A Review of Integrative Medicine in Gynaecological Oncology.

In recent years complementary and alternative medicine (CAM) has increasingly been the focus of international research. Numerous subsidised trials (7903) and systematic reviews (651) have been published, and the evidence is starting to be integrated into treatment guidelines. However, due to insufficient evidence and/or insufficient good quality evidence, this has mostly not translated to practice recommendations in reviews by the Cochrane collaboration gynaecology group. There is nevertheless a not insignificant number of CAM providers and users. The percentage of oncology patients who use CAM varies between 5 and 90 %. Doctors have been identified as the main providers of CAM. Half of gynaecologists offer CAM because of personal conviction or on suggestion from colleagues. This must be viewed in a critical light, since CAM is mostly practiced without appropriate training, often without sufficient evidence for a given method - and where evidence exists, practice guidelines are lacking - and lack of safety or efficacy testing. The combination of patient demand and lucrativeness for doctors/alternative medicine practitioners, both based on supposed effectiveness CAM, often leads to its indiscriminate use with uncertain outcomes and significant cost for patients. On the other hand there is published, positive level I evidence for a number of CAM treatment forms. The aim of this article is therefore to review the available evidence for CAM in gynaecological oncology practice. The continued need for research is highlighted, as is the need to integrate practices supported by good evidence into conventional gynaecological oncology.

The influence of upstream IL-2 -330 (T/G) and TNF-α -308 (A/G) polymorphisms on glutamine-supplemented cytokine release.

Various studies have shown that dietary glutamine can modify the course of an immune response, through altering the release of cytokines. Nutritional supplementation of glutamine may therefore be of advantage to patients, particularly those with compromised immunity. Given that polymorphisms in cytokine genes can also affect cytokine levels, we have undertaken a study to identify whether there was a differential effect of glutamine supplementation in the context of different IL-2 -330 (T/G) and TNF-α -308 (A/G) genotypes. Overall, there was no significant impact of glutamine supplementation on IL2 release. However, analysing low, medium and high expressors independently, there was an effect of high glutamine levels on cytokine release from the low and medium expressors. Likewise, there was no effect of glutamine supplementation on the TNF-α release, although a tendency to lower cytokine release at high levels of glutamine. Irrespective of the glutamine concentrations, there was no difference in IL2 release between the IL2 -330 genotypes; there was an effect of the TNF-α genotypes, with the AG and GG genotypes showing greater cytokine release than from the AA genotype.

[Anti-inflammatory and analgesic electrotherapy. Evidence in rheumatology?]. / Antiinflammatorische und analgetische Stromformen: Evidenz in der Rheumatologie?

The objective of this article is an assessment of the evidence on antiinflammatory and analgesic current in rheumatology. Three trials on the effects of TENS (transcutaneous electrical nerve stimulation) with RA-patients (rheumatoid arthritis) showed good analgesic effect, while one study on EMS (electrical muscle stimulation) demonstrated a benefit in muscle strength and function. No anti-inflammatory effect could be verified. The overall validity is limited due to the small number of studies and the methodical quality of the analyzed trials.

Pharmacokinetic behaviour of levodopa and 3-O-methyldopa after repeat administration of levodopa/carbidopa with and without entacapone in patients with Parkinson's disease.

Addition of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) prolongs plasma metabolism of levodopa (LD). Objectives were to determine the clinical response after EN addition and the plasma degradation of LD and 3-O-methyldopa [3-OMD]. Not optimum treated hospitalised patients with Parkinson's disease received the same LD dosage on the first day only with carbidopa (CD) and on the second day with CD and EN (t.i.d.) within a standardised setting. We scored motor symptoms and measured LD- and 3-OMD levels on both days at fixed moments. Motor impairment significant better improved probably due to significant higher maximum concentrations [C(max)] and computed area under the curve values of LD levels during the LD/CD/EN condition. Time to C(max) of LD was significantly delayed after the first two LD/CD/EN intakes. An impact of EN on 3-OMD levels appeared. A possibly augmented LD absorption and a prolonged LD metabolism after EN supplementation may contribute to a more continuous LD delivery to the brain.

MTHFR C677T polymorphism, folic acid and hyperhomocysteinemia in levodopa treated patients with Parkinson's disease.

