Methods to improve efficacy of orally administered bioactive peptides using bovine colostrum as an exemplar.

BACKGROUND: Oral administration of bioactive peptides has potential clinical advantages, but its applicability is limited due to gastric and pancreatic enzyme proteolysis. OBJECTIVE: To examine whether the co-packaging of bovine colostrum (BC), a rich source of IgG, immune and growth factors, with the food additives trehalose (carbohydrate), stearine (fat), casein (protein present in BC) or soy flour (plant based with high protease inhibitory activity) enhances the stability of BC against digestion. DESIGN: Samples alone and in combination (BC+ 10% wt/wt trehalose, stearine, casein or soy) were exposed to HCl/pepsin, followed by trypsin and chymotrypsin ("CT"). Assessment of proliferation used gastric AGS cells (Alamar blue), IgG function measured bovine IgG anti-E.coli binding and ELISAs quantified growth factor constituents. In vivo bioassay assessed ability of BC alone or with soy to reduce injury caused by dextran sodium sulphate (DSS, 4% in drinking water, 7 days, test products started 2 days prior to DSS). RESULTS: Proliferative activity of BC reduced 61% following HCl/pepsin and CT exposure. This was truncated 50% if soy was co-present, and also protected against loss of total IgG, IgG E.coli binding, TGFß, lactoferrin and EGF (all P<0.01 vs BC alone). Co-packaging with trehalose was ineffective in preventing digestion whereas casein or stearine provided some intermediate protective effects. Rats given BC alone showed beneficial effects on weight gain, disease activity index, tissue histology and colonic MPO. Soy alone was ineffective. BC+ soy combination showed the greatest benefit with a dose of 7 mg/kg (6.4 BC + 0.6 soy flour) having the same degree of benefit as using 20 mg/kg BC alone. CONCLUSION: Soy, and to a lesser extent casein, enhanced the biostability of BC against digestive enzymes. Co-packaging of BC with other food products such as soy flour could result in a decreased dose being required, improving cost-effectiveness and patient compliance.

Bovine Colostrum: Its Constituents and Uses.

Colostrum is the milk produced during the first few days after birth and contains high levels of immunoglobulins, antimicrobial peptides, and growth factors. Colostrum is important for supporting the growth, development, and immunologic defence of neonates. Colostrum is naturally packaged in a combination that helps prevent its destruction and maintain bioactivity until it reaches more distal gut regions and enables synergistic responses between protective and reparative agents present within it. Bovine colostrum been used for hundreds of years as a traditional or complementary therapy for a wide variety of ailments and in veterinary practice. Partly due to concerns about the side effects of standard Western medicines, there is interest in the use of natural-based products of which colostrum is a prime example. Numerous preclinical and clinical studies have demonstrated therapeutic benefits of bovine colostrum for a wide range of indications, including maintenance of wellbeing, treatment of medical conditions and for animal husbandry. Articles within this Special Issue of Nutrients cover the effects and use bovine colostrum and in this introductory article, we describe the main constituents, quality control and an overview of the use of bovine colostrum in health and disease.

Sodium co-limits and catalyzes macronutrients in a prairie food web.

Nitrogen and phosphorus frequently limit terrestrial plant production, but have a mixed record in regulating the abundance of terrestrial invertebrates. We contrasted four ways that Na could interact with an NP fertilizer to shape the plants and invertebrates of an inland prairie. We applied NP and Na to m2 plots in a factorial design. Aboveground invertebrate abundance was independently co-limited by NaCl and NP, but with +NP plots supporting more individuals. We suggest the disparity arises because NP enhanced plant height by 35% (1 SD) over controls, providing both food and habitat, whereas NaCl provides only food. Belowground invertebrates showed evidence of serial co-limitation, where NaCl additions alone were ineffectual, but catalyzed access to NP. This suggests the increased belowground food availability in NP plots increased Na demand. Na and NP supply rates vary with climate, land use, and with inputs like urine. The co-limitation and catalysis of N and P by Na thus has the potential for predicting patterns of abundance and diversity across spatial scales.

Docosahexaenoic Acid and Cognition throughout the Lifespan.

