Analyzing the dynamics of meningococcal vaccinations initiatives by local government units in Poland (2017-2021) - Scope, challenges and recommendations.

INTRODUCTION: Meningococcal vaccinations are recommended by Polish public health authorities but lack coverage under health insurance, prompting Local Government Units (LGUs) to implement local health policy programs. This study examines the effectiveness and impact of LGU-driven meningococcal vaccination initiatives in Poland between 2017 and 2021. MATERIAL AND METHODS: A retrospective analysis utilized data from reports on local public health interventions submitted annually to the Ministry of Health in Poland. The study focused on the number of meningococcal vaccination programs, their scope, the vaccinated population, and associated program costs. Additionally, nationwide data on meningococcal disease incidence and vaccine uptake were analyzed. RESULTS: Within LGUs programs, 48,617 individuals received meningococcal vaccinations, constituting approximately 10% of all vaccinations in Poland during the study period. Notably, cities with poviat rights spearheaded programs covering 54% of the total participants. The total cost incurred by these initiatives amounted to EUR 2,553,661. CONCLUSIONS: While LGUs activities positively contributed to increased meningococcal vaccination rates, the overall engagement of local governments remains limited. The findings underscore the importance of expanding local government involvement in meningococcal vaccination programs to address public health needs effectively. Improved collaboration and increased funding may enhance the reach and impact of these initiatives.

Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial ß-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver.

BACKGROUND AND PURPOSE: Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen-induced Hmgcr-knockout (KO) mouse model, a multi-omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. EXPERIMENTAL APPROACH: We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time-dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr-KO mice. KEY RESULTS: Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid ß-oxidation and very high accumulation of long-chain (LC) acylcarnitines in both male and female mice. Gene expression and KO-related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole-body hypoglycaemia. CONCLUSION AND IMPLICATIONS: Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial ß-oxidation. Moreover, statin-induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation.

Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases.

Male sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematological cancer, as well as higher LOY in CD4 + T-lymphocytes in men with prostate cancer vs. controls. However, nothing is known about LOY in leukocytes infiltrating TME and we address this aspect here. We studied frequency and functional effects of LOY in blood, TME and non-tumorous tissue. Regulatory T-lymphocytes (Tregs) in TME had the highest frequency of LOY (22%) in comparison to CD4 + T-lymphocytes and cytotoxic CD8 + T-lymphocytes. LOY score using scRNA-seq was also linked to higher expression of PDCD1, TIGIT and IKZF2 in Tregs. PDCD1 and TIGIT encode immune checkpoint receptors involved in the regulation of Tregs function. Our study sets the direction for further functional research regarding a probable role of LOY in intensifying features related to the suppressive phenotype of Tregs in TME and consequently a possible influence on immunotherapy response in CRC patients.

Loss of chromosome Y in regulatory T cells.

BACKGROUND: Mosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples. RESULTS: Regulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells. CONCLUSIONS: Here, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes.

Comparative Analysis of Symptomatology in Hospitalized Children with RSV, COVID-19, and Influenza Infections.

BACKGROUND The clinical course of respiratory syncytial virus (RSV), SARS-CoV-2, and influenza infections comprises many non-specific symptoms, which makes diagnosis difficult. The aim of this study was to retrospectively analyze the symptomatology of these infections in children and to search for correlations between them. MATERIAL AND METHODS A total of 121 children with a positive RSV (n=61), influenza (n=31), or SARS-CoV-2 (n=29) antigen test were enrolled in this retrospective analysis. Children were aged up to 71 months (median, 8 months). The collected data were collated by performing statistical analysis using the chi-square test and comparing the results using OR (odds ratio) and 95%CI (confidence interval). RESULTS There was a higher risk of fever in children with influenza than in those with RSV. Patients infected with RSV had a higher risk of nasal blockage than those with SARS-CoV-2. Dyspnea was more common in RSV infection than in influenza. Severe, sleep-awakening cough was more frequent in children with RSV than in those with COVID-19. Influenza was more prevalent in children aged >24 months than in those aged 7-24 months. RSV-infected children had a higher risk of numerous auscultatory changes compared to those with SARS-CoV-2. In the case of RSV infection, symptoms requiring hospitalization occurred later than in SARS-CoV-2 infection. CONCLUSIONS Children aged >24 months were at higher risk of contracting influenza. Numerous auscultatory changes, nasal blockage, and dyspnea were more common in children with RSV. There was a higher risk of dyspnea in children with RSV. Fever was more frequent in children with influenza. However, none of the symptoms clearly indicated the etiology of the infection.

