Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies.

Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer's disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aß) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau's influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aß immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases.

Ketamine and the Disinhibition Hypothesis: Neurotrophic Factor-Mediated Treatment of Depression.

Ketamine is a promising alternative to traditional pharmacotherapies for major depressive disorder, treatment-resistant depression, and other psychiatric conditions that heavily contribute to the global disease burden. In contrast to the current standard of care medications for these disorders, ketamine offers rapid onset, enduring clinical efficacy, and unique therapeutic potential for use in acute, psychiatric emergencies. This narrative presents an alternative framework for understanding depression, as mounting evidence supports a neuronal atrophy and synaptic disconnection theory, rather than the prevailing monoamine depletion hypothesis. In this context, we describe ketamine, its enantiomers, and various metabolites in a range of mechanistic actions through multiple converging pathways, including N-methyl-D-aspartate receptor (NMDAR) inhibition and the enhancement of glutamatergic signaling. We describe the disinhibition hypothesis, which posits that ketamine's pharmacological action ultimately results in excitatory cortical disinhibition, causing the release of neurotrophic factors, the most important of which is brain-derived neurotrophic factor (BDNF). BDNF-mediated signaling along with vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) subsequently give rise to the repair of neuro-structural abnormalities in patients with depressive disorders. Ketamine's efficacious amelioration of treatment-resistant depression is revolutionizing psychiatric treatment and opening up fresh vistas for understanding the underlying causes of mental illness.

Prescribed psychotropic medication patterns among treated Foster Care enrollees: a single institution study.

Background: While several state-based studies have shown that children in foster care are more likely to be prescribed psychotropic medications and experience concomitant medication use both within and among medication class, these patterns have not been explored in the state of Nevada, which lacks state mandated oversight of psychotropic prescribing for foster care enrolled youth. Methods: Data from an electronic medical record system from a single institution were analyzed to examine the prevalence of psychotropic prescribing and concomitant medication use in children ages 2 to 19 who were enrolled and received psychotropic prescriptions between July 2019 to June 2022. Results: Out of 569 distinct psychotropic medication treatment episodes within this cohort, the most frequent psychotropic classes prescribed were non-stimulant ADHD medications (alpha-agonists and atomoxetine, 31.5%), atypical antipsychotics (22.1%), antidepressants (20.6%), and stimulants (16.0%). The use of stimulants and non-stimulant ADHD medications decreased in older age groups while the use of antidepressants and antipsychotics increased in older age groups. During the three-year period studied, 24.0% of psychotropic medications prescriptions increased in dosage. Treatments were prescribed for only one month in 43.8% of youth. In children prescribed psychotropic medications, concomitant medication use for at least 60 days occurred in 28.0% of children who had any psychotropic medication prescribed. Conclusion: Within the cohort of 273 foster care enrolled subjects aged 2 to 19 years old who received psychotropic medication prescriptions, non-stimulant ADHD medications (both alpha-agonists and atomoxetine) and atypical antipsychotics were more commonly co-prescribed additional psychotropic medication compared to other co-prescribed medication categories. This study illustrates prescribing patterns in a community mental health clinic focused on judicious prescribing of psychotropic medications in foster care enrolled youth. Despite this, 41% of the youth treated in this clinic received at least one prescription for psychotropic medication, and of those, 27.8% were prescribed more than one psychotropic medication at the same time. More studies are necessary to understand the underlying causes of high prevalence of concomitant medication use and prescribing practices of psychotropic medications use in foster care involved pediatric populations.

Nutrition therapy for adverse reactions to histamine in food and beverages.