Docosahexaenoic acid (DHA) is the predominant omega-3 (n-3) polyunsaturated fatty acid (PUFA) found in the brain and can affect neurological function by modulating signal transduction pathways, neurotransmission, neurogenesis, myelination, membrane receptor function, synaptic plasticity, neuroinflammation, membrane integrity and membrane organization. DHA is rapidly accumulated in the brain during gestation and early infancy, and the availability of DHA via transfer from maternal stores impacts the degree of DHA incorporation into neural tissues. The consumption of DHA leads to many positive physiological and behavioral effects, including those on cognition. Advanced cognitive function is uniquely human, and the optimal development and aging of cognitive abilities has profound impacts on quality of life, productivity, and advancement of society in general. However, the modern diet typically lacks appreciable amounts of DHA. Therefore, in modern populations, maintaining optimal levels of DHA in the brain throughout the lifespan likely requires obtaining preformed DHA via dietary or supplemental sources. In this review, we examine the role of DHA in optimal cognition during development, adulthood, and aging with a focus on human evidence and putative mechanisms of action.

Dietary docosahexaenoic acid alleviates autistic-like behaviors resulting from maternal immune activation in mice.

The prevalence of autism spectrum disorders over the last several decades has risen at an alarming rate. Factors such as broadened clinical definitions and increased parental age only partially account for this precipitous increase, suggesting that recent changes in environmental factors may also be responsible. One such factor could be the dramatic decrease in consumption of anti-inflammatory dietary omega-3 (n-3) polyunsaturated fatty acids (PUFAs) relative to the amount of pro-inflammatory omega-6 (n-6) PUFAs and saturated fats in the Western diet. Docosahexaenoic acid (DHA) is the principle n-3 PUFA found in neural tissue and is important for optimal brain development, especially during late gestation when DHA rapidly and preferentially accumulates in the brain. In this study, we tested whether supplementation of a low n-3 PUFA diet with DHA throughout development could improve measures related to autism in a mouse model of maternal immune activation. We found that dietary DHA protected offspring from the deleterious effects of gestational exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid on behavioral measures of autism and subsequent adulthood immune system reactivity. These data suggest that elevated dietary levels of DHA, especially during pregnancy and nursing, may help protect normal neurodevelopment from the potentially adverse consequences of environmental insults like maternal infection.

Dietary DHA during development affects depression-like behaviors and biomarkers that emerge after puberty in adolescent rats.

DHA is an important omega-3 PUFA that confers neurodevelopmental benefits. Sufficient omega-3 PUFA intake has been associated with improved mood-associated measures in adult humans and rodents, but it is unknown whether DHA specifically influences these benefits. Furthermore, the extent to which development and puberty interact with the maternal diet and the offspring diet to affect mood-related behaviors in adolescence is poorly understood. We sought to address these questions by 1) feeding pregnant rats with diets sufficient or deficient in DHA during gestation and lactation; 2) weaning their male offspring to diets that were sufficient or deficient in DHA; and 3) assessing depression-related behaviors (forced swim test), plasma biomarkers [brain-derived neurotrophic factor (BDNF), serotonin, and melatonin], and brain biomarkers (BDNF) in the offspring before and after puberty. No dietary effects were detected when the offspring were evaluated before puberty. In contrast, after puberty depressive-like behavior and its associated biomarkers were worse in DHA-deficient offspring compared with animals with sufficient levels of DHA. The findings reported here suggest that maintaining sufficient DHA levels throughout development (both pre- and postweaning) may increase resiliency to emotional stressors and decrease susceptibility to mood disorders that commonly arise during adolescence.

Androgen regulation of corticotropin-releasing hormone receptor 2 (CRHR2) mRNA expression and receptor binding in the rat brain.

Stress-induced affective disorders, such as depression and anxiety, are more prevalent in females than in males. The reduced vulnerability to these disorders in males may be due to the presence of androgens, which are known to dampen the stress response and reduce anxiety-like behaviors. However, a neurobiological mechanism for this sex difference has yet to be elucidated. Corticotropin-releasing hormone receptor 2 (CRHR2) has been implicated in regulating anxiety-type behaviors and is expressed in stress-responsive brain regions that also contain androgen receptors (AR). We hypothesized that androgen may exert its effects through actions on CRHR2 and we therefore examined the regulation of CRHR2 mRNA and receptor binding in the male rat forebrain following androgen administration. Young adult male Sprague/Dawley rats were gonadectomized (GDX) and treated with the non-aromatizable androgen, dihydrotestosterone propionate (DHTP) using hormone filled Silastic capsules. Control animals received empty capsules. Using quantitative real-time RT-PCR, CRHR2 mRNA levels were determined in block-dissected brain regions. DHTP treatment significantly increased CRHR2 mRNA expression in the hippocampus, hypothalamus, and lateral septum (p<0.01) when compared to vehicle-treated controls. A similar trend was observed in amygdala (p= 0.05). Furthermore, in vitro autoradiography revealed significantly higher CRHR2 binding in the lateral septum in androgen-treated males, with the highest difference observed in the ventral lateral region. Regulation of CRHR2 mRNA by AR was also examined using an in vitro approach. Hippocampal neurons, which contain high levels of AR, were harvested from E17-18 rat fetuses, and maintained in primary culture for 14 days. Neurons were then treated with dihydrotestosterone (DHT; 1 nM), DHT plus flutamide (an androgen receptor antagonist), or vehicle for 48 h. CRHR2 mRNA levels were measured using quantitative real-time RT-PCR. Consistent with in vivo studies, DHT significantly increased CRHR2 mRNA expression in hippocampal neurons (p<.02) compared to vehicle-treated controls. Flutamide treatment prevented the effect of DHT on CRHR2 mRNA indicating that DHT's effect on CRHR2 expression is AR-mediated. Thus, the CRHR2 gene appears to be a target for regulation by AR and these data suggest a potential mechanism by which androgen may alter mood and anxiety-related behaviors.

