Effects of exposure to physical factors on homeopathic preparations as determined by ultraviolet light spectroscopy

Clinical trials have reported statistically significant and clinically relevant effects of homeopathic preparations. We applied ultraviolet (UV) spectroscopy to investigate the physical properties of homeopathic preparations and to contribute to an understanding of the not-yet-identified mode of action. In previous investigations, homeopathic preparations had significantly lower UV light transmissions than controls. The aim of this study was to explore the possible effects of external factors (UV light and temperature) on the homeopathic preparations. Homeopathic centesimal (c) dilutions, 1c to 30c, of copper sulfate (CuSO(4)), decimal dilutions of sulfur (S(8)), 1x to 30x, and controls (succussed potentization medium) were prepared, randomized, and blinded. UV transmission was measured at six different time points after preparation (from 4 to 256 days). In addition, one series of samples was exposed to UV light of a sterilization lamp for 12 h, one was incubated at 37 degrees Celsius for 24 h, and one was heated to 90 degrees Celsius for 15 min. UV light transmission values from 190 or 220 nm to 340 nm were measured several times and averaged. After each exposure, UV transmission of the homeopathic preparations of CuSO(4) was significantly reduced compared to the controls, particularly after heating to 37 degrees Celsius. Overall, the nonexposed CuSO(4) preparations did not show significantly lower UV transmission compared to controls; however, the pooled subgroup of measurements at days 26, 33, and 110 yielded significant differences. UV light transmission for S(8) preparations did not show any differences compared to controls. Our conclusion is that exposure to external factors, incubation at 37 degrees Celsius in particular, increases the difference in light transmission of homeopathic CuSO(4) preparations compared to controls.

Inhibition of the miR-143/145 cluster attenuated neutrophil differentiation of APL cells

MicroRNAs can influence hematopoietic cell lineage commitment and aberrant expression of hematopoietic miRNAs contributes to AML pathology. We found that miR-143 and miR-145 expression is significantly repressed in primary AML patient samples as compared to neutrophils of healthy donors. Further analysis revealed impaired neutrophil differentiation of APL cells upon inhibition of miR-145 expression. Lastly, we identified p73 as transcriptional regulator of miR-143/145 during neutrophil differentiation of APL cells. Our data suggest that low miR-145 levels in APL, possibly due to aberrant expression of p73 transcription factors, contribute to the differentiation block seen in this disease.

Learned irrelevance and associative learning is attenuated in individuals at risk for psychosis but not in asymptomatic first-degree relatives of schizophrenia patients: translational state markers of psychosis?

Learned irrelevance (LIrr) refers to a form of selective learning that develops as a result of prior noncorrelated exposures of the predicted and predictor stimuli. In learning situations that depend on the associative link between the predicted and predictor stimuli, LIrr is expressed as a retardation of learning. It represents a form of modulation of learning by selective attention. Given the relevance of selective attention impairment to both positive and cognitive schizophrenia symptoms, the question remains whether LIrr impairment represents a state (relating to symptom manifestation) or trait (relating to schizophrenia endophenotypes) marker of human psychosis. We examined this by evaluating the expression of LIrr in an associative learning paradigm in (1) asymptomatic first-degree relatives of schizophrenia patients (SZ-relatives) and in (2) individuals exhibiting prodromal signs of psychosis ("ultrahigh risk" [UHR] patients) in each case relative to demographically matched healthy control subjects. There was no evidence for aberrant LIrr in SZ-relatives, but LIrr as well as associative learning were attenuated in UHR patients. It is concluded that LIrr deficiency in conjunction with a learning impairment might be a useful state marker predictive of psychotic state but a relatively weak link to a potential schizophrenia endophenotype.

