Proposed treatment strategy for reactive hypoglycaemia.

Background/aim: Managing reactive hypoglycaemia (RH) poses challenges due to limited and often ineffective treatment options. We report a case series and draw on this to propose a stepwise treatment approach consisting of lifestyle modifications, metformin, GLP-1 analogues, and the use of flash glucose monitoring technology. Method: A retrospective review was conducted to analyse the management of 11 cases presenting with recurrent RH symptoms. Result: Two patients experienced successful resolution of symptoms through lifestyle modifications. Metformin alone was effective in treating seven out of nine patients who received pharmacological treatment. Two patients with previous upper gastrointestinal surgery showed a partial response to metformin and benefited further from additional long-acting GLP-1 analogue. Pharmacological intervention led to significant reductions in insulin and C-peptide levels in repeat mixed meal tolerance tests (P-values 0.043 for insulin and 0.006 for C-peptide). Finally, flash glucose monitoring technology was useful in early detection and preventing episodes of hypoglycaemia in one of these patients with persistent symptoms. Conclusion: These findings highlight the potential efficacy of escalated treatment strategies for RH, including the use of metformin, GLP-1 analogues, and flash glucose monitoring technology.

Mixed infection of Actinomyces israelii and Fusobacterium nucleatum presenting as a neck mass.

This report presents the case of a mixed infection of Actinomyces israelii and Fusobacterium nucleatum, presenting as an extensive neck mass progressing through tissue planes and causing bony destruction. Despite multiple abscess aspirates, imaging and serological investigations, the causative organisms proved elusive over the course of the patient's long admission, only to be identified postdischarge. The patient was successfully initiated on a prolonged course of intravenous antibiotics and did not suffer from any complications. This report aims to raise awareness of the presentation, pathogenicity and treatment of Actinomyces and Fusobacteria infections, given a notable difficulty in diagnosis.

Pre-hospital National Early Warning Score (NEWS) is associated with in-hospital mortality and critical care unit admission: A cohort study.

BACKGROUND: National Early Warning Score (NEWS) is increasingly used in UK hospitals. However, there is only limited evidence to support the use of pre-hospital early warning scores. We hypothesised that pre-hospital NEWS was associated with death or critical care escalation within the first 48 h of hospital stay. METHODS: Planned secondary analysis of a prospective cohort study at a single UK teaching hospital. Consecutive medical ward admissions over a 20-day period were included in the study. Data were collected from ambulance report forms, medical notes and electronic patient records. Pre-hospital NEWS was calculated retrospectively. The primary outcome was a composite of death or critical care unit escalation within 48 h of hospital admission. The secondary outcome was length of hospital stay. RESULTS: 189 patients were included in the analysis. The median pre-hospital NEWS was 3 (IQR 1-5). 13 patients (6.9%) died or were escalated to the critical care unit within 48 h of hospital admission. Pre-hospital NEWS was associated with death or critical care unit escalation (OR, 1.25; 95% CI, 1.04-1.51; p = 0.02), but NEWS on admission to hospital was more strongly associated with this outcome (OR, 1.52; 95% CI, 1.18-1.97, p < 0.01). Neither was associated with hospital length of stay. CONCLUSION: Pre-hospital NEWS was associated with death or critical care unit escalation within 48 h of hospital admission. NEWS could be used by ambulance crews to assist in the early triage of patients requiring hospital treatment or rapid transport. Further cohort studies or trials in large samples are required before implementation.

Symptomatic Acute Hepatitis C Infection Following a Single Episode of Unprotected Sexual Intercourse.

A previously healthy 23-year-old MSM presented with jaundice, systemic upset, and rash 2 months after a single episode of unprotected sexual intercourse. Liver biochemistry was grossly deranged, with markedly elevated transaminases and hyperbilirubinaemia. Serology was positive for genotype 1a hepatitis C virus (HCV) and in the absence of other causes, acute HCV infection was suspected. He was subsequently successfully treated with pegylated interferon and ribavirin for 24 weeks and made a full clinical and biochemical recovery.