The Usage of Cryopreserved Reproductive Material in Cancer Patients Undergoing Fertility Preservation Procedures.

BACKGROUND: Many cancer treatment methods can affect fertility by damaging the reproductive organs and glands that control fertility. Changes can be temporary or permanent. In order to preserve the fertility of cancer patients and protect the genital organs against gonadotoxicity, methods of fertility preservation are increasingly used. Considering that some patients ultimately decide not to use cryopreserved reproductive material, this review analysed the percentage of post-cancer patients using cryopreserved reproductive material, collected before treatment as part of fertility preservation. METHODS: A systematic search of studies was carried out in accordance with the Cochrane Collaboration guidelines, based on a previously prepared research protocol. The search was conducted in Medline (via PubMed), Embase (via OVID), and the Cochrane Library. In addition, a manual search was performed for recommendations/clinical practice guidelines regarding fertility preservation in cancer patients. RESULTS: Twenty-six studies met the inclusion criteria. The studies included in the review discussed the results of cryopreservation of oocytes, embryos, ovarian tissue, and semen. In 10 studies, the usage rate of cryopreserved semen ranged from 2.6% to 21.5%. In the case of cryopreserved female reproductive material, the return/usage rate ranged from 3.1% to 8.7% for oocytes, approx. 9% to 22.4% for embryos, and 6.9% to 30.3% for ovarian tissue. In studies analysing patients' decisions about unused reproductive material, continuation of material storage was most often indicated. Recovering fertility or death of the patient were the main reasons for rejecting cryopreserved semen in the case of men. CONCLUSION: Fertility preservation before gonadotoxic treatment is widely recommended and increasingly used in cancer patients. The usage rate is an important indicator for monitoring the efficacy of these methods. In all of the methods described in the literature, this indicator did not exceed 31%. It is necessary to create legal and organizational solutions regulating material collection and storage and to create clear paths for its usage in the future, including by other recipients.

Respecting the Patient's Right to Information in Hospital Wards in Poland - Socio-Economic Determinants of Patients' Opinions.

Background: Implementation of the patient's statutory right to information is one of determinants the quality and safety of medical services. The patients' opinions survey is an element of patient-centric care, which is now one of the most important things in modern healthcare. The main aim of the work is to examine patients' opinions on the observance of patients' right to information in the hospital and quality of healthcare in the hospital. A secondary objective was to examine the impact of socioeconomic variables on patients' opinions. Materials and Methods: The study was based on the Computer-Assisted Web Interview (CAWI) questionnaire, carried out in March 2022. The sample included 801 persons. Respondents were patients hospitalized within a maximum of 12 months. The questionnaire contained closed questions about the quality of medical care, observance of the patient's right to information. Results: Probability of referral was measured using the Net Promoter Score (NPS). Respondents answered the question about the recommendation on a scale from 0 to 10. People who rated the hospital ward at 10 and 9 are promoters, people who rated the hospital ward at 8 and 7 are neutral people. In turn, people who rated the hospital ward at 6, 5, 4, 3, 2, 1 or 0 are critics, ie people who will not recommend the hospital to their relatives. Most patients in hospital wards were the detractors (37%). The percentage of promoters was only 1% lower (36%) than that of the detractors. Patients was rated medical and nursing staff at a similar level with regard to the observance of the patient's right to information. Conclusion: Most statistically significant differences in the assessment of medical care in the hospital ward were associated with such sociodemographic variables as age and income. People aged 55-64 and 65+ rated most of the analyzed aspects better.

Effect of intranasal oxytocin on palatable food consumption and c-Fos immunoreactivity in relevant brain areas in rats.