Certain mutations (TT homozygous; CT heterozygous; CC wild-type) of the methylenetetrahydrofolate (MTHFR) gene and long-term levodopa application in patients with Parkinson's disease (PD) support onset of hyperhomocysteinemia. Total plasma homocysteine (t-hcys) depends on B6, B12, folic acid, all of which support remyelination from t-hcys to methionine. Objective of this trial were to compare B6, B12, folic acid and t-hcys levels in plasma of 83 levodopa treated PD patients and 44 controls. PD patients with the CT or TT genotype had significant higher t-hcys levels than controls or PD patients with the CC allele. Concentrations of B6 or B12 did not differ, but folic acid was significant higher in PD patients with the CT mutation. We recommend MTHFR genotyping, t-hcys monitoring and early vitamin supplementation in PD patients. The folic acid increase in PD patients with the CT allele is hypothetically due to an endogenous upregulation of folic acid absorption to decrease t-hcys.

Copper-induced hepatotoxicosis with hepatic stellate cell activation and severe fibrosis in North Ronaldsay lambs: a model for non-Wilsonian hepatic copper toxicosis of infants.

Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.

Origin of maternally transferred antibodies against rabies in foxes (Vulpes vulpes).

During previous experiments, maternal antibodies against rabies were detected in the sera of fox cubs whelped by orally immunised vixens. These antibodies appear to be transferred exclusively via the colostrum. No evidence of maternally transferred immunity in the form of immunoglobulin G was found in 80 fox embryos collected from 19 rabies-immune vixens originating from areas where oral rabies vaccine baits had been distributed.

Effects of oral creatine supplementation in a patient with MELAS phenotype and associated nephropathy.

An 18-year-old male patient with MELAS phenotype and 2 previous episodes of cerebral stroke, recurrent seizures and nephropathy, was treated with creatine monohydrate after the acute onset of psychomental regression and changing states of somnolence and aggressive and agitated behaviour. These symptoms disappeared completely after 4 weeks of treatment with creatine after which the patient regained all his previous mental abilites. Brain (white matter) proton magnetic resonance spectroscopy (chemical shift imaging) performed at 6 and 12 months of treatment showed lactic acid (Lac) accumulation and high creatine (Cr) levels in relation to choline-containing compounds (Cho). Urinary creatinine excretion as an indicator of the muscle and brain creatine pool increased upon short-term (12 days) high-dosage creatine supplementation (20 g per day) while plasma creatinine concentrations as possible indicators both of increasing creatine pool and of renal insufficiency increased during the course (28 months) of low-dosage creatine supplementation (5 g per day). Deterioration of renal function was finally indicated by urea retention and by impairment of renal creatinine clearance. These observations suggest that creatine supplementation may have a neuroprotective effect in patients with MELAS and episodes of acute mental deterioration. Adverse effects of creatine supplementation on renal function must be considered especially in patients with preexisting nephropathy.

Intraepidermal free nerve fiber endings in the hairless skin of the rat as revealed by the zinc iodide-osmium tetroxide technique.

The nerve fiber distribution in the epidermis of the hairless rat skin was studied light microscopically by means of zinc iodide-osmium tetroxide staining. Two different morphological types of free nerve fiber endings could be detected: clusters of relatively thick nerve fibers stretched up through the spinous layer up to the granular layer sending off terminal branches. In addition, many solitary thin varicose nerve fibers were seen within the epidermis. The observed discrepancies in nerve fiber diameters appeared to be larger than those reported for human intraepidermal nerve fibers in recent immunohistochemical studies. Moreover, dendritic cells, most probably representing Langerhans cells, could be selectively stained. These cells appeared to be in a close location to thin varicose nerve fibers. Both types of demonstrated free nerve endings have to be functionally connected with different sensoric functions. Possibly, a subpopulation of the thin nerve fibers might possess primarily a nociceptive task, whereas the thick ones have most probably to be regarded as mechanoreceptive. The nerve fibers innervating dendritic cells appear to be identical to the peptidergic ones which may regulate the antigen-presenting capacity of these cells. Due to its selectivity for intraepidermal nerve fibers, the used method might supplement immunohistochemical procedures in a helpful manner.

Transient classical swine fever virus infection in wild boar piglets partially protected by maternal antibodies.

An experimental study was conducted to investigate the clinical course of classical swine fever (CSF) in wild boar piglets partially protected by maternal antibodies. Five healthy wild boar piglets with a low serum titre of colostral antibodies against CSF virus were challenged with virulent CSF virus at the age of three months. Apart of reduced food intake and diarrhoea no major clinical symptoms were noticed after challenge. These signs were seen during the second and third week of infection, afterwards the piglets recovered completely. CSF virus could be re-isolated from blood samples taken on day 12 and day 19 post challenge. From blood samples taken later on and from the organ material taken at post mortem examinations no CSF virus could be isolated anymore. It can be concluded that the presence of maternal antibodies influences the clinical course of CSF in terms that the outcome is rather transient than lethal. Such wild boar could play a crucial role in the spread of CSF virus and might contribute to the maintenance of long lasting epizootics.

