Recurrent nocturnal hypoglycaemia as a cause of morning fatigue in treated Addison’s disease – Favourable response to dietary management: A case report

Background: Addison’s disease, or primary adrenal insufficiency, is often associated with reduced well-being and fatigue despite use of currently recommended adrenal hormone replacement. Hypoglycaemia is a known manifestation of glucocorticoid deficiency, but is generally considered rare in adults and not relevant to troubling ongoing symptoms in patients with Addison’s disease. Case presentation: A 43 year old woman with a three year history of Addison’s disease complained of severe morning fatigue and headaches, despite standard glucocorticoid replacement therapy in the form of thrice daily hydrocortisone and mineralocorticoid replacement with fludrocortisone. Alternative glucocorticoid replacement regimens and the addition of dehydroepiandrosterone replacement therapy had no effect. Nocturnal hypoglycaemia was suspected and a 4-day continuous glucose monitor system (CGMS) revealed hypoglycaemia (interstitial glucose \u3c 2.2mmol/L) between 0200–0400 h on 3 of 4 days. The patient was counselled to take an evening snack designed to ensure slow absorption of ingested carbohydrates. Nocturnal hypoglycaemia was then absent on follow up CGMS assessment. The patient noted a marked symptomatic improvement in morning symptoms, but with persistent fatigue during the day. Conclusion: Currently, the best strategy for control of non-specific symptoms in treated Addison’s disease is unknown, but it may be that investigation for hypoglycaemia and treatment, where necessary, could assist some sufferers to achieve improved wellbeing. A systematic study of this phenomenon in Addison’s disease is required

The effect of cognitive behavioral stress management on perceived stress, biological stress markers and weight loss/regain, from a diet-induced weight loss program: A randomized controlled trial

Obesity and psychosocial stress are inter-related chronic conditions which lead to increased cardiovascular morbidity and mortality. The aim of this parallel randomized controlled trial was to determine whether the addition of a structured cognitive behavioral stress management (CBSM) on to a commercial online weight loss program, resulted in greater weight loss than the standard weight loss program in isolation. Eligible participants were adults between the ages 18–65, BMI 30–45 kg/m2, with no major systemic or psychiatric conditions. Seventy-four participants were assigned according to simple randomization using computer generated random numbers to either a 3-month online Weight Watchers® program (n = 36), or Weight Watchers® plus 10 weekly sessions of CBSM (n = 38). The primary outcome was weight at 3 months compared to baseline. Secondary outcomes were weight at 12 months and subjective/objective stress system measures and metabolic markers at 3 and 12 months. The study was powered at 90% to detect a 5 kg difference in weight between the two groups at 3 months. Independent sample t-tests were used to analyze the difference in weight (in kg) between the groups and paired sample t-tests were used to analyze the difference within group at different time intervals. At follow-up, there was no significant difference in weight loss between the groups (1.8 kg, 2.1 kg). However, CBSM was effective in reducing psychological measures of stress (p \u3c 0.05) and salivary cortisol (waking, 20-min post-waking) at 3-months; with the effect on stress persisting at 12-months within the CBSM group. The reduction in PSS at 3 months was significantly greater in the CBSM group (3.84, p = 0.028) compared to WW only group at 3 months. Addition of CBSM to a standard weight loss intervention did not improve the weight loss over the standard approach on its own, but the CBSM intervention improved psychological stress parameters and cortisol secretion in participants living with obesity

Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix

Desmoplasia describes the deposition of extensive extracellular matrix and defines primary pancreatic ductal adenocarcinoma (PDA). The acellular component of this stroma has been implicated in PDA pathogenesis and is being targeted therapeutically in clinical trials. By analyzing the stromal content of PDA samples from numerous annotated PDA data sets and correlating stromal content with both anatomic site and clinical outcome, we found PDA metastases in the liver, the primary cause of mortality to have less stroma, have higher tumor cellularity than primary tumors. Experimentally manipulating stromal matrix with an anti-lysyl oxidase like-2 (anti-LOXL2) antibody in syngeneic orthotopic PDA mouse models significantly decreased matrix content, led to lower tissue stiffness, lower contrast retention on computed tomography, and accelerated tumor growth, resulting in diminished overall survival. These studies suggest an important protective role of stroma in PDA and urge caution in clinically deploying stromal depletion strategies

The role of cyclic nucleotides in guinea-pig bladder contractility

1. The effects of phosphodiesterase (PDE) inhibition and forskolin pretreatment on the contractile responses of guinea-pig urinary bladder strips to electrical field stimulation, carbachol, ATP and KCl were studied. 2. Inhibition of cyclic AMP-specific PDE4 isozymes by rolipram significantly reduced the contractile response of bladder strips to field stimulation. Rolipram also suppressed the contractile response to low concentrations of carbachol, but potentiated the response to high concentrations. The contractile response to ATP was significantly reduced by rolipram treatment, but that to KCl was unaltered. 3. Inhibition of cyclic GMP-specific PDE5 isozymes by zaprinast had no effects on the contractile response of bladder strips to field stimulation, ATP or KCl. Zaprinast suppressed the contractile responses to 1 μM carbachol and potentiated the response to high concentrations. 4. Contractile responses to field stimulation and to carbachol after pretreatment with the adenylyl cyclase activator, forskolin, were qualitatively similar to those caused by rolipram treatment. β-Adrenoceptor blockade with propranolol partially reversed the inhibitory effects of rolipram on the response to field stimulation. 5. Rolipram significantly reduced the contractile response of bladder strips from sensitized guinea-pigs to ovalbumin challenge, but zaprinast was ineffective. PDE inhibition had similar effects on the responsiveness of control and of sensitized guinea-pig bladder strips to field stimulation, carbachol, ATP and KCl. 6. The data suggest that the contractile response of guinea-pig bladder strips can be modified by increases in cyclic AMP levels

CGH2466, a combined adenosine receptor antagonist, p38 mitogen-activated protein kinase and phosphodiesterase type 4 inhibitor with potent in vitro and in vivo anti-inflammatory activities

1. Theophylline, a phosphodiesterase inhibitor and adenosine receptor antagonist, is used in asthma and chronic obstructive pulmonary disease (COPD) treatment. However, the relatively low effectiveness of theophylline have recently led to reduced usage. The goal of the present study was to identify a theophylline-like compound with improved effectiveness. 2. We discovered CGH2466, which not only antagonised the adenosine A(1), A(2b) and A(3) receptors with IC(50) values of 19±4, 21±3 and 80±14 nM, respectively, but also inhibited the p38 mitogen-activated protein (MAP) kinases α and β and the phosphodiesterase 4D (PDE4D) isoenzyme with IC(50) values of 187±18, 400±38 and 22±5 nM, respectively. 3. Despite similar potencies on individual targets, CGH2466 inhibited the production of cytokines and oxygen radicals by human peripheral blood leucocytes in vitro, more potently (IC(50) values between 30 and 50 nM) than the standard p38 MAP kinase inhibitor SB203580 (30 nM to >1 μM), the PDE4 inhibitor cilomilast (120–400 nM) and the broad spectrum adenosine receptor antagonist CGS15943 (>10 μM). 4. When given either orally or locally into the lungs, CGH2466 (3 to 10 mg kg(−1)) inhibited the ovalbumin- or lipopolysaccharide-induced airway inflammation in mice more potently than the single receptor antagonists or enzyme inhibitors used alone. 5. In conclusion, CGH2466 through its combined activities at multiple targets exerted a powerful anti-inflammatory effect and therefore may have beneficial therapeutic value in diseases such as asthma and COPD