Effects of Spascupreel versus hyoscine butylbromide for gastrointestinal cramps in children.

BACKGROUND: Gastrointestinal spasms and cramps are common in children as well as in adults. Alternative medical practices such as chiropractice and homeopathy are becoming increasingly popular in Europe and the USA. The effectiveness and tolerability of the homeopathic preparation Spascupreel was compared with that of hyoscine butylbromide treatment in children <12 years of age. METHODS: An observational cohort study in 204 children <12 years was conducted over a 1 week treatment period. The efficacy of the respective therapies were evaluated on the effect on severity of spasms and clinical symptoms (pain/cramps, sleep disturbances, distress, eating or drinking difficulties and frequent crying). Compliance was evaluated on a four-point scale from 'very good' to 'low'. Evaluation was done by the practitioner based on information given by the patient or minder. RESULTS: The analysis showed comparative improvements with the homeopathic preparation and hyoscine butylbromide therapy on severity of spasms, pain/cramps, sleep disturbances, eating or drinking difficulties, and frequent crying, all as evaluated by the practitioner. Both treatments were very well tolerated. CONCLUSIONS: For patients opting for a homeopathic therapy, Spascupreel seems to be an effective and well tolerated alternative to conventional therapies in children suffering from gastrointestinal spasms.

Antiviral activity of Engystol: an in vitro analysis.

OBJECTIVES: To study the effects of the homeopathic preparation Engystol (Biologische Heilmittel HEEL GmbH, Baden-Baden, Germany) on a panel [corrected] of human pathogenic viruses in vitro. DESIGN: The effects of Engystol were studied using plaque-reduction assays and virus titration assays, and by quantification of newly synthesized viral proteins in virus-specific enzyme-linked immunoabsorbent assays (ELISAs). SUBJECTS: The DNA viruses Adeno 5 and herpes simplex type 1 (HSV-1), the RNA virus respiratory syncytial virus (RSV), and human rhinovirus (HRV). RESULTS: A 73% reduction of Adeno 5 specific proteins and an 80% reduction in HSV-1 specific proteins were observed in ELISAs of virus-infected cells treated with Engystol after infection. The effects appeared to be dose-dependent. With these viruses, similar results were observed in titration assays of viral offspring from cells treated with Engystol. Pretreatment of adenovirus with Engystol did not inhibit the infectivity of the virus suspension and no Engystol-induced stimulation of interferon-alpha could be observed. Plaque-reduction assays with the RNA viruses, RSV and HRV, showed reductions in infectivity by 37% (RSV) and 20% (HRV), respectively. CONCLUSIONS: The results indicate antiviral activity of Engystol independent of the activation of the cellular interferon system.

[Treatment of inflammatory diseases of the upper respiratory tract -- comparison of a homeopathic complex remedy with xylometazoline]. / Behandlung von Entzündungen im Bereich der oberen Atemwege -- Vergleich eines homöopathischen Komplexpräparates mit Xylometazolin.

INTRODUCTION: The primary objective of treatment of inflammatory diseases of the upper respiratory tract (rhinitis, uncomplicated sinusitis) with local decongestants is to relieve obstruction and to improve associated symptoms. Restoration of unrestricted respiration and drainage of the nasal sinuses reduce the risk of further complications (i.e. chronicity). OBJECTIVE: To determine whether the therapeutic effects of the homeopathic complex remedy Euphorbium compositum nasal drops SN are comparable to those of xylometazoline with respect to efficacy and tolerability. METHODS: Open, multicenter, prospective, active-controlled cohort study in patients with inflammatory processes and diseases of the upper respiratory tract. The primary outcome was to demonstrate non-inferiority of the homeopathic complex remedy to xylometazoline. RESULTS: Clinically relevant reductions in the intensities of disease-specific symptoms were observed with both therapies. Non-inferiority of the homeopathic complex remedy to xylometazoline could be shown for all studied variables and in no case did the lower boundary of the 95% confidence interval cross the threshold of 0.5 score points. Tolerability was good with for both therapies. CONCLUSIONS: This cohort study indicates a comparable efficacy and tolerability profile of the homeopathic complex remedy Euphorbium compositum nasal drops SN and the reference substance xylometazoline in patients with inflammatory processes and diseases of the upper respiratory tract.