Adverse reactions to food are suspected in one third of the German population, but only 10% of these assumed hypersensitivity reactions can be clinically confirmed. While diagnosis of food allergies is fairly easy due to objective laboratory parameters, non-allergic hypersensitivity reactions are difficult to diagnose because these objective markers are lacking so far. Adverse reactions to histamine are often suspected to be the cause of a wide range of symptoms, especially when no allergic pathomechanism can be identified. In order to confirm such a suspicion, it is inevitable to validate a reproducible association between consumption of histamine-rich food and beverages and symptoms to identify causative agents and to exclude other disorders. Thereafter, avoidance tests should be performed on the basis of individual requirements. General advice with a lot of restraints is often unnecessarily strict. Nutrition therapy aims at a reduction of symptoms to a minimum while maintaining a high quality of life.

A Popular myth - low-histamine diet improves chronic spontaneous urticaria - fact or fiction?

BACKGROUND: Chronic spontaneous urticaria (CsU) is a frequent dermatological disease that might last for months or years with high impact on quality of life. Known causes are autoreactive phenomena, infections or intolerances, rarely IgE-mediated allergies. One-third of CsU patients benefit from a low-pseudoallergen diet. Additionally, it is often discussed, that reducing histamine ingestion alone might improve clinical symptoms and quality of life in CsU patients despite the uncertain role of the histamine-degrading enzyme diamine oxidase (DAO). OBJECTIVE: Aim of this study was to investigate the impact of low-histamine diet on symptoms and quality of life in patients with CsU. METHODS: Patients suffering from CsU accompanied by gastrointestinal symptoms were included in the study. They underwent low-histamine diet for at least 3 weeks. During the whole study, urticaria activity score (UAS) was recorded daily in a patient's diary. Quality of life was assessed during screening, baseline and post diet visits by completing questionnaires (DLQI and Cu-Q(2)oL). DAO activity was measured before and after elimination diet. RESULTS: A total of 75% of the patients had a benefit from the low-histamine diet. Thirty-four of 56 patients (61%) reached the primary endpoint of the study, an improvement of UAS 4 of ≥3. Overall, a significant reduction from 9.05 to 4.23 points (P = 0.004) was achieved; the average reduction in a strongly affected subgroup was 8.59 points (P < 0.001). DAO activity remained stable. CONCLUSION: Low-histamine diet is a therapeutically useful, simple and cost-free tool to decrease symptoms and increase quality of life in CsU patients with gastrointestinal involvement. Further research is needed to understand the role of diamine oxidase.

[Debating histamine intolerance: are adverse reactions to histamine-containing foods fact or fiction?]. / Streitthema Histaminintoleranz : Gibt es tatsächlich Unverträglichkeitsreaktionen nach Aufnahme histaminhaltiger Nahrungsmittel?

Low-histamine diets are very popular and often self-imposed among people suspecting histamine intolerance. Most of these diets avoid a huge variety of foods containing more or less histamine, which has a considerable impact on their quality of life, but in most cases no long-term benefit. Underlying a diminished capacity for histamine degradation, the lack of partial or complete symptom improvement might be due to the fact that endogenous histamine release could also be responsible for symptoms. The role of ingested histamine-below the level for intoxication-is discussed controversially. However, it is obvious that the histamine content of a certain food alone is not enough to predict its tolerance. If histamine intolerance is suspected, an individual diagnostic and therapeutic procedure is mandatory in order to minimize avoidance and to preserve a high quality of life. Ideally this is done in a close cooperation between allergists and nutritionists.

Stirring unmagnetized plasma.

A new concept for spinning unmagnetized plasma is demonstrated experimentally. Plasma is confined by an axisymmetric multicusp magnetic field and biased cathodes are used to drive currents and impart a torque in the magnetized edge. Measurements show that flow viscously couples momentum from the magnetized edge (where the plasma viscosity is small) into the unmagnetized core (where the viscosity is large) and that the core rotates as a solid body. To be effective, collisional viscosity must overcome the ion-neutral drag due to charge-exchange collisions.

[Diagnostic and therapeutic procedure for two popular but quite distinct adverse reactions to food - fructose malabsorption and histamine intolerance]. / Diagnostisches und therapeutisches Vorgehenbei zwei populären, aber sehr unterschiedlichen Nahrungsmittelunverträglichkeiten - Fructosemalabsorption und Histaminintoleranz.