An attenuated Salmonella enterica serovar Typhimurium strain lacking the ZnuABC transporter induces protection in a mouse intestinal model of Salmonella infection

Salmonella enterica serovar Typhimurium has long been recognised as a zoonotic pathogen of economic significance in animals and humans. Attempts to protect humans and livestock may be based on immunization with vaccines aimed to induce a protective response. We recently demonstrated that the oral administration of a Salmonella enterica serovar Typhimurium strain unable to synthesize the zinc transporter ZnuABC is able to protect mice against systemic salmonellosis induced by a virulent homologous challenge. This finding suggested that this mutant strain could represent an interesting candidate vaccine for mucosal delivery. In this study, the protective effect of this Salmonella strain was tested in a streptomycin-pretreated mouse model of salmonellosis that is distinguished by the capability of evoking typhlitis and colitis. The here reported results demonstrate that mice immunized with Salmonella enterica serovar Typhimurium (S. Typhimurium) SA186 survive to the intestinal challenge and, compared to control mice, show a reduced number of virulent bacteria in the gut, with milder signs of inflammation. This study demonstrates that the oral administration a of S. Typhimurium strain lacking ZnuABC is able to elicit an effective immune response which protects mice against intestinal S. Typhimurium infection. These results, collectively, suggest that the streptomycin-pretreated mouse model of S. typhimurium infection can represent a valuable tool to screen S. typhimurium attenuated mutant strains and potentially help to assess their protective efficacy as potential live vaccines.

Differences in Median Ultraviolet Light Transmissions of Serial Homeopathic Dilutions of Copper Sulfate, Hypericum perforatum, and Sulfur

Homeopathic remedies are produced by potentising, that is, the serial logarithmic dilution and succussion of a mother tincture. Techniques like ultraviolet spectroscopy, nuclear magnetic resonance, calorimetry, or thermoluminescence have been used to investigate their physical properties. In this study, homeopathic centesimal (c) potencies (6c to 30c) of copper sulfate, Hypericum perforatum, and sulfur as well as succussed water controls were prepared. Samples of these preparations were exposed to external physical factors like heat, pressure, ultraviolet radiation, or electromagnetic fields to mimic possible everyday storage conditions. The median transmissions from 190nm to 340nm and 220nm to 340nm were determined by ultraviolet light spectroscopy on five measurement days distributed over several months. Transmissions of controls and potencies of sulfur differed significantly on two of five measurement days and after exposure to physical factors. Transmissions of potencies exposed to ultraviolet light and unexposed potencies of copper sulfate and Hypericum perforatum differed significantly. Potency levels 6c to 30c were also compared, and wavelike patterns of higher and lower transmissions were found. The Kruskal-Wallis test yielded significant differences for the potency levels of all three substances. Aiming at understanding the physical properties of homeopathic preparations, this study confirmed and expanded the findings of previous studies.

Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation

Pregnane X receptor (PXR) is an important nuclear receptor xenosensor that regulates the expression of metabolic enzymes and transporters involved in the metabolism of xenobiotics and endobiotics. In this study, ultra-performance liquid chromatography (UPLC) coupled with electrospray time-of-flight mass spectrometry (TOFMS), revealed altered urinary metabolomes in both Pxr-null and wild-type mice treated with the mouse PXR activator pregnenolone 16alpha-carbonitrile (PCN). Multivariate data analysis revealed that PCN significantly attenuated the urinary vitamin E metabolite alpha-carboxyethyl hydroxychroman (CEHC) glucuronide together with a novel metabolite in wild-type but not Pxr-null mice. Deconjugation experiments with beta-glucuronidase and beta-glucosidase suggested that the novel urinary metabolite was gamma-CEHC beta-D-glucoside (Glc). The identity of gamma-CEHC Glc was confirmed by chemical synthesis and by comparing tandem mass fragmentation of the urinary metabolite with the authentic standard. The lower urinary CEHC was likely due to PXR-mediated repression of hepatic sterol carrier protein 2 involved in peroxisomal beta-oxidation of branched-chain fatty acids (BCFA). Using a combination of metabolomic analysis and a genetically modified mouse model, this study revealed that activation of PXR results in attenuated levels of the two vitamin E conjugates, and identification of a novel vitamin E metabolite, gamma-CEHC Glc. Activation of PXR results in attenuated levels of the two vitamin E conjugates that may be useful as biomarkers of PXR activation.

