Intentional weight loss in overweight and obese patients with heart failure: A systematic review.

Approximately 30-49% of heart failure (HF) patients are living with obesity. The recommended body mass index (BMI) for the general population is 18.5-24.9 kg/m2. The obesity paradox suggests that HF patients with obesity (HFpwO) have a better prognosis compared to normal BMI. Guideline recommendations on ideal BMI for HFpwO are limited. This systematic review aims to examine the evidence base for intentional weight loss in HFpwO on the following parameters: mortality, hospitalization, symptoms, quality of life (QOL), effects on left ventricular ejection fraction (LVEF) and adverse events. A total of 22 studies were identified: lifestyle intervention (n = 9), pharmacotherapy (n = 3), bariatric surgery (n = 10). Mortality and hospitalization, symptoms, QOL, and LVEF were reported in 8, 15 and 14 studies, respectively. All studies had moderate to high risk of bias except one randomized controlled trial (RCT) which evaluated semaglutide in HF with preserved ejection fraction (HFpEF) patients. Semaglutide resulted in weight loss with improvement in QOL. Lifestyle intervention led to weight loss, minimal adverse events, and improvement in symptoms in both HF with reduced ejection fraction (HFrEF) and HFpEF patients. In six observational studies, bariatric surgery in HFrEF patients achieved weight loss and improvement in LVEF safely in most patients but some patients developed worsening HF perioperatively. There is a need for high-quality adequately powered RCTs on intentional weight loss in HFpwO with survival and hospitalization outcomes. All forms of weight loss intervention studied in this review were likely to result in significant weight loss, improved symptoms and QOL. Careful monitoring is required due to an increase in certain adverse events.

Time to unshackle the medical treatment of obesity in the NHS.

Obesity affects one in four people in the United Kingdom and costs the National Health Service (NHS) ∼£6.5 billion annually. The glucagon-like peptide-1 (GLP-1) receptor analogues, such as once-daily subcutaneous Liraglutide 3.0 mg (Saxenda®) and once-weekly subcutaneous Semaglutide 2.4 mg (Wegovy®), were approved by the National Institute of Health and Care Excellence (NICE) as a treatment for obesity and funded by the NHS for 2 years. Our local data shows that Saxenda is effective at reducing body weight and glycaemia in people with obesity and diabetes; however, the supply issues of GLP-1 receptor analogues have contributed to the unavailability of Saxenda and Wegovy in our service. Our patients are devastated that they cannot access NICE-approved GLP-1 receptor analogues for obesity. The 2-year GLP-1 receptor analogue treatment limit for obesity alongside a lack of funded NHS services and supply issues represent barriers to treatment for people living with obesity who have clear medical indications.

Application of connectivity index of cubic fuzzy graphs for identification of danger zones of tsunami threat.

Fuzzy graphs are very important when we are trying to understand and study complex systems with uncertain and not exact information. Among different types of fuzzy graphs, cubic fuzzy graphs are special due to their ability to represent the membership degree of both vertices and edges using intervals and fuzzy numbers, respectively. To figure out how things are connected in cubic fuzzy graphs, we need to know about cubic α-strong, cubic ß-strong and cubic δ-weak edges. These concepts better help in making decisions, solving problems and analyzing things like transportation, social networks and communication systems. The applicability of connectivity and comprehension of cubic fuzzy graphs have urged us to discuss connectivity in the domain of cubic fuzzy graphs. In this paper, the terms partial cubic α-strong and partial cubic δ-weak edges are introduced for cubic fuzzy graphs. The bounds and exact expression of connectivity index for several cubic fuzzy graphs are estimated. The average connectivity index for cubic fuzzy graphs is also defined and some results pertaining to these concepts are proved in this paper. The results demonstrate that removing some vertices or edges may cause a change in the value of connectivity index or average connectivity index, but the change will not necessarily be related to both values. This paper also defines the concepts of partial cubic connectivity enhancing node and partial cubic connectivity reducing node and some related results are proved. Furthermore, the concepts of cubic α-strong, cubic ß- strong, cubic δ-weak edge, partial cubic α-strong and partial cubic δ-weak edges are utilized to identify areas most affected by a tsunami resulting from an earthquake. Finally, the research findings are compared with the existing methods to demonstrate their suitability and creativity.