Claiming to suffer from adverse food reactions is popular. In contrast to the classical food allergy, there are some pathomechanisms which are evidently dose-dependent. Thus the procedure in diagnosis and therapy must undoubtedly differ from the practice when food allergy is suspected or proven. Nevertheless many patients suffering from dose-dependent adverse reactions to food are given strict elimination diets, which is neither necessary nor helpful and decreases their quality of life broadly. This holds especially true for fructose malabsorption and histamine intolerance. For the latter, the term adverse reaction to ingested histamine is preferred, because histamine intolerance implies that symptoms are caused entirely by an enzyme defect. Why this is not very likely to be the only reason is discussed in this article. Both adverse reactions require an individual approach especially with regard to nutrition therapy. Therefore the task of diagnosis should be to establish an individual profile of tolerated and not tolerated foods taking into account that tolerance can greatly vary by meal composition, frequency and individual triggering factors. In view of this, therapeutic recommendations should not be based on the absolute quantities of the eliciting substance to be eliminated but on a feasible transfer into daily life. Thereby food restriction can be minimized and a high quality of life will be maintained.

Systematic review and evidence-based consensus guideline on prevention of allergy and atopic eczema of the German Network on Allergy Prevention (ABAP).

Allergies are a meaningful public-health problem. Until now no evidence-based recommendations for allergy prevention exist. An evidence based guideline for primary and secondary prevention of allergies was developed in the course of the German Network on Allergy Prevention (Aktionsbündnis Allergiepräven-tion, ABAP) with support of the German Ministry of Health. Results of the systematic evidence search and the consented recommendations are presented here. After an appropriate search strategy was developed, a systematic literature search was performed in electronic databases (Cochrane library, MEDLINE, EMBASE). Furthermore four selected journals were hand-searched and reference lists of actual reviews as well as grey literature was screened. Some 3 500 references were retrieved initially and a two-stage filter process on the relevance was applied by screening titles and abstracts and subsequently full-text papers. For the critical methodological appraisal modifications of international checklists were used. A total of 323 studies were included and evaluated. These comprised 3 Cochrane Reviews, 7 meta-analyses, 37 randomized controlled trials (RCTs) as well as 102 cohort and 174 case-control-studies. The following levels of evidence were applied: 3x1a, 21x1b, 5x2a, 59x2b, 1x3a, 45x3b, 189x4. These studies were summarized in a form of a systematic review and corresponding recommendations were formulated. The latter were consented by members of the abap steering committee in two consensus meeting where the method of a nominal group process was applied. For the first time recommendations for the prevention of allergies were developed on a high methodological standard. The content and modifications reflect the existing evidence.

Pseudoallergic reactions in chronic urticaria are associated with altered gastroduodenal permeability.

BACKGROUND: In a subgroup of patients with chronic urticaria (CU) the disease is caused by pseudoallergic reactions to food. The aim of this study was to investigate whether disturbances of the gastrointestinal barrier function play a role in the pathomechanism of the disease. METHODS: In 55 patients with CU gastrointestinal permeability was measured with an in vivo triple-sugar-test before and after 24 days of a diet low in pseudoallergens. Sucrose served as marker for gastroduodenal permeability, lactulose/mannitol ratio for intestinal permeability. RESULTS: Basal gastroduodenal and intestinal permeability were significantly higher in patients with urticaria as compared to controls. In 29 of the 55 patients skin symptoms decreased or completely disappeared during the diet (responders). Compared to nonresponders (n = 26), responders had a significantly higher gastroduodenal permeability before treatment (0.36 +/- 0.04 vs 0.15 +/- 0.01% sucrose; P < 0.001), which decreased after the diet (0.17 +/- 0.02; P < 0.001). The number of patients with Helicobacter pylori infections did not differ between the two groups. CONCLUSIONS: The results indicate that in a subgroup of patients with CU and pseudoallergy an impaired gastroduodenal barrier function may be of pathophysiological importance. The underlying mechanisms seem to be independent of H. pylori infection.

