Mark A. Cohen

Gut hormone PYY3-36 physiologically inhibits food intake

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.

Chronic intraparaventricular nuclear administration of orexin A in male rats does not alter thyroid axis or uncoupling protein-1 in brown adipose tissue.

Orexin A, synthesised in the posterolateral hypothalamus, has widespread distribution including the paraventricular nucleus (PVN), which is rich in thyrotropin-releasing hormone (TRH) neurones. Nerve fibres in the PVN synapse on neurones that send polysynaptic projections to brown adipose tissue (BAT), which is important in thermogenesis. A number of observations suggests orexin A may be involved in regulation of metabolism and thermogenesis. We investigated the effect of orexin A injected intracerebroventricularly (ICV) on thyroid-stimulating hormone (TSH) and thyroid hormones in male rats. We then examined the effect of chronic iPVN injections of orexin A on plasma TSH and uncoupling protein-1 (UCP-1) protein in BAT. Orexin A (3 nmol) administered ICV significantly suppressed plasma TSH at 10 and 90 min. Orexin A (0.3 nmol) administered into the PVN twice daily for 3 days significantly increased day-time 2-h food intake, but did not significantly alter nocturnal food intake. Though chronic iPVN orexin A altered diurnal food intake, there was no effect on 24-h food intake or body weight. Furthermore, orexin A administered chronically into the PVN did not alter UCP-1 level in BAT, or plasma hormones relative to saline injected animals. Chronic iPVN orexin A does not appear to influence thermogenesis through activation of UCP-1 or the thyroid axis.

Physiology: Does gut hormone PYY3|[ndash]|36 decrease food intake in rodents? (reply)

The results of Tschöp et al. on the lack of effect of peripheral administration of PYY3–36 on food intake in rodents are at odds with both the published literature (our Table 1) and with earlier data generated by the Tschöp laboratory.

Real-life experience of tolvaptan use in the treatment of severe hyponatraemia due to syndrome of inappropriate antidiuretic hormone secretion.

European guidelines do not recommend tolvaptan for treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH), principally owing to concerns about risk of overly rapid correction of hyponatraemia. This study evaluated the real‐life effectiveness and safety of tolvaptan.

Predicting the conformation of proteins from sequences. Progress and future progress

A new paradigm for predicting the secondary and tertiary structure of functional proteins from sequence data has emerged from detailed models of how natural selection, conservation, and neutral drift, the three fundamental factors in molecular evolution, leave their mark upon protein sequences. Structural information is extracted from a set of aligned homologous sequences via an analysis of patterns of conservation and variation between proteins with quantitatively defined evolutionary relationships. Tertiary structural information is obtained prior to the assignment of secondary structure, where it plays an important role. Throughout, structural predictions are made with the active involvement of a biochemist whose expertise and insight is critical both for making the prediction and in analyzing its successful and unsuccessful parts. Secondary structure predictions are evaluated based on their ability to sustain an effort to model tertiary structure. Several predictions made using the new paradigm can now be compared with those made under the classical paradigm, including a neural network. The results obtained from the new paradigm are clearly superior to those obtained with the classical paradigm, at least within the protein families that were examined.

A case of pituitary apoplexy masquerading as hyperemesis gravidarum

Case report A 31-year-old woman was admitted to hospital at 10 weeks ’ gestation in her fi rst pregnancy, with severe vomiting, a 3-week history of severe headache and ketonuria. Prior to the pregnancy, she had regular cycles and conceived spontaneously. Her past medical history was unremarkable. A diagnosis of hyperemesis gravidarum was made. Symptoms resolved aft er rehydration and anti-emetics. Booking tests and ultrasound were normal. At 16 weeks ’ gestation, she complained of decreased vision in her left eye. An optician noted left -sided ptosis. By 18 weeks ’ gestation, she developed a dull left -sided headache and diplopia. On review by a neurologist at 23 weeks, her symptoms had resolved and there was no obvious neurological defi cit (visual acuity was 6/6 in her right eye and 6/5 in her left ). An MRI scan revealed a cystic lesion within the pituitary fossa, representing haemorrhage into a preexisting solid or cystic lesion. Th e lesion was extending into the left cavernous sinus with evidence of compression of the optic chiasma. Endocrine assessment found a serum prolactin of 5,120 mU/l; 9 a.m. cortisol of 748 nmol/l; low-normal free thyroxine of 10.7 (9 – 19) pmol/l and a thyroid-stimulating hormone of 2.7 mU/l (0.4 – 4.1). Th yroxine replacement (25 μ g) was started for presumed secondary hypothyroidism. She experienced recurrence of frontal headache at 34 weeks ’ gestation but examination was unremarkable. Th e neurosurgeon recommended planned delivery by caesarean section. Th is was performed at 39 weeks ’ gestation and she remained well postpartum.