Label-free detection and quantification of ultrafine particulate matter in lung and heart of mouse and evaluation of tissue injury.

While it is known that air borne ultrafine particulate matter (PM) may pass through the pulmonary circulation of blood at the alveolar level between lung and heart and cross the air-blood barrier, the mechanism and effects are not completely clear. In this study the imaging method fluorescence lifetime imaging microscopy is adopted for visualization with high spatial resolution and quantification of ultrafine PM particles in mouse lung and heart tissues. The results showed that the median numbers of particles in lung of mice exposed to ultrafine particulate matter of diameter less than 2.5 µm was about 2.0 times more than that in the filtered air (FA)-treated mice, and about 1.3 times more in heart of ultrafine PM-treated mice than in FA-treated mice. Interestingly, ultrafine PM particles were more abundant in heart than lung, likely due to how ultrafine PM particles are cleared by phagocytosis and transport via circulation from lungs. Moreover, heart tissues showed inflammation and amyloid deposition. The component analysis of concentrated airborne ultrafine PM particles suggested traffic exhausts and industrial emissions as predominant sources. Our results suggest association of ultrafine PM exposure to chronic lung and heart tissue injuries. The current study supports the contention that industrial air pollution is one of the causative factors for rising levels of chronic pulmonary and cardiac diseases.

Imperial Satiety Protocol: A new non-surgical weight-loss programme, delivered in a health care setting, produces improved clinical outcomes for people with obesity.

'Imperial Satiety Protocol' (I-SatPro) is a new multifaceted approach to weight loss for people with obesity (PwO), encompassing dietary advice, time-restricted eating, physical activity and coaching to support behaviour change. Participants (n = 84) attended fortnightly I-SatPro group sessions for 30 weeks, with 70% of participants completing. On completion at 30 weeks, the mean weight loss was 15.2 ± 1.1 kg (13.2 ± 0.8% from baseline, P < .0001), which was maintained to 52 weeks (16.6 ± 1.5 kg, 14.1 ± 1.2%, P < .0001). Weight loss was not associated with reduced energy expenditure. In participants with type 2 diabetes and pre-diabetes (n = 16), glycated haemoglobin fell from 50 to 43 mmol/mol (P < .01). Systolic blood pressure fell by 12 mmHg (P < .0001). Triglycerides fell by 0.37 mmol/L (P < .01) and high-density lipoprotein rose by 0.08 mmol/L (P < .01). Short Form-36 (SF-36) functioning and wellbeing scores increased in all domains post I-SatPro intervention. For selected PwO, I-SatPro delivers clinically meaningful weight loss, and the potential for long-term health and wellbeing improvements.

Environmental responsiveness of tubulin glutamylation in sensory cilia is regulated by the p38 MAPK pathway.

Glutamylation is a post-translational modification found on tubulin that can alter the interaction between microtubules (MTs) and associated proteins. The molecular mechanisms regulating tubulin glutamylation in response to the environment are not well understood. Here, we show that in the sensory cilia of Caenorhabditis elegans, tubulin glutamylation is upregulated in response to various signals such as temperature, osmolality, and dietary conditions. Similarly, tubulin glutamylation is modified in mammalian photoreceptor cells following light adaptation. A tubulin glutamate ligase gene ttll-4, which is essential for tubulin glutamylation of axonemal MTs in sensory cilia, is activated by p38 MAPK. Amino acid substitution of TTLL-4 has revealed that a Thr residue (a putative MAPK-phosphorylation site) is required for enhancement of tubulin glutamylation. Intraflagellar transport (IFT), a bidirectional trafficking system specifically observed along axonemal MTs, is required for the formation, maintenance, and function of sensory cilia. Measurement of the velocity of IFT particles revealed that starvation accelerates IFT, which was also dependent on the Thr residue of TTLL-4. Similarly, starvation-induced attenuation of avoidance behaviour from high osmolality conditions was also dependent on ttll-4. Our data suggest that a novel evolutionarily conserved regulatory system exists for tubulin glutamylation in sensory cilia in response to the environment.

