Endocrine problems in pregnancy

This paper aims to describe the pathophysiology and management of the main endocrine complications of pregnancy. For each endocrine dysfunction, the issues with the fetus, the mother, obstetric complications, and the long term prognosis for the disease itself need to be considered. Key management issues are highlighted with each condition. Thyroid dysfunction and goitre are common while management is relatively straightforward. Adrenal, pituitary, and parathyroid diseases present less commonly in pregnancy. Early recognition of endocrine disease in pregnancy and appropriate management has the potential to improve outcome for the mother and fetus in the short and long term.     

Brain attack: needing resuscitation

The brain is extremely susceptible to focal ischaemia. Following vascular occlusion, a core of severely damaged brain tissue develops, surrounded by an ischaemic penumbra. This potentially-salvageable penumbra may be estimated by advanced neuroimaging techniques, particularly by diffusion-perfusion mismatch. Clinical trials have demonstrated the efficacy of intravenous thrombolysis within three hours of onset of ischaemic stroke in reducing short-term disability. Recanalisation is enhanced by intra-arterial thrombolysis, sonothrombolysis and clot-retrieval devices. Occasionally, reperfusion injury may lead to clinical deterioration. The search continues for effective neuroprotectants. Brain perfusion needs to be maintained through blood and intracranial pressure management. Hemicraniectomy for 'malignant' cerebral oedema reduces death and disability. Elevated glucose should be controlled and hypoxia alleviated. Public education of symptoms and the need for immediate presentation to a medical facility is needed. Stroke unit care reduces death and disability with little increase in cost. Current evidence supports urgent efforts to resuscitate the brain after stroke.     

Acute asthma in children: Relationships among CD14 and CC16 genotypes, plasma levels, and severity

RATIONALE: The majority of previous studies investigating asthma genetics have focused on cohorts with stable disease and have not defined mechanisms important during acute asthma. CD14 and CC16 each play a key role in biologically important inflammatory pathways and the gene of each has a functional promoter-region polymorphism. OBJECTIVES: This study was designed to determine the influence of these polymorphisms on plasma levels of their products and clinical disease during acute asthma. We hypothesized that genotype-related differences in CD14 and CC16 production would be more marked during acute asthma and related to disease severity. METHODS: We studied 148 children on presentation with acute asthma and again in convalescence. CD14 C-159T and CC16 A38G genotypes were determined, and plasma levels of soluble CD14 (sCD14) and CC16 were measured at both times. MEASUREMENTS AND MAIN RESULTS: During acute asthma, plasma sCD14 levels were higher for the whole group (p = 0.003), but increases were only in subjects with CD14 -159TT (p = 0.003) and -159CT (p = 0.004), and not in those with -159CC. Plasma CC16 levels were also elevated acutely for the whole group (p = 0.013), but only in those with CC16 38GG (p = 0.043) and 38AG (p = 0.014), and not in those with CC16 38AA. Subjects with CD14 -159CC and CC16 38AA were more likely to have moderate or severe acute asthma. CONCLUSIONS: Plasma levels of sCD14 and CC16 were higher during acute asthma in the subjects. Those with CD14 -159CC and CC16 38AA had no change in sCD14 and CC16 levels and more severe asthma.     

Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice

BACKGROUND/AIMS: The biological effects of ischaemic preconditioning include NF-kappaB activation, increased TNF synthesis, stimulation of cell cycle entry and hepatoprotection against ischaemia-reperfusion (IR) injury. Low dose TNF initiates the priming phase of liver regeneration via NF-kappaB and IL-6. To determine whether (1) IL-6 is released during preconditioning and confers protection against hepatic IR injury, and (2) IL-6 could mediate the biological effects of preconditioning. METHODS: Wildtype (wt) and TNF-/- C57BL6 mice were subjected to 90 min partial hepatic ischaemia and 2-44 h reperfusion with or without prior 10 min ischaemic preconditioning. To restitute liver injury, TNF-/- mice were administered murine TNF 5 microg/kg iv 1 min prior to IR. Murine recombinant IL-6 (500 ng/kg iv) was administered 30 min prior to IR, either to wt mice or to TNF-/--repleted mice; in the latter case, 1 min before preconditioning. RESULTS: In wt mice, IL-6 attenuated hepatic IR injury and stimulated cell cycle entry. IR injury in TNF-repleted TNF-/- mice was not ameliorated by preconditioning. However, prior IL-6 administration conferred hepatoprotection (IL-6/preconditioned: 349+/-169 U/L vs vehicle/preconditioned: 1250+/-608 U/L, P<0.01). CONCLUSIONS: IL-6 is one likely mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning.     

Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-resistant depression

This study presents the case of a 35-year-old breastfeeding mother who delivered her fourth child 5 months previously and was prescribed 100 mg amisulpride twice daily and 250 mg desvenlafaxine in the morning for treatment-resistant depression. Arriving at this regimen took approximately 2 months postbirth. Because she was keen to continue breastfeeding her infant, and published data on the use of amisulpride and desvenlafaxine were very limited, the clinical team sought assistance from the therapeutic drug monitoring laboratory to quantify infant dose-exposure to guide consideration of continuing breastfeeding. A sampling schedule for milk and plasma from mother and plasma from her infant was agreed and drug concentrations were measured by high-performance liquid chromatography. Absolute (theoretic) infant dose (μg/kg/d) was calculated as the product of the average concentration in milk and an assumed milk intake of 0.15 L/kg/day (294 mg/kg/day for desvenlafaxine and 183 mg/kg/day for amisulpride), and relative infant dose was estimated as absolute infant dose expressed as a percentage of the maternal dose in μg/kg/day (7.8% for desvenlafaxine and 6.1% for amisulpride). Consistent with the infant being partially breastfed, the ratio of drug in the infant's plasma to that in mother's plasma was lower at 1.7% for desvenlafaxine and 3.9% for amisulpride. A pediatric assessment of the infant found achievement of expected developmental progress for age and no detectable drug-related adverse effects. Assessing the safety of breastfeeding was difficult because it involved simultaneous use of two drugs for which there was limited previous experience. However, after discussion of the infant dose-exposure data and lack of adverse effects, the mother elected to continue partial breastfeeding for the next few months. The clinical team plans a reassessment of the infant's progress in 3 months.     

Identification and Management of Patients at Elevated Cardiometabolic Risk in Canadian Primary Care: How Well Are We Doing?

Background

We evaluated the risk assessment and management patterns employed by primary care physicians in patients at elevated cardiometabolic risk.

Methods

Between April 2011 and March 2012, multiple physicians from 9 Primary Care Teams (PCTs) and 88 physicians from traditional nonteam (Solo) practices completed a practice assessment on the management of 2461 patients > 40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least 1 of the following: dyslipidemia, type 2 diabetes mellitus (T2DM), or hypertension.

Results

Individuals with dyslipidemia, T2DM, or hypertension tended to have a body mass index ≥ 25 kg/m². Waist circumference measurements, obtained for only 392/829 (47.0%) Solo patients, revealed that 88.9% of these individuals were abdominally obese and that at least 52.2% of Solo patients had metabolic syndrome. Cardiovascular risk, determined by the physicians for 83.5% of all patients without T2DM and typically performed using traditional risk engines, was often miscalculated (43.2% PCTs, 58.8% Solo; P = 0.0007). Healthy behavioural modifications were infrequently recommended (< 50%). Pharmacotherapy was widely used (> 70%) but treatment targets were infrequently met. The composite outcome of guideline-recommended low-density lipoprotein cholesterol, glycemic, and blood pressure targets was met by 9.0% and 8.1% of patients managed by PCT and Solo physicians respectively.

Conclusions

Obesity and cardiovascular risk were underassessed and the latter often underestimated. Patients were infrequently counselled on the benefits of healthy behavioural changes. A paradigm change in assessing and managing obesity and cardiovascular risk via aggressive lifestyle interventions is warranted in individuals at elevated cardiometabolic risk.     

Left Atrial Appendage Occlusion Study II (LAAOS II)

Background

Occlusion of the left atrial appendage (LAA) is a potential alternative to anticoagulation for patients with atrial fibrillation (AF); however, evidence of its safety and efficacy is lacking. The Left Atrial Appendage Occlusion Study II (LAAOS II) explored the feasibility of a definitive trial of LAA occlusion for stroke prevention in AF.

