Self-inflicted hammer blows to the head-Literature and case review.

Self-inflicted hammer blows to the head are rare occurrences in forensic medicine, particularly when they are lethal. In the majority of cases, no distinction between self-inflicted injury versus assault has to be made. However, when assault is claimed and such distinction is required, the task may be challenging.

Application of the "bubbling" procedure to dead body portraits in forensic identification.

Purpose: A procedure is needed for bodies with disfiguring injuries to the face and the use of their portrait for visual identification.

Method: We present the application of a simple image processing procedure, otherwise known as "bubbling," which is based on the concept of "perceptual filling-in," to images for visual identification in the forensic context. The method is straight forward and can be performed using readily available software and hardware.

Aldophosphamide-thiazolidine (NSC-613060) an oxazaphosphorine cytostatic that crosses the blood brain barrier.

The pharmacologically active metabolite of cyclophosphamide is aldophosphamide. With cysteine, aldophosphamide forms stable aldophosphamide-thiazolidine which under physiological pH and temperature conditions hydrolyzes to aldophosphamide and cysteine. Aldophosphamide-thiazolidine was synthesized and tested for its ability as a cytostatic.

Causes and possibilities to circumvent cyclophosphamide toxicity.

Cyclophosphamide is an inert prodrug converted into 4-hydroxycyclophosphamide (OHCP) by hepatic hydroxylation. OHCP is in equilibrium with its tautomeric aldophosphamide (ALDO). From ALDO, the cytotoxic active metabolites are formed enzymatically by phosphodiesterases; these are the alkylating metabolite phosphoramide mustard (PAM) and the proapoptotic aldehyde 3-hydroxypropanal (HPA).

Oxazaphosphorine cytostatics: from serendipity to rational drug design.

On the basis of the discovery that the proapoptotic aldehyde 3-hydroxypropanal is a cyclophosphamide metabolite, a novel mechanism of action of oxazaphosphorine cytostatics is presented and confirmed by animal experiments. Furthermore, it is shown that new oxazaphosphorine cytostatics, which are on orders of magnitude more effective than already existing, can be developed on the basis of the new model for the mechanism of action.

Immunostimulating and cancer-reductive experimental therapy with the oxazaphosphorine cytostatic SUM-IAP.

SUM-IAP is an aldo-ifosfamide-perhydrothiazine derivative that, under physiological conditions, spontaneously hydrolyzes to SUM-aldo-ifosfamide. In SUM-IAP, one 2-chloroethyl group of the alkylating function of aldo-ifosfamide-perhydrothiazine is substituted by a mesyl-ethyl group. The compound was synthesized to investigate the influence of the alkylating function of aldo-ifosfamide on the antitumor activity of oxazaphosphorine cytostatics.

Influence of the alkylating function of aldo-Ifosfamide on the anti-tumor activity.

The present work investigates the influence of different DNA damages caused by different isophosphoramide mustards on the 3-hydroxypropanal-assisted apoptotic antitumor activity of oxazaphosphorine cytostatics using I-aldophosphamide-perhydrothiazine (IAP) and mesyl-I-aldophosphamide-perhydrothiazine (SUM-IAP) for in-vitro and in-vivo experiments. IAP and SUM-IAP hydrolyze spontaneously to the corresponding I-aldophosphamide derivatives. They differ in the chemical structure of the alkylating moiety, whereas IAP has two chlorethyl groups in the SUM-IAP molecule, one chlorethyl group is substituted by a mesylethyl group.

β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function.

Unlabelled: The canonical Wnt/β-catenin signaling pathway is crucial for blood-brain barrier (BBB) formation in brain endothelial cells. Although glucose transporter 1, claudin-3, and plasmalemma vesicular-associated protein have been identified as Wnt/β-catenin targets in brain endothelial cells, further downstream targets relevant to BBB formation and function are incompletely explored. By Affymetrix expression analysis, we show that the cytochrome P450 enzyme Cyp1b1 was significantly decreased in β-catenin-deficient mouse endothelial cells, whereas its close homolog Cyp1a1 was upregulated in an aryl hydrocarbon receptor-dependent manner, hence indicating that β-catenin is indispensable for Cyp1b1 but not for Cyp1a1 expression.

Blood-Brain Barrier Breakdown Determines Differential Therapeutic Outcome in Genetically Diverse Forms of Medulloblastoma.

Medulloblastoma driven by Wnt/β-catenin and Sonic hedgehog pathway mutations show favorable and poor patient survival upon treatment, respectively. In this Cancer Cell issue, Phoenix and colleagues (2016) report disruption of the blood-brain barrier by Wif1 specifically in Wnt-driven medulloblastoma, resulting in increased treatment response and survival in mouse models.

Enhancement of antitumor activity of the oxazaphosphorine cytostatic SUM-IAP by N-methylformamide.

Purpose: SUM-IAP has been developed with the aim to optimize therapeutic response and minimize toxic reactions of oxazaphosphorine cytostatics. In therapy tests in mice, the primary tumor was successfully eradicated, but animals died due to formation of lethal metastases. We supposed that high activities of SUM-IAP detoxifying enzymes caused metastasis formation in the liver.

The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function.

Rationale: Endothelial dysfunction is an early event in cardiovascular disease and characterized by reduced production of nitric oxide (NO). The F-BAR protein NO synthase traffic inducer (NOSTRIN) is an interaction partner of endothelial NO synthase and modulates its subcellular localization, but the role of NOSTRIN in pathophysiology in vivo is unclear.

Objective: We analyzed the consequences of deleting the NOSTRIN gene in endothelial cells on NO production and cardiovascular function in vivo using NOSTRIN knockout mice.