Peripheral and central injections of oxytocin (OT) in laboratory animals decrease eating for energy and palatability, but the hypophagic response is dependent on the administration route. Human studies rely on intranasal (IN) administration of the peptide, the route underutilized in OT animal feeding studies thus far. Therefore, we examined the effect of IN OT on various aspects of food consumption in rats: (a) overnight deprivation-induced standard chow intake, (b) episodic (2-h) consumption of calorie-dense and palatable high-fat high-sugar (HFHS) chow, (c) 2-h episodic intake of palatable and calorie-dilute sucrose and Intralipid solutions, and (d) 2-h sucrose solution intake in rats habituated to ingesting this solution daily for several weeks. Finally, we assessed c-Fos changes in response to the acute IN OT administration in rats habituated to daily sugar consumption. We found that IN 20µg OT decreased deprivation-induced intake of standard chow and HFHS chow in nondeprived rats without affecting water consumption. IN OT also reduced 2-hour episodic fluid consumption of sucrose, but not Intralipid. In the habitual sugar consumption paradigm, acute IN OT diminished sucrose solution intake in animals accustomed to the 2-hour/day sucrose meal regimen. In rats habitually consuming sucrose, IN OT altered c-Fos immunoreactivity in brain areas related to energy homeostasis and reward, including the central nucleus of the amygdala, the hypothalamic paraventricular and the arcuate nuclei. We conclude that IN OT is an effective appetite suppressant for carbohydrate/sugar diets in rats and its effects involve feeding-related brain circuits.

Size matters: the impact of nucleus size on results from spatial transcriptomics.

BACKGROUND: Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tissue slice. This may, in turn, negatively affect comprehensive capturing the transcriptomics profile in a single slice, especially for tissues having large differences in the size of nuclei. METHODS: Here, we defined the effect of Consecutive Slices Data Integration (CSDI) on unveiling accurate spot clustering and deconvolution of spatial transcriptomic spots in human postmortem brains. By considering the histological information as reference, we assessed the improvement of unsupervised clustering and single nuclei RNA-seq and ST data integration before and after CSDI. RESULTS: Apart from the escalated number of defined clusters representing neuronal layers, the pattern of clusters in consecutive sections was concordant only after CSDI. Besides, the assigned cell labels to spots matches the histological pattern of tissue sections after CSDI. CONCLUSION: CSDI can be applied to investigate consecutive sections studied with ST in the human cerebral cortex, avoiding misinterpretation of spot clustering and annotation, increasing accuracy of cell recognition as well as improvement in uncovering the layers of grey matter in the human brain.

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men.

BACKGROUND: The COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription. METHODS: Publicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells. We further studied LOY in whole blood for 211 COVID-19 patients treated at intensive care units (ICU) from the first and second waves of the pandemic. Of these, 139 patients were subject to cell sorting for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs. RESULTS: Reanalysis of available scRNA-seq data revealed LDNs and monocytes as the cell types most affected by LOY. Subsequently, DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively. Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY. Moreover, LOY correlated with increasing WHO score (median difference 1.59%, 95% HDI 0.46% to 2.71%, p=0.025), death during ICU treatment (median difference 1.46%, 95% HDI 0.47% to 2.43%, p=0.0036), and history of vessel disease (median difference 2.16%, 95% HDI 0.74% to 3.7%, p=0.004), among other variables. In 16 recovered patients, sampled during ICU stay and 93-143 days later, LOY decreased significantly in whole blood and PBMCs. Furthermore, the number of LDNs at the recovery stage decreased dramatically (median difference 76.4 per 10,000 cell sorting events, 95% HDI 55.5 to 104, p=6e-11). CONCLUSIONS: We present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing.

The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation, and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population, and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor, and peripheral blood from 52 reportedly sporadic breast cancer patients. Targeted resequencing of 542 cancer-associated genes revealed subclonal somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3, and TSHR in the normal mammary gland at considerable allelic frequencies (9 × 10-2- 5.2 × 10-1), indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low-level subclonal (in 10-2-10-4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumorous mammary gland tissue of breast-conserving surgery patients.

Ash from Poultry Manure Incineration as a Substitute for Phosphorus Fertiliser.

The goal of the tests was to separate a phosphate concentrate from ash and to assess its fertiliser use efficiency in anthropogenic land. Ash obtained from poultry manure incineration is an interesting fertiliser, as it contains both of the necessary nutrients, i.e., phosphorus and potassium. The ash selected for the tests contained 15.73 wt% P2O5, and 6.75 wt% K2O. CaO also constituted the main component (44.79 wt%). Phosphorus in crystalline form was present as hydroxyapatite and carbonate apatite. The first stage, applied in order to separate a phosphate concentrate from ash, involved a number of physicochemical methods: (i) a method based on grain wettability differences; (ii) a method based on grain density differences; and (iii) methods based on size distribution differences. Wet sieving made it possible to separate a fraction with a P2O5 content of 24.56 wt%. The second stage, applied to assess fertiliser use efficiency, involved cassette tests as well as pot and field cultivation using as fertiliser, the obtained product as well as raw ash and commercial ones. Therefore, the conducted research allowed for the development of a methodology for the management of ash from the incineration of a poultry manure and their use as a substitute for phosphorus fertiliser. The tested material was applied in various doses. Using the obtained phosphate concentrate at a dose of 95 g/m3 resulted in a comparable yield as in the case of the commercial fertiliser at a dose recommended by the producer (75 g/m3). Unprocessed ash had to be used in larger amounts, i.e., 165 g/m3, to have a comparable yield as a commercial fertiliser.