Beyond Weight Loss: Establishing a Postbariatric Surgery Patient Support Group-What Do Patients Want?

Purpose: There are limited resources for long-term specialist follow-up after bariatric surgery. In selected centres, patients can access a postoperative support group, but there is no clear evidence to guide their delivery. Materials and Methods: A retrospective study of bariatric surgery patients (n = 152) who had been discharged from specialist follow-up (mean time since surgery 5.5 years), covering weight history, physical and psychosocial comorbidities, and the need for a postoperative bariatric support group. Results: Fifty-eight percent wanted a postbariatric surgery patient support group. This was not associated with operation type or the amount of weight lost or regained. However, those who wanted a support group were significantly more likely to be struggling to keep the weight off, to be unhappy with the way they look, or to be experiencing difficulties returning to work. Conclusions: These data point to an unmet patient requirement for a postoperative support group that is independent of weight loss success. More research is required to ascertain how such a group should be delivered, but our data would suggest that supporting patients with weight loss maintenance, body image, and return to work is an important part of postoperative care, and these needs extend well beyond the immediate period of specialist follow-up.

Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight.

The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRß) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRß in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRß in the VMH as a major physiological regulator of food intake and energy homeostasis.

Validity of very short answer versus single best answer questions for undergraduate assessment.

BACKGROUND: Single Best Answer (SBA) questions are widely used in undergraduate and postgraduate medical examinations. Selection of the correct answer in SBA questions may be subject to cueing and therefore might not test the student's knowledge. In contrast to this artificial construct, doctors are ultimately required to perform in a real-life setting that does not offer a list of choices. This professional competence can be tested using Short Answer Questions (SAQs), where the student writes the correct answer without prompting from the question. However, SAQs cannot easily be machine marked and are therefore not feasible as an instrument for testing a representative sample of the curriculum for a large number of candidates. We hypothesised that a novel assessment instrument consisting of very short answer (VSA) questions is a superior test of knowledge than assessment by SBA. METHODS: We conducted a prospective pilot study on one cohort of 266 medical students sitting a formative examination. All students were assessed by both a novel assessment instrument consisting of VSAs and by SBA questions. Both instruments tested the same knowledge base. Using the filter function of Microsoft Excel, the range of answers provided for each VSA question was reviewed and correct answers accepted in less than two minutes. Examination results were compared between the two methods of assessment. RESULTS: Students scored more highly in all fifteen SBA questions than in the VSA question format, despite both examinations requiring the same knowledge base. CONCLUSIONS: Valid assessment of undergraduate and postgraduate knowledge can be improved by the use of VSA questions. Such an approach will test nascent physician ability rather than ability to pass exams.

Direct profiling of the phospholipid composition of adult Caenorhabditis elegans using whole-body imaging mass spectrometry.

A protocol for the direct analysis of the phospholipid composition in the whole body of adult soil nematode, Caenorhabditis elegans (C. elegans), was developed, which combined freeze-cracking of the exoskeletal cuticle and matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). Biomolecules in the m/z range from 700 to 900 were more effectively detected in the freeze-cracked than from simple frozen adult nematode bodies. Different distribution of biomolecules was observed in a nematode body when the matrix was applied with a sublimation deposition method. The whole-body IMS technique was applied on genetically deficient mutant C. elegans to combine whole-body lipidomics and genetics, by comparing the fatty acid compositions, especially of the phosphatidylcholine (PC) species, between the wild-type and fat-1 mutants, which lack the gene encoding an n-3 fatty acid desaturase. A significant reduction of PC(20:5/20:5) and PC(20:4/20:5) and a marked increase of PC(20:4/20:4), PC(20:3/20:4), and PC(20:3/20:3) were detected in the fat-1 mutants in positive ion mode. In addition, phospholipid compositions other than PCs were analyzed in negative ion mode. A loss of a possible phosphatidylinositol (PI) with 18:0/20:5 and a compensative accumulation of putative PI(18:0/20:4) were detected in the fat-1 mutants. In conclusion, the whole-body MALDI-IMS technique is useful for the profiling of multiple biomolecules in C. elegans in both intra- and inter-individual levels.