The homeopathic preparation Vertigoheel versus Ginkgo biloba in the treatment of vertigo in an elderly population: a double-blinded, randomized, controlled clinical trial.

OBJECTIVE: Alternative medical practices are common in the treatment of vertigo. This study compared the effects of Ginkgo biloba treatment with the homeopathic remedy Vertigoheel (Biologische Heilmittel Heel GmbH, Baden-Baden, Germany). DESIGN: Randomized, double-blinded, parallel group study. SUBJECTS: One hundred and seventy (170) patients, ages 60-80 years, with atherosclerosis-related vertigo. INTERVENTIONS: Patients were randomly allocated to receive treatment with either Vertigoheel (n = 87) or G. biloba (n = 83). OUTCOME MEASURES: The results were analyzed for the non-inferiority of Vertigoheel to G. biloba on the combined endpoint of changes from baseline to week 6 in dizziness score (assessed by questionnaire), frequency, duration, and intensity of vertigo episodes (recorded in patient diaries). RESULTS: Both treatments improved vertigo status. From a baseline mean value of 26.1 +/- 5.2 (on a 50-point scale) in the Vertigoheel group, the dizziness questionnaire score improved by -10.6 +/- 10.0, and by -10.7 +/- 9.0 from 25.8 - 4.7 in the G. biloba group. Statistical analysis of this endpoint showed that Vertigoheel was not inferior to G. biloba. The 95% confidence interval for the difference between treatment did not reach the inferiority threshold of 0.36 at any of the time points tested. The results were supported by the results of a line walking test, Unterberger's stepping test, and patient and physician global assessments of therapeutic effect. Both treatments were well tolerated. CONCLUSIONS: Vertigoheel is an appealing alternative to established G. biloba therapy for atherosclerosis-related vertigo.

Treatment of vertigo with a homeopathic complex remedy compared with usual treatments: a meta-analysis of clinical trials.

The increasing interest in alternative medical practices has led to a number of controlled studies on herbal and homeopathic agents. This paper presents the results of a meta-analysis of four recent clinical trials evaluating the homeopathic preparation Vertigoheel (VH) compared with usual therapies (betahistine, Ginkgo biloba extract, dimenhydrinate) for vertigo in a total of 1388 patients. Two trials were observational studies and the other two were randomised double-blind controlled trials. The duration of treatment (6-8 weeks) and dosage were comparable in all studies. Treatments were evaluated for the variables "number of vertigo episodes", "intensity of episodes" and "duration of episodes". As the studies differed in the age of patients and in the baseline values of vertigo, the individual reductions of number, intensity and duration of episodes were adjusted on equal age and baseline values (total means). An analysis of variance (with studies as random effects) showed no relevant influence of studies on the adjusted reductions and no relevant interaction between studies and treatment effects. The meta-analysis of all four trials showed equivalent reductions with VH and with control treatment: mean reduction of the number of daily episodes 4.0 for VH and 3.9 for control (standard error 0.11 for both groups); mean reduction of the duration (on a scale 0-4) for VH 1.1 and for the control 1.0 (standard error 0.03 for both groups); mean reduction of the intensity (on a scale 0-4) for VH 1.18 and for the control 1.8 (standard error 0.03 for both groups). In the non-inferiority analysis from all trials, VH was non-inferior in all variables. The results show the applicability of meta-analyses on the data from studies with homeopathicdrugs and support the results from the individual studies indicating good efficacy and tolerability of VH in patients with vertigo.

The effects of a complex homeopathic medicine compared with acetaminophen in the symptomatic treatment of acute febrile infections in children: an observational study.