Advances in the development of new biomarkers for Alzheimer's disease.

Alzheimer's disease (AD) is a complex, heterogeneous, progressive disease and is the most common type of neurodegenerative dementia. The prevalence of AD is expected to increase as the population ages, placing an additional burden on national healthcare systems. There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost. The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity, including pathogenic proteins, markers of synaptic dysfunction, and markers of inflammation in the blood. There is a considerable potential in using microRNA (miRNA) as markers of AD, and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients. Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease. This review focuses on the recent developments of blood, plasma, and ocular biomarkers for the diagnosis of AD.

Behavioral plasticity: Role of neuropeptides in shaping feeding responses.

Behavioral plasticity refers to changes occurring due to external influences on an organism, including adaptation, learning, memory and enduring influences from early life experience. There are 2 types of behavioral plasticity: "developmental", which refers to gene/environment interactions affecting a phenotype, and "activational" which refers to innate physiology and can involve structural physiological changes of the body. In this review, we focus on feeding behavior, and studies involving neuropeptides that influence behavioral plasticity - primarily opioids, orexin, neuropeptide Y, and oxytocin. In each section of the review, we include examples of behavioral plasticity as it relates to actions of these neuropeptides. It can be concluded from this review that eating behavior is influenced by a number of external factors, including time of day, type of food available, energy balance state, and stressors. The reviewed work underscores that environmental factors play a critical role in feeding behavior and energy balance, but changes in eating behavior also result from a multitude of non-environmental factors, such that there can be no single mechanism or variable that can explain ingestive behavior.

Chronic Intermittent Sucrose Consumption Facilitates the Ability to Discriminate Opioid Receptor Blockade with Naltrexone in Rats.

The opioid antagonist naltrexone (NTX) decreases intake of preferred diets in rats at very low doses relative to doses needed to decrease intake of "bland" laboratory chow. In the absence of an opioid agonist, NTX is not discriminable using operant techniques. In the current study, we found that rats given intermittent access to a 25% sucrose solution learned to discriminate between various naltrexone doses and saline. None of the rats given only water learned to discriminate between naltrexone and saline. When access to the sucrose solution was discontinued for 14 days, the rats lost the ability to discriminate between NTX and saline. We also studied the changes of c-Fos IR in selected brain regions in rats treated with saline versus NTX that were drinking water or 25% sucrose. An injection of NTX or saline resulted in a significant drug, diet, and interaction effect in various brain regions associated with feeding behavior, particularly the amygdala, accumbens, and hypothalamic sites. Thus, we found that ingestion of a sucrose solution results in the ability of rats to reliably discriminate naltrexone administration. In addition, sucrose and naltrexone altered c-Fos IR in an interactive fashion in brain regions known to be involved in ingestion behavior.

The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms.

The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the Drosophila melanogaster brain. Therefore, genetic and pharmacological studies were performed to identify how central Hmgcr regulates Drosophila energy metabolism and feeding behavior. We found that inhibiting Hmgcr, in insulin-producing cells of the Drosophila pars intercerebralis (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing Hmgcr expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the Hmgcr induced hyperphagia phenotype requires a conserved insulin-regulated α-glucosidase, target of brain insulin (tobi). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.

Oxytocin as a potential pharmacological tool to combat obesity.