Characteristic intraepidermal nerve fibre endings of the intervibrissal fur in the mystacial pad of the rat: morphological details revealed by intravital methylene blue staining and the zinc iodide-osmium tetroxide technique.

Light microscopic observations employing intravital methylene blue staining and impregnation by the zinc iodide-osmium tetroxide technique are presented for intraepidermal nerve fibre endings of the intervibrissal fur in the mystacial pad of the rat snout. Both procedures revealed anatomical details of the intraepidermal nerve fibre plexus in epidermal hillocks often located very close to the mouths of hairs. These nerve fibres appeared to resemble those described in previous immunohistochemical studies as cluster or bush endings. The methylene blue preparations demonstrated the existence of an intensely stained enlargement at the site of the branching point of the nerve fibres which seemed to be functionally related to the development of such nerve fibre plexuses. Due to their close association with hairs, these nerve fibre plexuses are most likely to be mechanoreceptive. Additionally, solitary varicose nerve fibres were found loosely distributed within the epidermis. The visualisation of 2 different morphological types of nerve fibre endings extends the validity of the concept of punctate sensibility into the epidermis. Methylene blue staining appeared to be somewhat superior to the zinc iodide-osmium tetroxide technique. Due to their selectivity for intraepidermal nerve fibres, the methods applied here supplement immunohistochemical procedures in a helpful manner.

Dietary omega-3, omega-6, and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytes. A randomized volunteer study.

Dietary omega-3 fatty acids retard coronary atherosclerosis. Previously, we demonstrated that dietary omega-3 fatty acids reduce platelet-derived growth factor (PDGF)-A and PDGF-B mRNA levels in unstimulated, human mononuclear cells (MNCs). In a randomized, investigator-blinded intervention trial, we have now compared the effect of ingestion of 7 g/d omega-3, omega-6, or omega-9 fatty acids for 4 weeks versus no dietary intervention on PDGF-A, PDGF-B, heparin-bound epidermal growth factor (HB-EGF), monocyte chemoattractant protein-1 (MCP-1), and interleukin-10 gene expression in unstimulated MNCs and in monocytes that were adherence-activated ex vivo in a total of 28 volunteers. In unstimulated MNCs, mRNA steady-state levels of PDGF-A, PDGF-B, and MCP-1 were reduced by 25+/-10%, 31+/-13%, and 40+/-14%, respectively, after omega-3 fatty acid ingestion, as assessed by quantitative polymerase chain reaction (all P<0.05). In monocytes that were adherence-activated ex vivo for 4 and 20 hours, mRNA steady-state levels of PDGF-A, PDGF-B, and MCP-1 were reduced by 25+/-13%, 20+/-15%, and 30+/-8%, respectively (all P<0.05). Interleukin-10 and HB-EGF mRNA steady-state levels were not influenced by omega-3 fatty acid ingestion. Expression of all respective mRNAs in control volunteers or in those ingesting omega-6 or omega-9 fatty acids were not altered. We conclude that human gene expression for PDGF-A, PDGF-B, and MCP-1, factors thought relevant to atherosclerosis, is constitutive, is constant, and can be reduced only by dietary omega-3 fatty acids in unstimulated and adherence-activated monocytes.

The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration.

Mainstream cigarette smoke (CS) trapped in phosphate-buffered saline solutions (smoke-bubbled PBS) has been shown to induce a strong stress response in cultured cells. This is reflected, for example, by the expression of stress genes such as c-fos and haem oxygenase, a transient decrease in the translation efficiency and the induction of cell cycle arrest. In these studies, peroxynitrite, the reaction product of nitric oxide (NO) and superoxide (O2-.), was identified as an active principle formed by CS in aqueous solutions. In the present study, we show that the CS-induced stress response is critically dependent on the intracellular glutathione (GSH) content which itself becomes diminished in cells exposed to smoke-bubbled PBS. Investigations using c-fos expression as a measure for cellular stress revealed a direct correlation between the smoke-bubbled PBS concentration necessary for stress-dependent c-fos expression and the intracellular GSH concentration observed in different cell lines. Correspondingly, 3T3 fibroblasts artificially depleted of GSH by pretreatment with buthionine-sulphoximine (BSO), an inhibitor of GSH synthesis, require significantly lower amounts of smoke-bubbled PBS to obtain a detectable c-fos expression, whereas, supplementation of the medium with N-acetyl-cysteine is an efficient treatment for the inhibition of a CS-induced c-fos response. We also show that the smoke-bubbled PBS-dependent loss of intracellular GSH is mainly attributable to the aldehyde fraction of CS, although these aldehydes by themselves cannot induce c-fos in these cells. The smoke-bubbled PBS-dependent c-fos response can, however, be mimicked when peroxynitrite and CS-related aldehydes, at the concentrations calculated to appear in smoke-bubbled PBS, are used in combination for cell exposure. Taken together, these results suggest that in cells exposed to aqueous extracts of CS, smoke-related aldehydes decrease the intracellular GSH content significantly, allowing peroxynitrite to interfere with specific target molecules resulting in the stress-specific expression of c-fos.

