Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical,Genetic, and Functional Insights into Novel Mutations

In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C‐terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.     

The increase in human plasma antioxidant capacity after red wine consumption is due to both plasma urate and wine polyphenols

By using red wine, dealcoholized red wine, polyphenols-stripped red wine, ethanol-water solution and water, the role of wine polyphenols and induction of plasma urate elevation on plasma antioxidant capacity was examined in humans (n=9 per beverage). Healthy males randomly consumed each beverage in a cross-over design. Plasma antioxidant capacity (measured by ferric reducing antioxidant power, FRAP), ethanol, catechin and urate concentrations were determined before and 30, 60, 90, 120 and 180 min after beverage intake. Dealcoholized red wine and polyphenols-stripped red wine induced similar increase in FRAP values which represented nearly half the effect of the original red wine. This indicates that consumption of red wine involves two separate mechanisms in elevation of plasma FRAP values and both wine phenols and plasma urate contribute to that effect.     

Doppler hemodynamic study in portal hypertension and hepatic encephalopathy

BACKGROUND/AIMS: The aim of our study was to evaluate and compare the differences in the parameters of portal hypertension in two groups of patients with liver cirrhosis, with and without hepatic encephalopathy (HE). METHODOLOGY: 30 patients with liver cirrhosis, 17 (56.7%) of them with HE, were investigated by clinical, neurological, laboratory, endoscopic methods and with color Doppler ultrasonography (CDU) at the Institute for Digestive Diseases, Clinical Center of Serbia, Beograde. RESULTS: Significant correlation was found between the diameters of the right liver lobe and the portal vein (p=0.01), and also between the diameters of the spleen and splenic vein (p=0.0002), in both groups of patients. Mean portal vein diameter significantly increases (p=0.01) in patients with HE (14.87 +/- 1.86mm), compared to those without HE (13.2 +/- 2.31mm), while mean splenic vein diameter was not significantly different in the two groups. In patients with ascites, CDU showed significantly lower (p=0.03) portal flow velocity (11.87 +/- 6.25cm/ sec), compared to those without ascites (14.33 +/- 4.41cm/sec). Splenic flow velocity was not significantly different (16.00 +/- 6.60cm/sec with ascites and 14.61 +/- 5.29cm/sec without ascites). In patients with HE, portal flow velocity was significantly lower (9.00 +/- 5.41cm/sec) compared to those without HE (14.0 +/- 7.03cm/sec) (p=0.04). Mean splenic flow velocity was significantly lower (p=0.03) in patients with HE (12.60 +/- 4.16cm/sec), compared to those without HE (17.77 +/- 5.91cm/sec). Portal flow velocity shows linear decrease, related to the increase of the liver damage (Child-Pugh score), while splenic velocity was not related to this parameter. CONCLUSIONS: Ultrasonographic parameters of portal hypertension show significant correlation between the diameters of liver/portal vein and spleen/splenic vein. Portal hemodynamic parameter (blood flow velocity) is significantly related to the stages of liver damage, presence of ascites and HE, while splenic hemodynamics is specific and not directly related to these parameters.     

High Dose Adenosine Stress Echocardiography for Noninvasive Detection of Coronary Artery Disease

Objectives. The aim of this study was to assess the tolerability and incremental diagnostic value of high adenosine doses in stress echocardiography testing in patients with coronary artery disease (CAD).

Background. In comparison with other pharmacologic stress echocardiography tests, standard dose adenosine stress has suboptimal sensitivity for detecting milder forms of CAD.

Methods. Adenosine stress echocardiography was performed in 58 patients using a starting dose of 100 μg/kg body weight per min over 3 min followed by 140 μg/kg per min over 4 min (standard dose). If no new wall motion abnormality appeared, the dose was increased to 200 μg/kg per min over 4 min (high dose). All patients underwent coronary angiography. Significant CAD was defined as ≥50% diameter stenosis in at least one major coronary artery. Thirty-three patients had one-vessel and seven had multivessel CAD. Coronary angiographic findings were normal in 18 patients.