Methods

A cross-sectional study of 1889 consecutive patients undergoing cardiac surgery was performed to determine the prevalence of AF and risk factors for stroke. We also randomized 51 patients with AF and increased stroke risk to LAA occlusion (n = 26) or no occlusion and oral anticoagulation (n = 25) to assess the rate of recruitment and the safety of LAA amputation.

Results

In the cross-sectional study, 204 patients (10.8%) had AF and 98 (5.2%) met trial eligibility. Fifty-one patients were recruited into the trial at a rate of 1.6 patients per centre per month. No patient with occlusion had significant bleeding at the LAA site. At 1 year, 4 patients (15.4%) in the occlusion arm and 5 patients (20.0%) in the no-occlusion arm experienced death, myocardial infarction (MI), stroke, noncerebral systemic emboli, or major bleeding (relative risk [RR], 0.71; 95% confidence interval [CI], 0.19-2.66; P = 0.61). The predominant component of the composite was stroke, with 1 in the occlusion arm and 3 in the no-occlusion arm.

Conclusions

LAA occlusion can be safely performed at the time of cardiac surgery. A large trial to evaluate the clinical efficacy of LAA occlusion in patients undergoing cardiac surgery is possible in motivated centres with some modifications to the design of LAAOS II.     

Limited P-glycoprotein mediated efflux for anti-epileptic drugs

A variety of anti-epileptic drugs (AEDs) were tested for their ability to be transported by P-glycoprotein (P-gp) through Caco-2 monolayers using bi-directional (apical (Ap) to basolateral (Bas), and Bas to Ap) studies. Transport rates were equivalent in both directions for vigabatrin, gabapentin, phenobarbitone, lamotrigine and carbamazepine, being 0.7 × 10^{? 6}, 0.1 × 10^{? 6}, 34 × 10^{? 6}, 36 × 10^{? 6} and 55 × 10^{? 6} cm/s, respectively. Phenytoin displayed a 20% increase in Ap to Bas transport, while topiramate and ethosuximide each had greater transport in the uptake direction, with both drugs showing no efflux. None of the transport rates for these drugs were affected by P-gp inhibitors. However, the efflux rate for acetazolamide was 3-fold higher than its uptake and this was significantly reduced by P-gp inhibitors. Thus, only one anti-epileptic, acetazolamide, was shown to be weak P-gp substrate, suggesting that P-gp efflux may not be a factor in relation to the development of resistance of epilepsy therapy.     

Synthesis of metal(II) [M = Cu, Mn, Zn] Schiff base complexes and their Pro-apoptotic activity in liver tumor cells via caspase activation

Hepatocellular carcinoma is the fifth most common cancer responsible for more than 600,000 deaths per year. It is a typical vascular tumor which at earlier stages does not exhibit remarkable development of tumor; however, at advance stages, it is richly supplied by blood vessels and damages hepatocyte, the main functional cell types in the liver. Currently, surgery and chemotherapy are the main treatment strategies. However, the chemotherapeutic agents are usually unable to discriminate between normal and cancerous cells, and hence adverse effects of drug toxicities have become the major concerns in chemotherapy. Thus, inducing caspase dependent cytotoxicity in cancer cells via apoptosis has become one of the interesting and effective strategies for fighting this disease. The current study is an effort to further explore this area of research. Mn(II), Cu(II), and Zn(II) Schiff base complexes were prepared by condensation of 2-hydroxy-1-naphthaldehyde with either 4-nitrobenzene-1,2-diamine or 4-methylbenzene-1,2-diamine and characterized by Spectroscopic (FT-IR, UV–Vis, NMR, and MS) and microanalysis. The ligands, in comparison to their metal complexes, were evaluated for their anticancer and proapoptotic properties in human hepatocarcinoma (HepG2) cells. Results showed that the complexes are more potent proapoptotic agents than the parent ligands. All the tested compounds showed dose-dependent antiproliferative activity comparable with 5-fluorouracil (IC₅₀ = 4.6 μg/mL). All the synthesized Schiff base ligands and respective metal complexes showed potential anticancer activity. Out of them, some compounds showed IC₅₀ value as low as 1.24–3.56 μg/mL. Compounds 3 and 7 inhibited HepG2 cell proliferation by inducing apoptosis via activation of caspase cascade.