Idiopathic copper toxicosis.

Liver diseases of infancy and childhood are generally rare and within the spectrum of these disorders, only a few subtypes are related to abnormal hepatic copper accumulation. Idiopathic copper toxicosis has been defined as such a subtype; although this disease is characterized by distinct clinical and pathologic features, its exact etiology is still controversial. On the basis of a review of the literature, supplemented by our own observations of 138 cases endemic to western Austria, we hypothesize that idiopathic copper toxicosis is caused by a synergy of an autosomal-recessive inherited defect in copper metabolism and excess dietary copper. Increased awareness of the disease should enable early diagnosis and lead to successful treatment, thereby improving the overall poor prognosis of affected patients.

Synaptic connectivity in cultured hypothalamic neuronal networks.

We have developed a novel approach to analyze the synaptic connectivity of spontaneously active networks of hypothalamic neurons in culture. Synaptic connections were identified by recording simultaneously from pairs of neurons using the whole cell configuration of the patch-clamp technique and testing for evoked postsynaptic current responses to electrical stimulation of one of the neurons. Excitatory and inhibitory responses were distinguished on the basis of their voltage and time dependence. The distribution of latencies between presynaptic stimulation and postsynaptic response showed multiple peaks at regular intervals, suggesting that responses via both monosynaptic and polysynaptic paths were recorded. The probability that an excitatory event is transmitted to another excitatory neuron and results in an above-threshold stimulation was found to be only one in three to four. This low value indicates that in addition to evoked synaptic responses other sources of excitatory drive must contribute to the spontaneous activity observed in these networks. The various types of synaptic connections (excitatory and inhibitory, monosynaptic, and polysynaptic) were counted, and the observations analyzed using a probabilistic model of the network structure. This analysis provides estimates for the ratio of inhibitory to excitatory neurons in the network (1:1.5) and for the ratio of postsynaptic cells receiving input from a single GABAergic or glutamatergic neuron (3:1). The total number of inhibitory synaptic connections was twice that of excitatory connections. Cell pairs mutually connected by an excitatory and an inhibitory synapse occurred significantly more often than predicted by a random process. These results suggests that the formation of neuronal networks in vitro is controlled by cellular mechanisms that favor inhibitory connections in general and specifically enhance the formation of reciprocal connections between pairs of excitatory and inhibitory neurons. These mechanisms may contribute to network formation and function in vivo.

Episodic variations of prolactin, thyroid-stimulating hormone, luteinizing hormone, melatonin and cortisol in infertile women with subclinical hypothyroidism.

Preliminary data have suggested that female infertility due to corpus luteum insufficiency may be caused by subclinical hypothyroidism [exaggerated thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) stimulation]. L-Thyroxine supplementation has been recommended to achieve pregnancies in subclinical hypothyroid women. This controlled study was carried out in order to investigate the biochemical diagnosis of subclinical hypothyroidism as a possible infertility factor. Five infertile patients (aged 25-36 years) with subclinical hypothyroidism (n = 4, stimulated TSH >20 microU/ml) or primary hypothyroidism (n = 1) and five healthy controls (aged 22-39 years) with normal thyroid function (stimulated TSH <15 microU/ml), regular cycles and no history of infertility were studied in the early follicular phase. In the pre-study evaluation, eight of 23 volunteers (34.8%) had to be excluded because of subclinical hypothyroidism with stimulated TSH values (TSHs) >15 microU/ml. Cycle function of patients and controls was compared by the method of LH pulse pattern analysis. Therefore blood samples were drawn every 10 min during a 24 h period. Sleep was recorded from midnight to 7 a.m. Repetition of the TRH tests at the end of the 24 h blood sampling period confirmed the difference in stimulated TSH values of the two study groups. Pulse analysis for luteinizing hormone (LH), TSH and prolactin showed no differences between patients and controls for pulse frequency, amplitude, height, length, area under curve (AUC) and the 24 h mean. Even the hypothyroid patient had a normal LH pulse pattern. Additional measurement of melatonin in pooled sera every 30 min gave the well-documented diurnal profiles during day and night for both groups. Patients had significantly higher melatonin values at seven time points during the night. Peaks for LH, TSH, prolactin and cortisol were correlated with the sleep stages wake, rapid eye movement, 1 + 2 and 3 + 4. We concluded that corpus luteum insufficiency in female infertility cannot be explained by subclinical hypothyroidism and thus should not be treated with L-thyroxine for fertility reasons.

