Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia – P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val¹⁵⁸Met (rs4680) and PRODH Gln¹⁹Pro (rs2008720) and Arg¹⁸⁵Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.     

Iron dysregulation in Alzheimer's disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents

Considering the multi-etiological character of Alzheimer's disease (AD), the current pharmacological approaches using drugs oriented towards a single molecular target possess limited ability to modify the course of the disease and thus, offer a partial benefit to the patient. In line with this concept, novel strategies include the use of a cocktail of several drugs and/or the development of a single molecule, possessing two or more active neuroprotective-neurorescue moieties that simultaneously manipulate multiple targets involved in AD pathology. A consistent observation in AD is a dysregulation of metal ions (Fe²⁺, Cu²⁺ and Zn²⁺) homeostasis and consequential induction of oxidative stress, associated with beta-amyloid aggregation and neurite plaque formation. In particular, iron has been demonstrated to modulate the Alzheimer's amyloid precursor holo-protein expression by a pathway similar to that of ferritin L-and H-mRNA translation through iron-responsive elements in their 5′UTRs. This review will discuss two separate scenarios concerning multiple therapy targets in AD, sharing in common the implementation of iron chelation activity: (i) novel multimodal brain-permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities; (ii) natural plant polyphenols (flavonoids), such as green tea epigallocatechin gallate (EGCG) and curcumin, reported to have access to the brain and to possess multifunctional activities, such as metal chelation-radical scavenging, anti-inflammation and neuroprotection.     

How we started performing endovenous thermal ablation procedures: a personal history

This story is a personal journey of two Dutch dermatologists pioneering in the field of endovenous laser ablation of varicose veins, illustrating how innovations find their way in medicine and, in particular, in surgical specialties. After the introduction of these thermal ablative procedures in 2001, we have fully embraced these minimally invasive techniques, and in the process, we have increased our understanding on its mechanism of action and confirmed the clinical relevance of treating varicose veins with endovenous laser ablation. In 2013, thermal ablation is considered a standard of care by physicians as well as patients with varicose veins.     

Optical-thermal mathematical model for endovenous laser ablation of varicose veins

Endovenous laser ablation (EVLA) is successfully used to treat varicose veins. However, the exact working mechanism is still not fully identified and the clinical procedure is not yet standardized. Mathematical modeling of EVLA could strongly improve our understanding of the influence of the various EVLA processes. The aim of this study is to combine Mordon's optical-thermal model with the presence of a strongly absorbing carbonized blood layer on the fiber tip. The model anatomy includes a cylindrically symmetric blood vessel surrounded by an infinite homogenous perivenous tissue. The optical fiber is located in the center of the vessel and is withdrawn with a pullback velocity. The fiber tip includes a small layer of strongly absorbing material, representing the layer of carbonized blood, which absorbs 45 % of the emitted laser power. Heat transfer due to boiling bubbles is taken into account by increasing the heat conduction coefficient by a factor of 200 for temperatures above 95 °C. The temperature distribution in the blood, vessel wall, and surrounding medium is calculated from a numerical solution of the bioheat equation. The simulations were performed in MATLAB? and validated with the aid of an analytical solution. The simulations showed, first, that laser wavelength did virtually not influence the simulated temperature profiles in blood and vessel wall, and, second, that temperatures of the carbonized blood layer varied slightly, from 952 to 1,104 °C. Our improved mathematical optical-thermal EVLA model confirmed previous predictions and experimental outcomes that laser wavelength is not an important EVLA parameter and that the fiber tip reaches exceedingly high temperatures.