The neuropeptide oxytocin (OT) has emerged as an important anorexigen in the regulation of food intake and energy balance. It has been shown that the release of OT and activation of hypothalamic OT neurons coincide with food ingestion. Its effects on feeding have largely been attributed to limiting meal size through interactions in key regulatory brain regions governing the homeostatic control of food intake such as the hypothalamus and hindbrain in addition to key feeding reward areas such as the nucleus accumbens and ventral tegmental area. Furthermore, the magnitude of an anorexigenic response to OT and feeding-related activation of the brain OT circuit are modified by the composition and flavor of a diet, as well as by a social context in which a meal is consumed. OT is particularly effective in reducing consumption of carbohydrates and sweet tastants. Pharmacologic, genetic, and pair-feeding studies indicate that OT-elicited weight loss cannot be fully explained by reductions of food intake and that the overall impact of OT on energy balance is also partly a result of OT-elicited changes in lipolysis, energy expenditure, and glucose regulation. Peripheral administration of OT mimics many of its effects when it is given into the central nervous system, raising the questions of whether and to what extent circulating OT acts through peripheral OT receptors to regulate energy balance. Although OT has been found to elicit weight loss in female mice, recent studies have indicated that sex and estrous cycle may impact oxytocinergic modulation of food intake. Despite the overall promising basic research data, attempts to use OT in the clinical setting to combat obesity and overeating have generated somewhat mixed results. The focus of this mini-review is to briefly summarize the role of OT in feeding and metabolism, address gaps and inconsistencies in our knowledge, and discuss some of the limitations to the potential use of chronic OT that should help guide future research on OT as a tailor-made anti-obesity therapeutic.

Mild Hypophagia and Associated Changes in Feeding-Related Gene Expression and c-Fos Immunoreactivity in Adult Male Rats with Sodium Valproate-Induced Autism.

A core yet understudied symptom of autism is aberrant eating behaviour, including extremely narrow food preferences. Autistic individuals often refuse to eat despite hunger unless preferred food is given. We hypothesised that, apart from aberrant preference, underfeeding stems from abnormal hunger processing. Utilising an adult male VPA rat, a model of autism, we examined intake of 'bland' chow in animals maintained on this diet continuously, eating this food after fasting and after both food and water deprivation. We assessed body weight in adulthood to determine whether lower feeding led to slower growth. Since food intake is highly regulated by brain processes, we looked into the activation (c-Fos immunoreactivity) of central sites controlling appetite in animals subjected to food deprivation vs. fed ad libitum. Expression of genes involved in food intake in the hypothalamus and brain stem, regions responsible for energy balance, was measured in deprived vs. sated animals. We performed our analyses on VPAs and age-matched healthy controls. We found that VPAs ate less of the 'bland' chow when fed ad libitum and after deprivation than controls did. Their body weight increased more slowly than that of controls when maintained on the 'bland' food. While hungry controls had lower c-Fos IR in key feeding-related areas than their ad libitum-fed counterparts, in hungry VPAs c-Fos was unchanged or elevated compared to the fed ones. The lack of changes in expression of feeding-related genes upon deprivation in VPAs was in contrast to several transcripts affected by fasting in healthy controls. We conclude that hunger processing is dysregulated in the VPA rat.

Whey-Adapted versus Natural Cow's Milk Formulation: Distinctive Feeding Responses and Post-Ingestive c-Fos Expression in Laboratory Mice.

The natural 20:80 whey:casein ratio in cow's milk (CM) for adults and infants is adjusted to reflect the 60:40 ratio of human milk, but the feeding and metabolic consequences of this adjustment have been understudied. In adult human subjects, the 60:40 CM differently affects glucose metabolism and hormone release than the 20:80 CM. In laboratory animals, whey-adapted goat's milk is consumed in larger quantities. It is unknown whether whey enhancement of CM would have similar consequences on appetite and whether it would affect feeding-relevant brain regulatory mechanisms. In this set of studies utilizing laboratory mice, we found that the 60:40 CM was consumed more avidly than the 20:80 control formulation by animals motivated to eat by energy deprivation and by palatability (in the absence of hunger) and that this hyperphagia stemmed from prolongation of the meal. Furthermore, in two-bottle choice paradigms, whey-adapted CM was preferred against the natural 20:80 milk. The intake of the whey-adapted CM induced neuronal activation (assessed through analysis of c-Fos expression in neurons) in brain sites promoting satiation, but importantly, this activation was less pronounced than after ingestion of the natural 20:80 whey:casein CM. Activation of hypothalamic neurons synthesizing anorexigenic neuropeptide oxytocin (OT) was also less robust after the 60:40 CM intake than after the 20:80 CM. Pharmacological blockade of the OT receptor in mice led to an increase in the consumption only of the 20:80 CM, thus, of the milk that induced greater activation of OT neurons. We conclude that the whey-adapted CM is overconsumed compared to the natural 20:80 CM and that this overconsumption is associated with weakened responsiveness of central networks involved in satiety signalling, including OT.