Multidimensional information on the chemical composition of single bacterial cells by confocal Raman microspectroscopy.

In many biotechnological processes, living microorganisms are used as biocatalysts. Biochemical engineering science is becoming more aware that individual cells of an organism in a process can be fairly inhomogeneous regarding their properties and physiological status. Raman microspectroscopy is a novel approach to characterize such differentiated populations. Cells of the anaerobic bacterium Clostridium beijerinckii were dried on transparent support surfaces. The laser beam of a confocal Raman microscope was focused on individual cells viewed through the objective. Single bacterial cells in size approximately 1 microm and sample mass approximately 1 pg could be analyzed within a few minutes, when placed on a calcium fluoride support and using excitation at 632.8 nm. Spectral features could be attributed to all major cell components. Cells from a morphologically differentiated culture sample showed different compositions, indicating the presence of subpopulations. As a reference, the storage polymer granulose was detected. The multidimensional information in Raman spectra gives a global view on all major components of the cell at once, complementing other more specific information-rich methods for single-cell analysis. The method can be used, for example, to study heterogeneities in a microbial population.

Orthostatic hypotension in aging humans.

We tested the hypothesis that hypotension occurred in older adults at the onset of orthostatic challenge as a result of vagal dysfunction. Responses of heart rate (HR) and mean arterial pressure (MAP) were compared between 10 healthy older and younger adults during onset and sustained lower body negative pressure (LBNP). A younger group was also assessed after blockade of the parasympathetic nervous system with the use of atropine or glycopyrrolate and after blockade of the beta(1)-adrenoceptor by use of metoprolol. Baseline HR (older vs. younger: 59 +/- 4 vs. 54 +/- 1 beats/min) and MAP (83 +/- 2 vs. 89 +/- 3 mmHg) were not significantly different between the groups. During -40 Torr, significant tachycardia occurred at the first HR response in the younger subjects without hypotension, whereas significant hypotension [change in MAP (DeltaMAP) -7 +/- 2 mmHg] was observed in the elderly without tachycardia. After the parasympathetic blockade, tachycardiac responses of younger subjects were diminished and associated with a significant hypotension at the onset of LBNP. However, MAP was not affected after the cardiac sympathetic blockade. We concluded that the elderly experienced orthostatic hypotension at the onset of orthostatic challenge because of a diminished HR response. However, an augmented vasoconstriction helped with the maintenance of their blood pressure during sustained LBNP.

In vivo assessment of 111In-labeled hematoporphyrin derivative in breast tumor-bearing animals.

The biological behavior of 111In-labeled HPD has been investigated in tumor-bearing animals. Mice mammary adenocarcinomas and 7,12-dimethylbenz(a)anthracine induced breast tumors in Sprague-Dawley female rats were clearly visualized by 111In-HPD nuclear scintigraphy. Optimal scans were obtained after a 48 h delay. In normal and tumor-bearing animals, the highest uptake of 111In-HPD 72 h post-injection was found in the liver, the spleen and the kidneys. Depending on the size and the extent of necrosis, the uptake of 111In-HPD by malignant breast tumors varied from 2.5% injected dose (ID) (range 0.14-5.3% ID) in mice to 1% (range 0.22-8.1% ID) in rats. Benign breast tumor uptake of 111In-HPD was less than 1% ID. No significant amount of the radiopharmaceutical was found in pulmonary abscesses and abdominal cysts (less than 0.1% ID). Scintigrams of these infectious or inflammatory lesions were normal. Malignant tumor to blood, heart and lung ratios averaged 50:1, 10:1 and 3:1 respectively. Tumor to brain ratio ranged from 72 to 444:1.

Scintigraphic detection of atherosclerotic plaques in rabbits with 111In-labeled hematoporphyrin derivative.