[Current therapy of idiopathic Parkinson disease. 2: Recent and alternative therapies]. / Aktuelle Therapie der idiopathischen Parkinson-Erkrankung. Teil 2: Neuere und alternative Therapieverfahren.

New possibilities in the medical treatment of Parkinson's disease are offered by the MAO-B inhibitor, selegiline, and L-dopa preparations with strongly accelerated or retarded kinetics. Possible new approaches to drug treatment might be, firstly, inhibition of the enzyme catechol-o-methyl-transferase, which influences the breakdown of dopamine, and secondly, administration of NADH with the aim of stimulating the body's own synthesis of dopamine. A third approach might be the reintroduction of stereotactic surgery with coagulation or stimulation of certain areas of the brain, that has now been made possible by the development of new and more subtle techniques. Neuroprotective and/or neuro-regenerative approaches, such as, for example, the administration or stimulation of growth factors and/or transplantation of neuronal dopaminergic cells might lead the treatment of Parkinson's disease from the palliative symptomatic approach it is today, to a future curative approach.

Association of human protein-tyrosine phosphatase kappa with members of the armadillo family.

We have identified a human receptor-like protein-tyrosine phosphatase (PTP) in the mammary carcinoma cell line SK-BR-3, which represents the human homolog of murine PTPkappa (Jiang, Y.-P., Wang, H., D'Eustachio, P., Musacchio, J. M., Schlessinger, J., and Sap, J. (1993) Mol. Cell. Biol. 13, 2942-2951) and was therefore termed hPTPkappa. We show here that hPTPkappa expression is dependent on cell density and find it colocalized with two members of the arm family of proteins, beta-catenin and gamma-catenin/plakoglobin, at adherens junctions. Using both in vitro and in vivo binding assays, we demonstrate specific complex formation between endogenous hPTPkappa and beta- and gamma-catenin/plakoglobin. In addition, we present evidence that suggests that beta-catenin may represent a substrate for the catalytic activity of hPTPkappa. The identification of specific binding partners for this receptor-like PTP provides insight into the mechanisms of its biological action and suggests a role for hPTPkappa in the regulation of processes involving cell contact and adhesion such as growth control, tumor invasion, and metastasis.

Calcium channel types contributing to excitatory and inhibitory synaptic transmission between individual hypothalamic neurons.

The contribution of L-, N-, P- and Q-type Ca2+ channels to excitatory and inhibitory synaptic transmission and to whole-cell Ba2+ currents through Ca2+ channels (Ba2+ currents) was investigated in rat hypothalamic neurons grown in dissociated cell culture. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were evoked by stimulating individual neurons under whole-cell patch-clamp conditions. The different types of high-voltage-activated (HVA) Ca2+ channels were identified using nifedipine, omega-Conus geographus toxin VIA (omega-CTx GVIA), omega-Agelenopsis aperta toxin IVA (omega-Aga IVA), and omega-Conus magus toxin VIIC (omega-CTx MVIIC). N-, but not P- or Q-type Ca2+ channels contributed to excitatory as well as inhibitory synaptic transmission together with Ca2+ channels resistant to the aforementioned Ca2+ channel blockers (resistant Ca2+ channels). Reduction of postsynaptic current (PSC) amplitudes by N-type Ca2+ channel blockers was significantly stronger for IPSCs than for EPSCs. In most neurons whole-cell Ba2+ currents were carried by L-type Ca2+ channels and by at least two other Ca2+ channel types, one of which is probably of the Q-type and the others are resistant Ca2+ channels. These results indicate a different contribution of the various Ca2+ channel types to excitatory and inhibitory synaptic transmission and to whole-cell currents in these neurons and suggest different functional roles for the distinct Ca2+ channel types.