A single-centre cohort study of National Early Warning Score (NEWS) and near patient testing in acute medical admissions.

INTRODUCTION: The utility of an early warning score may be improved when used with near patient testing. However, this has not yet been investigated for National Early Warning Score (NEWS). We hypothesised that the combination of NEWS and blood gas variables (lactate, glucose or base-excess) was more strongly associated with clinical outcome compared to NEWS alone. METHODS: This was a prospective cohort study of adult medical admissions to a single-centre over 20days. Blood gas results and physiological observations were recorded at admission. NEWS was calculated retrospectively and combined with the biomarkers in multivariable logistic regression models. The primary outcome was a composite of mortality or critical care escalation within 2days of hospital admission. The secondary outcome was hospital length of stay. RESULTS: After accounting for missing data, 15 patients out of 322 (4.7%) died or were escalated to the critical care unit. The median length of stay was 4 (IQR 7) days. When combined with lactate or base excess, NEWS was associated with the primary outcome (OR 1.18, p=0.01 and OR 1.13, p=0.03). However, NEWS alone was more strongly associated with the primary outcome measure (OR 1.46, p<0.01). The combination of NEWS with glucose was not associated with the primary outcome. Neither NEWS nor any combination of NEWS and a biomarker were associated with hospital length of stay. CONCLUSION: Admission NEWS is more strongly associated with death or critical care unit admission within 2days of hospital admission, compared to combinations of NEWS and blood-gas derived biomarkers.

A single-centre observational cohort study of admission National Early Warning Score (NEWS).

INTRODUCTION: Early warning scores are commonly used in hospitals to identify patients at risk of deterioration. The National Early Warning Score (NEWS) has recently been introduced to UK practice. However, it is not yet widely implemented. We aimed to compare NEWS to the early warning score currently used in our hospital--the Patient at Risk Score (PARS). METHODS: We conducted a prospective observational cohort study of all adult general medical patients admitted to a single hospital over a 20-day period. Physiological data and early warning scores recorded in bedside charts were collected on admission and a NEWS score was retrospectively calculated. The patient notes were reviewed at 48 h after admission. The primary outcome was a composite of critical care admission or death within 2 days of admission. The secondary outcome was hospital length of stay. RESULTS: NEWS was more strongly associated with the primary outcome than PARS (odds ratio 1.54, p < 0.001 compared to 1.42, p = 0.056). A NEWS of 3 or more was associated with the primary outcome (odds ratio 7.03, p = 0.003). Neither score was correlated with hospital length of stay. CONCLUSION: NEWS on admission is superior to PARS for identifying patients at risk of death or critical care admission within the first 2 days of hospital stay. Current guidelines advocate a threshold of 5 for triggering a clinical review. However, since a score of 3 or more was associated with a poor outcome, this recommendation should be reviewed. Both scores were poor predictors of hospital length of stay.

The failing heart: a bad case of the 'flu'.

A 24-year-old Nepali man presented to hospital with a short history of feeling unwell with a flu-like illness. He subsequently went into acute renal failure requiring several sessions of renal replacement therapy by haemofiltration. The underlying aetiology of his renal failure was unclear. His renal function recovered following haemofiltration and he was discharged home with a plan for outpatient follow-up and investigations. He re-presented to hospital 6 days later with severe fluid overload. Echocardiogram was suggestive of impaired left ventricular systolic function; subsequent cardiac MRI confirmed this and was indicative of a dilated cardiomyopathy. A diagnosis of dilated cardiomyopathy with cardiorenal syndrome was made, most likely secondary to viral myocarditis in view of his initial presentation. He was diuresed and treated with prognostic medications for heart failure. His symptoms resolved and on subsequent outpatient review he was feeling well.

Endogenous endophthalmitis caused by Citrobacter koseri originating from a renal abscess.