Usefulness of Carotid Plaques as Predictors of Obstructive Coronary Artery Disease and Cardiovascular Events in Asymptomatic Individuals With Diabetes Mellitus

Carotid intima-media thickness (CIMT) measurement and carotid plaque detection by B-mode ultrasound are frequently used as surrogates to predict coronary artery disease (CAD). However, their systematic use in routine clinical management of asymptomatic patients with diabetes mellitus (DM) has not been studied. The aim of the study was to identify carotid parameters that predict cardiovascular events in patients with asymptomatic type 2 DM by evaluating the relation between carotid disease and CAD. This multicenter, observational, prospective study included 259 asymptomatic patients with type 2 DM followed-up for 34 months after measurement of CIMT and carotid plaque with carotid ultrasound, and CAD assessment with computed tomography coronary angiography. Statistically significant differences between patients with and without carotid plaque were found for coronary plaque >50% stenosis (59 vs 36, p = 0.02). Greater maximal CIMT was associated with an increased risk of coronary plaque >50% (odds ratio 1.21 [1.02, 1.44], p = 0.03) and >70% stenosis (odds ratio 1.23 [1.01, 1.50], p = 0.04) after adjusting for traditional risk factors. At 34-month follow-up, the occurrence of total major adverse cardiovascular event was estimated to be 7.1% (mean age 68 years, 6% male and 1.1% female) in the whole study population. The subgroup of patients with carotid plaque showed increased incidence of major adverse cardiovascular event compared with patients with no carotid plaque (p = 0.005). In conclusion, carotid plaque was a strong predictor of future cardiovascular events and may be a prognostic marker in asymptomatic patients with type 2 DM. Carotid plaque and maximal intima-media thickness were independently associated with obstructive CAD.

Relationship between carotid atherosclerosis and coronary artery calcification in asymptomatic diabetic patients: A prospective multicenter study.

The value of screening sub‐clinical atherosclerosis in asymptomatic patients with type 2 diabetes mellitus (T2DM) remains controversial.

A case of profound hypercalcaemia and acute kidney injury

A 58 year old white man presented with a three month history of malaise, poor appetite, aching joints, and constipation. He also reported long standing dyspepsia and often self medicated with antacid tablets bought over the counter. In addition, he described having lower urinary tract symptoms of hesitancy and urgency. His medical history showed that he had been diagnosed with hypertension some years previously and was receiving treatment with a thiazide diuretic (bendroflumethiazide). He had a 20 pack year smoking history and was unemployed. On examination, his pulse was 100 beats/min, blood pressure was 121/75 mm Hg, and he had a low grade fever. He had dry mucous membranes and was mildly disoriented. Cardiovascular examination was normal. Some mild epigastric tenderness was elicited on deep palpation of the abdomen. Neurological examination was normal. The box shows his initial blood test results. Chest radiography was unremarkable. Dipstick urinalysis showed blood +3 and protein +2. Venous blood testing showed pH 7.45, lactate 1.4 mmol/L (1 mmol/L=9.01 mg/dL), and bicarbonate 23 mmol/L. A renal tract ultrasound scan showed preserved renal size and no evidence of obstruction. #### Initial blood test results (reference values in parenthesis)

2 Reading the Palimpsest: Contemporary Biochemical Data and the RNA World

The chemical behavior of contemporary living systems contains vestiges of the history of living chemistry on planet Earth. To read this “palimpsest” is a challenge of the first order (Benner et al. 1989). Some of the historical record has been written over by the demands of natural selection that have forced the evolution of new chemical structures to meet new biological challenges. Some has been lost in the noise arising from random events, the “neutral drift” that characterizes the structural divergence of biological molecules following the divergence of their host organisms (King and Jukes 1969; Kimura 1982). Some has undoubtedly been confused by lateral transfer of genetic information between phylogenetically distant organisms (Doolittle et al. 1990) and by “sequence convergence,” the independent emergence of polypeptide sequences that offer unique chemical solutions to particular biological problems. Three advances of the past decade have greatly improved our ability to deconvolute the information about earlier life forms written in the biological chemistry of contemporary organisms. First, substantial progress has been made toward an integration of structural theory from chemistry and evolutionary theory from biology (Benner and Ellington 1990b). The integrated theory allows us to proceed past the classic questions in biological chemistry (what happens at a chemical level in a living system) to ask why it happens. A number of questions in biological chemistry have been addressed within the context of the integrated theory, and models are now available to understand the evolutionary status of many molecular aspects of living systems. Most of...