The efficacy of 111In-labeled hematoporphyrin derivative (HPD) in localizing and detecting atheromas had been investigated with 10 atherogenic New Zealand white rabbits. Atherosclerotic plaques surgically induced in the abdominal aorta showed selective uptake of 111In-HPD over normal blood vessels averaging 0.01% ID/g tissue (range 0.003-0.023% ID/g). Normal aorta and thoracic artery concentrated an average of 0.0026% ID/g which is less than the mean blood activity of 0.0034% ID/mL. Statistical analysis demonstrated significant difference in the uptake of 111In-HPD by the atherosclerotic plaque segments as compared to normal abdominal aorta (P = 0.0023) and normal thoracic artery (P = 0.0012). In hypercholesteremic rabbits, the mean plaque segment to normal blood vessels ratio was 4:1 (range 2 to 9:1) sufficiently high to permit plaque delineation in the scintigram. Although 111In-HPD showed promise as a plaque imaging agent, further investigation with large animal models such as primates is needed to confirm current findings.

Albumin lung/heart ratio change. A simple clinical means of documenting increased pulmonary endothelial permeability to protein.

We investigated a simple method that can be used at the bedside for documenting the net accumulation of albumin in the lung. The technique employs measurement with a computer-linked gamma camera of the activity ratio in an area of the right lung compared with the same-sized area in the heart at 20 minutes and three hours following intravenous injection of technetium Tc 99m albumin. We applied this measurement to three groups of patients: a control group and patients with roentgenographic evidence of edema classified according to clinically available criteria as either hydrostatic edema or permeability edema to see if we could document differences among these groups. In control patients this ratio did not increase by more than seven units between the 20-minute and three-hour measurements. Of 18 patients classified by other routine clinical means as having hydrostatic pulmonary edema, 89% showed no increase in lung albumin accumulation. In 29 patients with permeability edema associated with the so-called adult respiratory distress syndrome, 31% showed evidence of net pulmonary albumin accumulation. These findings suggest that some patients otherwise classified as having hydrostatic edema have concomitant permeability changes in the microvasculature and that permeability edema represents a spectrum of endothelial damage.

In vivo assessment of 99mTc-labeled hematoporphyrin derivative in tumor-bearing animals.

The efficacy of 99mTc-labeled hematoporphyrin derivative in localizing neoplasms has been investigated with tumor-bearing animal models. Spontaneous mammary adenocarcinomas of outbred CFW strain Swiss-Webster white mice and chemical carcinogen induced breast tumors in female Sprague-Dawley white rats were clearly visualized in the scintigrams. Mice tissue distribution data demonstrate favourable tumor to organ ratios sufficiently high to permit tumor detection. [99mTc]HPD appears promising as a tumor imaging agent.

Imaging endocarditis with Tc-99m-labeled antibody--an experimental study: concise communication.

The sensitivity and specificity of Tc-99m-labeled antibacterial antibody (Tc-99m Ab) for detecting bacterial endocarditis were evaluated in an experimental model. Rabbit-produced antistaphylococcal antibody was extracted using Rivanol and chemically labeled with Tc-99m. This Tc-99m Ab was injected intravenously in New Zealand rabbits 24 hr after producing Staphylococcus aureus endocarditis of the aortic valve. Imaging and tissue analyses were performed on the following day. All 11 animals developed S. aureus aortic-valve vegetations and showed increased uptake of Tc-99m Ab at the aortic valve, 118 times higher than at the uninfected tricuspid valve. Although high hepatic radioactivity and anatomic uncertainties interfered with in vivo delineation of these lesions, images of the excised hearts showed all affected valves. Two rabbits inoculated with Escherichia coli did not develop endocarditis and had little uptake of Tc-99m Ab, while six rabbits with enterococcal endocarditis had no uptake of the Tc-99m Ab in their vegetations. The findings suggest potential value of Tc-99m Ab on the rapid diagnosis of endocarditis.