We present a rare case of endogenous endophthalmitis caused by Citrobacter koseri. A 69-year-old woman with a history of poorly controlled diabetes and a protracted urinary tract infection (UTI) presented with a painful swollen left eye. There was no history of eye surgery or trauma. Imaging revealed an abscess in the right kidney. Although endophthalmitis is very rare in healthy patient, it is more common in the immunocompromised. In this patient, several multiple system illnesses including poorly controlled diabetes appear to have worked synergistically to make endophthalmitis a realistic complication of an otherwise isolated and remote source of infection, in this case pyelonephritis. Endophthalmitis, in the absence of an obvious exogenous cause, should be investigated thoroughly to exclude metastatic microbial spread. In addition, chronic features of UTI in a patient with poorly controlled diabetes or who is otherwise immunosuppressed warrant the exclusion of an underlying renal abscess.

Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans.

Laparoscopic Roux-en-Y gastric bypass (LRYGBP) reduces appetite and induces significant and sustainable weight loss. Circulating gut hormones changes engendered by LRYGBP are implicated in mediating these beneficial effects. Laparoscopic sleeve gastrectomy (LSG) is advocated as an alternative to LRYGBP, with comparable short-term weight loss and metabolic outcomes. LRYGBP and LSG are anatomically distinct procedures causing differential entero-endocrine cell nutrient exposure and thus potentially different gut hormone changes. Studies reporting the comparative effects of LRYGBP and LSG on appetite and circulating gut hormones are controversial, with no data to date on the effects of LSG on circulating peptide YY3-36 (PYY3-36) levels, the specific PYY anorectic isoform. In this study, we prospectively investigated appetite and gut hormone changes in response to LRYGBP and LSG in adiposity-matched non-diabetic patients. Anthropometric indices, leptin, fasted and nutrient-stimulated acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), PYY3-36 levels and appetite were determined pre-operatively and at 6 and 12 weeks post-operatively in obese, non-diabetic females, with ten undergoing LRYGBP and eight adiposity-matched females undergoing LSG. LRYGBP and LSG comparably reduced adiposity. LSG decreased fasting and post-prandial plasma acyl-ghrelin compared to pre-surgery and to LRYGBP. Nutrient-stimulated PYY3-36 and active GLP-1 concentrations increased post-operatively in both groups. However, LRYGBP induced greater, more sustained PYY3-36 and active GLP-1 increments compared to LSG. LRYGBP suppressed fasting hunger compared to LSG. A similar increase in post-prandial fullness was observed post-surgery following both procedures. LRYGBP and LSG produced comparable enhanced satiety and weight loss. However, LSG and LRYGBP differentially altered gut hormone profiles.

A link between FTO, ghrelin, and impaired brain food-cue responsivity.

Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N6-methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO "obesity-risk" rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans.

Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice.

OBJECTIVE: AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase ß (CaMKKß) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS: Mice lacking either Camkkß or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS: Deletion of Camkkß in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS: Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.

Differential acylated ghrelin, peptide YY3-36, appetite, and food intake responses to equivalent energy deficits created by exercise and food restriction.

CONTEXT: Acute energy deficits imposed by food restriction increase appetite and energy intake; however, these outcomes remain unchanged when energy deficits are imposed by exercise. OBJECTIVE: Our objective was to determine the potential role of acylated ghrelin and peptide YY(3-36) (PYY(3-36)) in mediating appetite and energy intake responses to identical energy deficits imposed by food restriction and exercise. DESIGN: Twelve healthy males completed three 9-h trials (exercise deficit, food deficit, and control) in a randomized counterbalanced design. Participants ran for 90 min (70% of VO(2) max) at the beginning of the exercise deficit trial and then rested for 7.5 h. Participants remained sedentary throughout the food deficit and control trials. Test meals were consumed by participants at 2 and 4.75 h in all trials. The amount provided in the food deficit trial was restricted so that an energy deficit (equivalent to that imposed by exercise) was induced relative to control. Participants were permitted access to a buffet meal at 8 h. RESULTS: The energy deficits imposed by food restriction (4820 ± 151 kJ) and exercise (4715 ± 113 kJ) were similar. Appetite and ad libitum energy intake responded in a compensatory fashion to food restriction yet were not influenced by exercise. Plasma acylated ghrelin concentrations increased, whereas PYY(3-36) decreased, in response to food restriction (two-way ANOVA, trial × time interaction, P < 0.001 for each). Exercise did not induce such compensatory responses. CONCLUSIONS: These findings suggest a mediating role of acylated ghrelin and PYY(3-36) in determining divergent feeding responses to energy deficits imposed by food restriction and exercise.

