Quantitative 3D elemental microtomography of Cyclotella meneghiniana at 400-nm resolution

X-ray fluorescence tomography promises to map elemental distributions in unstained and unfixed biological specimens in three dimensions at high resolution and sensitivity, offering unparalleled insight in medical, biological, and environmental sciences. X-ray fluorescence tomography of biological specimens has been viewed as impractical—and perhaps even impossible for routine application—due to the large time required for scanning tomography and significant radiation dose delivered to the specimen during the imaging process. Here, we demonstrate submicron resolution X-ray fluorescence tomography of a whole unstained biological specimen, quantifying three-dimensional distributions of the elements Si, P, S, Cl, K, Ca, Mn, Fe, Cu, and Zn in the freshwater diatom Cyclotella meneghiniana with 400-nm resolution, improving the spatial resolution by over an order of magnitude. The resulting maps faithfully reproduce cellular structure revealing unexpected patterns that may elucidate the role of metals in diatom biology and of diatoms in global element cycles. With anticipated improvements in data acquisition and detector sensitivity, such measurements could become routine in the near future.     

Relation of circulating oxidized LDL to obesity and insulin resistance in children

Kelly AS, Jacobs DR Jr, Sinaiko AR, Moran A, Steffen LM, Steinberger J. Relation of circulating oxidized LDL to obesity and insulin resistance in children. Introduction: Circulating oxidized low‐density lipoprotein (LDL), a marker of oxidative stress, is associated with obesity, insulin resistance, metabolic syndrome, and cardiovascular disease in adults. However, little is known about its relation to insulin resistance and cardiovascular risk factors in children. The purpose of this study was to assess the relation of oxidative stress, measured by circulating oxidized LDL, with measures of adiposity and insulin resistance in children. Methods: Oxidized LDL, measures of body fatness (body mass index: BMI, percent body fat, waist circumference, percent trunk fat, abdominal visceral and subcutaneous fat), insulin resistance with euglycemic insulin clamp (Mlbm), blood pressure, and blood lipids were obtained in 78 children. Oxidized LDL was compared between normal weight children (BMI < 85th percentile) and overweight/obese children (BMI ≥ 85th percentile) and levels were evaluated for associations with body fatness and insulin resistance. Results: Oxidized LDL levels were significantly higher in overweight/obese vs. normal weight children (p < 0.0001). Oxidized LDL was significantly correlated with BMI, percent body fat, waist circumference, percent trunk fat, abdominal visceral fat, and abdominal subcutaneous fat (all p‐values <0.0001). Moreover, oxidized LDL was negatively correlated with Mlbm, even after adjustment for adiposity (p < 0.01). Conclusions: Oxidized LDL is significantly associated with adiposity and with insulin resistance, independent of body fatness, in children. Oxidative stress may be independently related to the development of insulin resistance early in life, especially in obese youth.     

The Roll of Toll-like Receptors in the Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis, recurrent fetal loss, and the presence of antiphospholipid antibodies (aPL). Recent data support the idea that the thrombotic activity in APS patients is attributed to enhanced cytokine release via activation of certain Toll-like receptors. To investigate these mechanisms more precisely, different experimental approaches were used to investigate this connection in detail. IgG fractions and/or monoclonal aPL, either generated from murine or human B cells were intensely used for stimulation experiments of monocytes, endothelial cells, or dendritic cells. All these stimuli induced an enhanced expression and secretion of cytokines, especially tumor necrosis factor (TNF)-α, caused by specific regulation or activation of Toll-like receptors. Using specific agonists or inhibitors could confirm the causal connection of these stimulatory effects. This review focuses on these recent developments, connecting the binding of aPL with the activity of Toll-like receptors, especially in monocytes, endothelial cells, and dendritic cells.     

Impaired cerebral autoregulation in primary biliary cirrhosis: implications for the pathogenesis of cognitive decline