A new approach to generate a safe double-attenuated Plasmodium liver stage vaccine

Recently it has been shown in rodent malaria models that immunisation with genetically attenuated Plasmodium parasites can confer sterile protection against challenge with virulent parasites. For the mass production of live attenuated Plasmodium parasites for vaccination, safety is a prerequisite. Knockout of a single gene is not sufficient for such a strategy since the parasite can likely compensate for such a genetic modification and a single surviving parasite is sufficient to kill an immunised individual. Parasites must therefore be at least double-attenuated when generating a safe vaccine strain. Genetic double-attenuation can be achieved by knocking out two essential genes or by combining a single gene knockout with the expression of a protein toxic for the parasite. We generated a double-attenuated Plasmodium berghei strain that is deficient in fatty acid synthesis by the knockout of the pdh-e1α gene, introducing a second attenuation by the liver stage-specific expression of the pore-forming bacterial toxin perfringolysin O. With this double genetically attenuated parasite strain, a superior attenuation was indeed achieved compared with single-attenuated strains that were either deficient in pyruvate dehydrogenase (PDH)-E1 or expressed perfringolysin O. In vivo, both single-attenuated strains resulted in breakthrough infections even if low to moderate doses of sporozoites (2,000-5,000) were administered. In contrast, the double genetically attenuated parasite strain, given at moderate doses of 5,000 sporozoites, did not result in blood stage infection and even when administered at 5- to 20-fold higher doses, only single and delayed breakthrough infections were observed. Prime booster immunisation with the double genetically attenuated parasite strain completely protected a susceptible mouse strain from malaria and even a single immunisation conferred protection in some cases and lead to a markedly delayed onset of blood stage infection in others. Importantly, premature rupture of the parasitophorous vacuole membrane by liver stage-specific perfringolysin O expression did not induce host cell death and soluble parasite proteins, which are released into the host cell cytoplasm, have the potential to be processed and presented via MHC class I molecules. This, in turn, might support immunological responses against Plasmodium-infected hepatocytes.

Virological and phylogenetic characterization of attenuated small ruminant lentivirus isolates eluding efficient serological detection

Three field isolates of small ruminant lentiviruses (SRLVs) were derived from a mixed flock of goats and sheep certified for many years as free of caprine arthritis encephalitis virus (CAEV). The phylogenetic analysis of pol sequences permitted to classify these isolates as A4 subtype. None of the animals showed clinical signs of SRLV infection, confirming previous observations which had suggested that this particular subtype is highly attenuated, at least for goats. A quantitative real time PCR strategy based on primers and probes derived from a highly variable env region permitted us to classify the animals as uninfected, singly or doubly infected. The performance of different serological tools based on this classification revealed their profound inadequacy in monitoring animals infected with this particular SRLV subtype. In vitro, the isolates showed differences in their cytopathicity and a tendency to replicate more efficiently in goat than sheep cells, especially in goat macrophages. By contrast, in vivo, these viruses reached significantly higher viral loads in sheep than in goats. Both env subtypes infected goats and sheep with equal efficiency. One of these, however, reached significantly higher viral loads in both species. In conclusion, we characterized three isolates of the SRLV subtype A4 that efficiently circulate in a mixed herd of goats and sheep in spite of their apparent attenuation and a strict physical separation between goats and sheep. The poor performance of the serological tools applied indicates that, to support an SRLV eradication campaign, it is imperative to develop novel, subtype specific tools.