CONTEXT: Children frequently suffer infections accompanied by fever, which is commonly treated with acetaminophen (paracetamol), a use not devoid of risk. OBJECTIVE: The effect of a complex homeopathic medicine (Viburcol, Heel Belgium, Gent, Belgium) was compared with that of acetaminophen in children with infectious fever. DESIGN: Non-randomized observational study. SETTING: Thirty-eight Belgian centers practicing homeopathy and conventional medicine. PATIENTS: Children <12 years old. INTERVENTIONS: Viburcol (drops) or acetaminophen (pills, capsules, or liquid form) for a maximum of 2 weeks. MAIN OUTCOME MEASURES: Fever, cramps, distress, disturbed sleep, crying, and difficulties with eating or drinking. Symptoms were graded by the practitioner on a scale from 0 to 3. Severity of infection was evaluated on a scale from 0 to 4. Data were captured on body temperature, subjective impression of health status, time to first improvement of symptoms, and global evaluation of treatment effects. Tolerability and compliance were monitored. RESULTS: Both treatment groups improved during the treatment period. Body temperature was reduced by 1.7 degrees C +/- 0.7 degrees C with Viburcol and by 1.9 degrees C +/- 0.9 degrees C with acetaminophen; fever score (scale from 0 to 3) from 1.7 +/- 0.6 to 0.1 +/- 0.2 with Viburcol and from 1.9 +/- 0.7 to 0.2 +/- 0.5 with acetaminophen (all values mean +/-SD). The overall severity of infection (scale from 0 to 4) decreased from 2.0 +/- 0.5 to 0.0 +/- 0.2 with Viburcol and from 2.2 +/- 0.7 to 0.2 +/- 0.6 with acetaminophen. There were no statistically significant differences between treatment groups in time to symptomatic improvement. Viburcol was noninferior to acetaminophen on all variables evaluated. Both treatments were very well tolerated, but the Viburcol group had a significantly greater number of patients with the highest tolerability score. CONCLUSIONS: In this patient population, Viburcol was an effective alternative to acetaminophen treatment and significantly better tolerated.

Inhibition of IL-1beta and TNF-alpha secretion from resting and activated human immunocytes by the homeopathic medication Traumeel S.

Traumeel S (Traumeel), a mixture of highly diluted (10(-1)-10(-9)) extracts from medicinal plants and minerals is widely used in humans to relieve trauma, inflammation and degenerative processes. However, little is known about its possible effects on the behavior of immune cells. The effects of Traumeel were examined in vitro on the ability of resting and PHA-, PMA- or TNF-alpha-activated human T cells, monocytes, and gut epithelial cells to secrete the prototypic pro-inflammatory mediators IL-1beta, TNF-alpha and IL-8 over a period of 24-72 h. Traumeel inhibited the secretion of all three agents in resting, as well as activated immune cells. IL-beta secretion was reduced by up to 70% in both resting and activated cells; TNF-alpha secretion was reduced by up to 65 and 54%, respectively, and IL-8 secretion was reduced by 50% in both resting and activated cells (P < 0.01 for all cells). Interestingly, the effect appeared to be inversely dose-related; maximal inhibition (usually 30-60% inhibition; P < 0.01) was seen with dilutions of 10(-3)-10(-6) of the Traumeel stock material. This finding suggests that Traumeel does not inhibit immune cells functions by exerting a toxic effect. Indeed, Traumeel did not affect T cell and monocyte proliferation. Although additional studies are needed to clarify the mode of action of Traumeel and to demonstrate causative relationship between the inhibition of cytokine/chemokine secretion in cell culture and the reported clinical effects of the preparation, our in vitro results offer a mechanism for the anti-inflammatory effects of Traumeel observed in clinical use.

Complementary medicine prescription patterns in Germany.

BACKGROUND: There is growing interest in complementary medicine worldwide and a corresponding need to know how patients and practitioners interact. OBJECTIVE: To chart the use of complementary medications compared with conventional treatments among practitioners and patients in Germany. METHODS: Comparative analysis of patients' data from a prospective cohort study of 4178 patients presenting with chronic as well as acute symptoms by 218 practitioners at 218 centers in all German federal states between 2001 and 2002. Practices focused on either conventional medicine, complementary medicine, or both. Data were gathered on prescription patterns, treatment satisfaction and adherence, and the degree of patient involvement in treatment decisions. RESULTS: Complementary medicine was preferentially prescribed over conventional medicine in patients <18 and >65 years old, in women, and in patients with chronic symptoms. Patients receiving complementary medications had, on average, higher rates of accompanying illnesses, received more preparations, and were more closely involved in the decision process than patients prescribed conventional therapies. The decision to use complementary medicine was based on both the patient's and the practitioner's wishes in 40.8% of the cases compared with 25.8% of the cases of conventional therapies. Tolerability and satisfaction with treatment appeared greater with complementary than with conventional therapies. CONCLUSIONS: Complementary medicine is generally well established in Germany, apparently in a dialogue with conventional medicine. Patients receiving complementary medicine appear to be more closely involved in the decision process and more satisfied with treatments than conventionally treated patients.