Metabolic state alters economic decision making under risk in humans.

BACKGROUND: Animals' attitudes to risk are profoundly influenced by metabolic state (hunger and baseline energy stores). Specifically, animals often express a preference for risky (more variable) food sources when below a metabolic reference point (hungry), and safe (less variable) food sources when sated. Circulating hormones report the status of energy reserves and acute nutrient intake to widespread targets in the central nervous system that regulate feeding behaviour, including brain regions strongly implicated in risk and reward based decision-making in humans. Despite this, physiological influences per se have not been considered previously to influence economic decisions in humans. We hypothesised that baseline metabolic reserves and alterations in metabolic state would systematically modulate decision-making and financial risk-taking in humans. METHODOLOGY/PRINCIPAL FINDINGS: We used a controlled feeding manipulation and assayed decision-making preferences across different metabolic states following a meal. To elicit risk-preference, we presented a sequence of 200 paired lotteries, subjects' task being to select their preferred option from each pair. We also measured prandial suppression of circulating acyl-ghrelin (a centrally-acting orexigenic hormone signalling acute nutrient intake), and circulating leptin levels (providing an assay of energy reserves). We show both immediate and delayed effects on risky decision-making following a meal, and that these changes correlate with an individual's baseline leptin and changes in acyl-ghrelin levels respectively. CONCLUSIONS/SIGNIFICANCE: We show that human risk preferences are exquisitely sensitive to current metabolic state, in a direction consistent with ecological models of feeding behaviour but not predicted by normative economic theory. These substantive effects of state changes on economic decisions perhaps reflect shared evolutionarily conserved neurobiological mechanisms. We suggest that this sensitivity in human risk-preference to current metabolic state has significant implications for both real-world economic transactions and for aberrant decision-making in eating disorders and obesity.

Subject standardization, acclimatization, and sample processing affect gut hormone levels and appetite in humans.

BACKGROUND & AIMS: Gut hormones represent attractive therapeutic targets for the treatment of obesity and type 2 diabetes. However, controversy surrounds the effects that adiposity, dietary manipulations, and bariatric surgery have on their circulating concentrations. We sought to determine whether these discrepancies are due to methodologic differences. METHODS: Ten normal-weight males participated in a 4-way crossover study investigating whether fasting appetite scores, plasma acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), and peptide YY3-36 (PYY3-36) levels are altered by study-induced stress, prior food consumption, and sample processing. RESULTS: Study visit order affected anxiety, plasma cortisol, and temporal profiles of appetite and plasma PYY3-36, with increased anxiety and cortisol concentrations on the first study day. Plasma cortisol area under the curve (AUC) correlated positively with plasma PYY3-36 AUC. Despite a 14-hour fast, baseline hunger, PYY3-36 concentrations, temporal appetite profiles, PYY3-36 AUC, and active GLP-1 were affected by the previous evening's meal. Sample processing studies revealed that sample acidification and esterase inhibition are required when measuring acyl-ghrelin and dipeptidyl-peptidase IV inhibitor addition for active GLP-1. However, plasma PYY3-36 concentrations were unaffected by addition of dipeptidyl-peptidase IV. CONCLUSIONS: Accurate assessment of appetite, feeding behavior, and gut hormone concentrations requires standardization of prior food consumption and subject acclimatization to the study protocol. Moreover, because of the labile nature of acyl-ghrelin and active GLP-1, specialized sample processing needs to be undertaken.