The ubiquitin E3 ligase NOSIP modulates protein phosphatase 2A activity in craniofacial development.

Holoprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP.

In vitro models of the blood-brain barrier.

The blood-brain barrier (BBB) proper is composed of endothelial cells (ECs) of the cerebral microvasculature, which are interconnected by tight junctions (TJs) that in turn form a physical barrier restricting paracellular flux. Tight control of vascular permeability is essential for the homeostasis and functionality of the central nervous system (CNS). In vitro BBB models have been in use for decades and have been of great benefit in the process of investigating and understanding the cellular and molecular mechanisms underlying BBB establishment.

Analysis of angiogenesis in the developing mouse central nervous system.

In order to study basic mechanisms of sprouting angiogenesis, researchers worldwide rely on the use of model tissues such as rodent retina, which becomes vascularized postnatally, to study the growth of blood vessels. By definition, models have to be simple, recapitulating angiogenic processes in a stereotyped and relatively easy accessible manner, allowing the application of standardized analyses. These criteria also apply in an ideal manner to the embryonic mouse hindbrain, which becomes vascularized by sprouting angiogenesis from a preformed perineural vascular plexus, leading to the stereotypical formation of a capillary subventricular plexus.

The Wnt/planar cell polarity signaling pathway contributes to the integrity of tight junctions in brain endothelial cells.

Wnt morphogens released by neural precursor cells were recently reported to control blood-brain barrier (BBB) formation during development. Indeed, in mouse brain endothelial cells, activation of the Wnt/β-catenin signaling pathway, also known as the canonical Wnt pathway, was shown to stabilize endothelial tight junctions (TJs) through transcriptional regulation of the expression of TJ proteins. Because Wnt proteins activate several distinct β-catenin-dependent and independent signaling pathways, this study was designed to assess whether the noncanonical Wnt/Par/aPKC planar cell polarity (PCP) pathway might also control TJ integrity in brain endothelial cells.

Wnt signaling in the vasculature.

The development of the vascular system requires orchestrated activities of various molecular pathways to assure the formation of a hierarchically branched tubular network. Furthermore, endothelial cell (EC) populations are heterogeneous to meet organ-specific requirements in the mature vasculature. This developmental scheme is probably best represented by the acquisition and maintenance of unique barrier properties known as the blood-brain barrier (BBB) in microvessels of the central nervous system (CNS).

Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression.

Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood-brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium.

The F-BAR protein NOSTRIN participates in FGF signal transduction and vascular development.

F-BAR proteins are multivalent adaptors that link plasma membrane and cytoskeleton and coordinate cellular processes such as membrane protrusion and migration. Yet, little is known about the function of F-BAR proteins in vivo. Here we report, that the F-BAR protein NOSTRIN is necessary for proper vascular development in zebrafish and postnatal retinal angiogenesis in mice.

Organ preservation treatment using TPF-a pilot study in patients with advanced primary and recurrent cancer of the oral cavity and the maxillary sinus.

Purpose: Induction chemotherapy with Taxotere, cisplatin, and 5-fluororacil (TPF) was mainly used in hypopharyngeal and laryngeal cancer patients for larynx preservation. This study aimed to assess feasibility and toxicity in oral cavity and maxillary sinus cancer patients.

Patients And Methods: Between 2003 and 2008, 21 patients (18 male, three female; mean age 58 years; 15 patients Eastern Cooperative Oncology Group > or =1) suffering from advanced squamous cell cancers of the oral cavity (seven primaries, eight locoregional recurrences) and the maxillary sinus (six patients) were prospectively treated with three cycles of TPF (q3w) and were scheduled to undergo definitive chemoradiation.

Rotational in vitro compliance measurement of diverse anastomotic configurations: a tool for anastomotic engineering.

Anastomotic configurations with a small internal diameter are prone to intimal hyperplasia which can cause occlusion within weeks or months. A link between intimal hyperplasia and inhomogenities of the elastic profile of the anastomosis has been established, making anastomotic engineering directed towards smoothing the compliance profile at the anastomotic site essential. Methods to date restrict the anastomotic compliance measurement to one plane.

Combined modality treatment of oral and oropharyngeal cancer including neoadjuvant intraarterial cisplatin and radical surgery followed by concurrent radiation and chemotherapy with weekly docetaxel - three year results of a pilot study.

Background: A new four-modality treatment of primary oral and oropharyngeal squamous cell carcinomas was evaluated with regard to feasibility, tolerance, and survival.

Patients And Methods: Seventy three operable patients (100%) with histologically proven untreated stage I to stage IV disease received at least one cycle of neoadjuvant intraarterial chemotherapy with 150 mg/m(2) cisplatin neutralized with sodium thiosulphate, followed by radical operation for the tumour with a simultaneous selective neck dissection (clinically negative neck), or modified radical neck dissection (nodal involvement), followed by adjuvant chemoradiation over 5 weeks (51.9 Gy, systemic docetaxel 25 mg/m(2), once every week).

In vitro cytotoxic dose-relation of cisplatin and sodium thiosulphate in human tongue and oesophageal squamous carcinoma cell lines.

Background: Intraarterial chemotherapy of oral and oropharyngeal cancer with cisplatin (cis-diamminedichloroplatinum [II]) has experienced a revival in the last decade. Side-effects of the therapy were very low with concomitant systemic infusion of the neutralizing agent sodium thiosulphate. The requisite dose of the chemotherapeutic agent which safely leads to apoptosis of oral cancer cells has not yet been assessed in vitro, nor has the combination of cisplatin and sodium thiosulphate been examined for the potential reduction of cytotoxicity in oral cancer cells.