Prevalence and Clinical Significance of DSM-5-Attenuated Psychosis Syndrome in Adolescents and Young Adults in the General Population: The Bern Epidemiological At-Risk (BEAR) Study

Objective: Section III of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lists attenuated psychosis syndrome as a condition for further study. One important question is its prevalence and clinical significance in the general population. Method: Analyses involved 1229 participants (age 16-40 years) from the general population of Canton Bern, Switzerland, enrolled from June 2011 to July 2012. "Symptom," "onset/worsening," "frequency," and "distress/disability" criteria of attenuated psychosis syndrome were assessed using the structured interview for psychosis-risk syndromes. Furthermore, help-seeking, psychosocial functioning, and current nonpsychotic axis I disorders were surveyed. Well-trained psychologists performed assessments using the computer-assisted telephone interviewing technique. Results: The symptom criterion was met by 12.9% of participants, onset/worsening by 1.1%, frequency by 3.8%, and distress/disability by 7.0%. Symptom, frequency, and distress/disability were met by 3.2%. Excluding trait-like attenuated psychotic symptoms (APS) decreased the prevalence to 2.6%, while adding onset/worsening reduced it to 0.3%. APS were associated with functional impairments, current mental disorders, and help-seeking although they were not a reason for help-seeking. These associations were weaker for attenuated psychosis syndrome. Conclusions: At the population level, only 0.3% met current attenuated psychosis syndrome criteria. Particularly, the onset/worsening criterion, originally included to increase the likelihood of progression to psychosis, lowered its prevalence. Because progression is not required for a self-contained syndrome, a revision of the restrictive onset criterion is proposed to avoid the exclusion of 2.3% of persons who experience and are distressed by APS from mental health care. Secondary analyses suggest that a revised syndrome would also possess higher clinical significance than the current syndrome.

Self-Reported Psychotic-Like Experiences Are a Poor Estimate of Clinician-Rated Attenuated and Frank Delusions and Hallucinations

Background: One reason for the decision to delay the introduction of an Attenuated Psychosis Syndrome in the main text of the fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders was the concern that attenuated psychotic symptoms (APS) might in fact be common features in adolescents and young adults from the general population of no psychopathological significance in themselves. This concern was based on reports of high prevalence rates of psychotic-like experiences (PLEs) in the general population and the assumption that PLEs are a good estimate of APS. Although the criterion validity of self-reported PLEs had already been studied with respect to clinician-rated psychotic symptoms and found insufficient, it had been argued that PLEs might in fact be more comparable with mild, subclinical expressions of psychotic symptoms and, therefore, with APS. The present paper is the first to specifically study this assumption. Sampling and Methods: The sample consisted of 123 persons seeking help at a service for the early detection of psychosis, of whom 54 had an at-risk mental state or psychosis, 55 had a nonpsychotic mental disorder and 14 had no full-blown mental disorder. PLEs were assessed with the Peters Delusion Inventory and the revised Launay-Slade Hallucination Scale, and psychotic symptoms and APS were assessed with the Structured Interview for Prodromal Syndromes. Results: At a level of agreement between the presence of any PLE (in 98.4% of patients) and any APS (in 40.7%) just exceeding chance (κ = 0.022), the criterion validity of PLEs for APS was insufficient. Even if additional qualifiers (high agreement or distress, preoccupation and conviction) were considered, PLEs (in 52.8%) still tended to significantly overestimate APS, and agreement was only fair (κ = 0.340). Furthermore, the group effect on PLE prevalence was, at most, moderate (Cramer's V ≤ 0.382). Conclusions: The prevalence of APS cannot be deduced from studies of PLEs. Thus, the high population prevalence rate of PLEs does not allow the conclusion that APS are common features of no pathological significance and would lack clinical validity as an Attenuated Psychosis Syndrome in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Rather, the population prevalence rate of APS has to be assumed to be largely unknown at present but is likely lower than indicated by epidemiological studies of PLEs. Therefore, dedicated studies are warranted, in which APS are assessed in a way that equates to their clinical evaluation.