hospitalization than before but were resumed after discharge (chemotherapy, radiotherapy, sleeping pills, psychoactive drugs). Hormone therapy, corticosteroids, analgesics WHO III and antidepressants remained constant. AM treatment consisted of Iscador? (mistletoe), other plant- or mineral-derived medication, baths, massage, eurythmy, art therapy, counseling and lactovegetarian diet. Compliance after discharge was highest with Iscador (90%) and lowest with art therapy (14%). Many patients remained in the care of AM physicians. Other CAM and psychological methods were initially used by 39.9% of patients. After 4 months, the use had decreased with few exceptions. CONCLUSION: During holistic palliative treatment in an anthroposophic hospital, certain conventional treatments featured less whereas others remained constant. After discharge, chemotherapy returned to previous levels, AM compliance remained high, the use of other CAM therapies low.

Antisense-mediated melanoma inhibitor of apoptosis protein downregulation sensitizes G361 melanoma cells to cisplatin

Malignant melanoma is an aggressive form of skin cancer that is highly resistant to conventional therapies. The melanoma inhibitor of apoptosis protein is a potent inhibitor of apoptosis and is overexpressed in melanoma cells, but undetectable in most normal tissues including melanocytes. We designed 20-mer phosphorothioate antisense oligonucleotides complementary to five putatively single-stranded sites on the melanoma inhibitor of apoptosis protein mRNA and investigated their ability to sensitize G361 melanoma cells to cisplatin. Inhibition of melanoma inhibitor of apoptosis protein mRNA and protein expression were measured by real-time polymerase chain reaction and immunoblotting. Cell viability and apoptosis were quantitated by colorimetric viability assays and by annexin V staining, respectively. Oligonucleotide M706 was identified as the most efficient antisense sequence which downregulated melanoma inhibitor of apoptosis protein mRNA and protein levels in G361 cells by 68 and 78%, respectively. The specificity of target downregulation was confirmed using scrambled sequence control oligonucleotides that only marginally decreased melanoma inhibitor of apoptosis protein expression. Whereas downregulation of melanoma inhibitor of apoptosis protein moderately inhibited cell growth by 26%, in combination with cisplatin, this resulted in a supra-additive effect with almost 57% reduction in G361 cell viability compared with cisplatin alone (17%) (P<0.05). Cell death was mainly due to apoptosis as demonstrated by a 3- to 4-fold increase in annexin V-positive cells and typical morphological changes compared with controls. In summary, we describe a new antisense oligonucleotide that efficiently downregulates melanoma inhibitor of apoptosis protein expression and sensitizes melanoma cells to cisplatin.

Tissue-transplant fusion and vascularization of myocardial microtissues and macrotissues implanted into chicken embryos and rats

Cell-based therapies and tissue engineering initiatives are gathering clinical momentum for next-generation treatment of tissue deficiencies. By using gravity-enforced self-assembly of monodispersed primary cells, we have produced adult and neonatal rat cardiomyocyte-based myocardial microtissues that could optionally be vascularized following coating with human umbilical vein endothelial cells (HUVECs). Within myocardial microtissues, individual cardiomyocytes showed native-like cell shape and structure, and established electrochemical coupling via intercalated disks. This resulted in the coordinated beating of microtissues, which was recorded by means of a multi-electrode complementary metal-oxide-semiconductor microchip. Myocardial microtissues (microm3 scale), coated with HUVECs and cast in a custom-shaped agarose mold, assembled to coherent macrotissues (mm3 scale), characterized by an extensive capillary network with typical vessel ultrastructures. Following implantation into chicken embryos, myocardial microtissues recruited the embryo's capillaries to functionally vascularize the rat-derived tissue implant. Similarly, transplantation of rat myocardial microtissues into the pericardium of adult rats resulted in time-dependent integration of myocardial microtissues and co-alignment of implanted and host cardiomyocytes within 7 days. Myocardial microtissues and custom-shaped macrotissues produced by cellular self-assembly exemplify the potential of artificial tissue implants for regenerative medicine.