Results. The high adenosine dose caused a slight but significant increase over baseline values in rate-pressure product. Limiting side effects occurred in two patients during the standard dose protocol and in one patient receiving the high dose regimen. The test was stopped in 30 patients after the standard adenosine dose regimen because of a provoked new wall motion abnormality. The sensitivity of adenosine echocardiography with the standard dose was 75% (95% confidence interval [CI] 63% to 87%). After completion of the standard dose protocol, 28 patients continued testing with the high dose adenosine protocol. The overall sensitivity of adenosine echocardiography, calculated as cumulative, increased to 92% (95% CI 84% to 100%) with the high dose (p < 0.05). The specificity of adenosine testing was 100% and 88%, respectively, with the standard and high dose regimen (p = 0.617).

Conclusions. We believe that use of a higher than usual adenosine dose protocol for stress testing may improve the diagnostic value of adenosine echocardiography, mainly by increasing sensitivity in patients with single-vessel disease without deterioration of the safety profile and with only a mild reduction in specificity.

(J Am Coll Cardiol 1996;28:1689–95)>     

Dipyridamole-Atropine-Induced Myocardial Infarction in a Patient with Patent Epicardial Coronary Arteries

BACKGROUND: The diagnostic accuracy of the physical and pharmacological stress echocardiography tests is higher than routine exercise electrocardiography. They have an acceptable safety profile and have been rarely associated with severe adverse effects. CASE REPORT: We present a case of acute anterior myocardial reinfarction immediately after exercise and pharmacological (dipyridamole-atropine) stress echocardiography testing 1 month after successful stent implantation in LAD. Our patient was a 43-year-old man with a history of heavy smoking and hypertension. Remarkably, the stress echocardiogram was non-diagnostic few hours before the infarction occurred. Angiography performed 4 months after the reinfarction revealed neither a culprit lesion nor stent thrombosis. CONCLUSION: Aggressive "last generation" pharmacological stress testing may provide optimal diagnostic accuracy, but as in our case, complications may occur, even after negative stress testing. To our knowledge, this is the first reported case of an acute myocardial infarction as a severe complication of stress testing, which developed in a patient after stent implantation.     

Tibial nerve decompression: Reliable exposure using shorter incisions

Background: Patients and surgeons recognize the value of procedures that minimize scarring and tissue dissection, but technical standards do not exist with regards to incision lengths needed for tibial nerve decompression. This article introduces reproducible techniques that reliably provide exposure for release of known anatomical compression points of the tibial nerve, while minimizing the length of required skin incisions. Methods: The senior author's approach to decompression of the tibial nerve at the soleus arch and the tarsal tunnel is presented. Typical incision lengths and surgical exposure are demonstrated photographically. The safety of using this technique is examined by review of the medical records of all patients undergoing this procedure from 2003 to 2011, looking for technical complications such as unintentional damage to nerves or adjacent structures. Results: 224 consecutive patients undergoing 252 total procedures underwent release of known anatomical compression points of the tibial nerve at either the tarsal tunnel, inner ankle, or the soleus arch. Typical incision lengths used for these procedures were 5 cm for the proximal calf and 4.5 cm for the tarsal tunnel. Review of medical records revealed no incidences of unintentional injury to nerves or adjacent important structures. Functional and neurological outcomes were not assessed. Conclusions: Tibial nerve decompression by release of known anatomical compression points can be accomplished safely and effectively via minimized skin incisions using the presented techniques. With appropriate knowledge of anatomy, this can be performed without additional risk of injury to the patient, making classically‐described longer incisions unnecessarily morbid. © 2012 Wiley Periodicals, Inc. Microsurgery, 2012.     

Changes in cardiac innervation during maturation in long-term diabetes

Diabetic autonomic neuropathy being a common complication of diabetes mellitus (DM) is related to an increased risk of cardiovascular mortality. However, mechanisms underlying changes of innervation density in affected hearts remain insufficiently understood. Hence, the aim of this study was to describe quantitative changes of intra-myocardial nerve terminals in hearts of diabetic rats of various ages.