Background: Cognitive impairment is recognised in the early stages of primary biliary cirrhosis (PBC). Aims: To determine the mechanisms that underlie the cognitive dysfunction that can occur in early‐stage PBC, with a particular focus on the role of autonomic dysfunction and altered cerebral autoregulation. Patients: Early‐stage PBC patients, and age‐ and sex‐matched controls. Interventions and main outcome measures: Brain magnetic resonance imaging to determine the relationship between structural brain abnormalities (T₂) and cerebral vasculature responsiveness assessed using the Valsalva manoeuvre. Dynamic assessment of cerebral vascular flow using transcranial Doppler was also performed in PBC subjects to derive the pulsatility index (a marker of cerebral resistance) and the autoregulatory slope index [ASI; ratio between the cerebral blood flow velocity and blood pressure (BP)]. Results: Cerebral resistance was increased (P=0.04), and cerebral autoregulation in response to the Valsalva was significantly impaired in the PBC group with markedly lower mean ASI values compared with the controls (7.8±7.0 vs ?8.5±8.4; P=0.002). All controls had normal cerebral autoregulation compared with only 20% of the PBC group. Indicators of sympathetic failure (BP change between Valsalva phases III–IV and low‐frequency heart rate variability) correlated with increasing globus pallidus (GP) T₂ values (P<0.05), beyond the effect of age. Conclusion: This study demonstrates the presence of increased cerebral vascular resistance and abnormal cerebral autoregulation in PBC patients, and identifies a potentially important association between the degree of abnormality in structural changes in the GP. These findings suggest that organic brain injury in PBC is directly related to autonomic dysfunction.     

The contribution of calcium/calmodulin-dependent protein-kinase II (CaMKII) to short-term plasticity at the neuromuscular junction

Calcium/calmodulin-dependent protein-kinase II (CaMKII) is a ubiquitous intracellular enzyme, which is implicated in learning and memory mechanisms in the central nervous system, however its contribution to peripheral cholinergic neurotransmission is not well characterized. This study evaluated the impact of CaMKII on the function of frog neuromuscular synapse using electrophysiological recordings. Application of the selective CaMKII inhibitor KN-93 (5 μM) did not significantly alter the parameters of evoked and spontaneous quantal acetylcholine release under low-frequency stimulation (0.03 Hz). KN-93, on the other hand, produced pronounced changes in short-term synaptic plasticity: particularly, KN-93 inhibits the second component of paired-pulse facilitation (interpulse intervals of 100 ms and longer) and strengthens the depression of synaptic transmission under high-frequency stimulation (50 Hz). These results imply that CaMKII plays an important role in presynaptic functions at the frog neuromuscular junction, and potentiates quantal acetylcholine release under high-frequency activity.     

Spontaneous coronary artery dissection in a young man - Case report

A 31 year old man with a 17-year-history of drug abuse (heroine and cannabis) was admitted with recurrent chest pain over a period of about three weeks. Chest discomfort severely worsened during the 5 hours before hospital admission. Electrocardiography revealed poor R-wave progression and non specific repolarization abnormalities. Echocardiography showed extensive left ventricular anterior and apical wall motion abnormalities and a ventricular thrombus located at the apex of the left ventricle was present. Subsequently, a diagnosis of acute coronary syndrome was made. Coronary angiography revealed spontaneous coronary artery dissection of the left anterior descending (LAD) artery with Thrombolysis In Myocardial Infarction (TIMI) flow 2 to 3. We managed the patient conservatively. The clinical course was uneventful and repeated angiography on day 4 demonstrated spontaneous healing of large parts of the dissection with TIMI 3 flow in the LAD.     

Chemical Biology, Molecular Mechanism and Clinical Perspective of ��-Secretase Modulators in Alzheimer��s Disease

Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer''s disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.     

Unique technique of surgery in an unusual variety of Scimitar syndrome: A Case Report

Scimitar syndrome is a rare congenital anomaly characterized by total or partial anomalous pulmonary venous drainage of the right lung to the inferior vena cava. We present a seven year old girl with a systolic murmur who was diagnosed as having a Scimitar syndrome with unusual drainage of the right pulmonary veins. The unique technique of surgery in this patient was appropriate to the unusual, previously not described anatomy.     

Diastolic Function Study with Conventional and Pulsed Tissue Doppler Echocardiography Imaging in Acromegalic Patients

Acromegaly is associated with myocardial hypertrophy and it can progress to diastolic and systolic dysfunction. Purpose: To evaluate diastolic function in acromegalic patients through conventional echocardiography (CD) and tissue Doppler imaging (TDI). Methods: Seventeen acromegalic patients were submitted to CD and TDI, and early (E) and atriogenic (A) transmitral flow were evaluated in mitral, septal, and tricuspid regions. Results: In comparison with controls the means of conventional (1.06), septal (1.01), and tricuspid (0.98) E/A ratio were significantly lower in acromegalic patients. E/A ratio <1.0 was demonstrated in 41% and 49% of acromegalics by DC and TDI, respectively, with no statistical difference among the two methods. An inverse linear correlation was shown between mitral E/A ratio and acromegalic age (r =−0.7). Conclusion: In this study, DC and TDI were equally effective in demonstrating diastolic dysfunction, a common finding in acromegalic patients.