Development of imaging mass spectrometry.

We have developed a mass microscope in which a microscope is combined with high-resolution matrix assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). This technique is a powerful tool for investigating the spatial distribution of biomolecules without the need for any time-consuming extraction, purification, and labeling procedures for biological tissue sections. The mass microscope provides clear images with regards to the distribution of hundreds of biomolecules in a single measurement, and also helps in determining the cellular profile of the biological system. In this review, we focus on some of the recent developments in clinical applications and describe how the mass microscope can be employed to assess pathomorphology and pharmacokinetics.

Biologically active bergenin derivatives from Bergenia stracheyi.

New bergenin derivatives, bergecins A and B (1 and 2, resp.), have been isolated from the AcOEt-soluble fraction of Bergenia stracheyi, along with bergenin (3), and their structures were elucidated on the basis of (1) H- and (13) C-NMR spectra, and by COSY, HMQC, and HMBC experiments. Compound 2 showed potent inhibitory potential against the enzyme lipoxygenase, while 1 was moderately active. On the other hand, both compounds exhibited significant antioxidant activities in 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay.

Pregnane derivatives from Potentilla evestita.

A new pregnane derivative, 2,6beta,7beta-trihydroxy-4-methyl-19-norpregna-1,3,5(10)-trien-17-one, has been isolated from the ethyl acetate soluble fraction of Potentilla evestita along with a pregnane derivative, 11alpha,17alpha,21-trihydroxypregna-4,16(22)-diene-3,20-dione, that is reported for the first time as a natural product. Their structures were elucidated with the aid of 1H and 13C NMR spectra and by COSY, HMQC, HMBC and NOESY experiments.

Kisspeptin and fertility.

The kisspeptins are a family of peptide hormones, which in recent years have been shown to play a critical role in the regulation of the hypothalamic-pituitary-gonadal axis, thus in turn influencing fertility and reproduction. This review examines the physiological role of kisspeptin and the kisspeptin receptor in the control of gonadotrophin and gonadal steroid hormone secretion and the implications of these findings with respect to fertility. In addition, the potential therapeutic use of kisspeptin in the treatment of reproductive disorders will be examined.

Biology of kisspeptins.

In recent years, a substantial body of evidence has accumulated suggesting that the hypothalamic peptide hormone kisspeptin and its cognate receptor, G-protein-coupled receptor 54, play a fundamental role both as gatekeepers for the initiation of puberty and in the regulation of the hypothalamic-pituitary-gonadal axis. This review discusses the physiology of the kisspeptin signalling system and examines how findings from animal and human studies have contributed to our understanding of the pathophysiology of idiopathic hypogonadotropic hypogonadism.

Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake.

OBJECTIVE: Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis. RESEARCH DESIGN AND METHODS: We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanism of action by determining sites of neuronal activation after ICV injection of PK2, the hypothalamic site of action of PK2, and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2's potential as a therapeutic target, we investigated the effect of chronic administration in lean and obese mice. RESULTS: Hypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake, whereas anti-PK2 antibody increased food intake, suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of alpha-melanocyte-stimulating hormone (alpha-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the alpha-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight in lean and obese mice. CONCLUSIONS: This is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is mediated partly via the melanocortin system.

Cashmirols A and B, new lipoxygenase inhibiting triterpenes from Sorbus cashmiriana.

Two new triterpenes, cashmirols A and B, along with three known compounds have been isolated from the AcOEt-soluble fraction of Sorbus cashmiriana, and their structures were elucidated by spectroscopic techniques including two-dimensional NMR. Both compounds displayed lipoxygenase enzyme inhibitory potential.

Isolation and structural determination of sorbinols A and B, new triterpenes from Sorbus cashmariana, by 1D and 2D NMR spectroscopy.

Two new pentacyclic triterpenes, sorbinols A (1) and B (2) have been isolated from the ethyl acetate fraction of Sorbus cashmariana and their structures assigned from (1)H and (13)C NMR spectra, DEPT and by 2D COSY, NOE, HMQC and HMBC experiments. Both 1 and 2 showed moderate inhibitory potential against the enzyme lipoxygenase.