[First Experience with Cranioplasty Using the Polyetheretherketone (PEEK) Implant - Retrospective Five-Year Follow-up Study]. / První zkusenosti s kranioplastikou pomocí implantátu z polyetereterketonu (PEEK) ­ retrospektivní studie pri petiletém sledování.

PURPOSE OF THE STUDY Cranioplasty is currently the most common neurosurgical procedure. The purpose of this study is to describe the first experience with successful use of the Cranio-Oss (PEEK) custom implant for cranioplasty. MATERIAL AND METHODS In the period 2012 to 2013, a total of 26 cranioplasties were performed. In fourteen patients, their own bone flap was used for reconstruction. In four cases, a synthetic Cranio-Oss bone implant made of PEEK was used. In six patients, the defect was covered by an intraoperatively-made Palacos implant and in two cases, minor defects were covered with a titanium mesh. The patients were followed up for at least five years. Cranio-Oss is a cranial implant made from polyetheretherketone (PEEK), a synthetic biocompatible material. The implant is created using the CAD/CAM method in the shape of the bone defect based on the CT scan. Creating optimal roughness of the implant surface and of the surface of the contact area attached to the bone bed is controlled and included already in the strategy for machining individual areas of the implant during its manufacturing at a 5-axis machining centre. RESULTS The Cranio-Oss implant was used in four younger patients to cover larger and complex-shaped defects. The mean age of patients in this group was 47 years. The implant was fixed to the skull by micro-plates. In all the cases the wound healed well with good cosmetic results without the necessity of revision with respect to the used implant. The follow-up CT scans always showed the implant in situ with no signs of malposition. DISCUSSION Autologous bone flap is the most suitable material for defect reconstruction after craniectomy. This option is affordable and represents one of the best methods of reconstruction of defects after craniectomy in terms of cosmetic results. In some cases, the original skull cannot be used for cranioplasty (e.g. if destructed by tumourous process, infected or in comminuted fractures). In such cases, the defect needs to be managed using a synthetic implant. In case of extensive defects, the most suitable option is a custom made implant from advanced biomaterials. CONCLUSIONS Authors prefer using autologous bone flaps during cranioplasty. In cases where this method is unavailable, a synthetic bone substitute has to be used. The first medium-term experience with the use of a Cranio-Oss implant made of PEEK showed that it is a suitable alternative to the patient's own bone. No complications associated with this synthetic implant were reported and its use to manage skull defects can be strongly recommended. With respect to legal and accreditationrelated difficulties connected with bone fragments storage and thanks to the continuous cost reduction of synthetic implants will their importance grow in the future. Key words: decompressive craniectomy, bone substitute, craniotrauma.

Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling.

As a member of the Janus (JAK) family of non-receptor tyrosine kinases, TYK2 mediates the signaling of pro-inflammatory cytokines including IL-12, IL-23 and type 1 interferon (IFN), and therefore represents an attractive potential target for treating the various immuno-inflammatory diseases in which these cytokines have been shown to play a role. Following up on our previous report that ligands to the pseudokinase domain (JH2) of TYK2 suppress cytokine-mediated receptor activation of the catalytic (JH1) domain, the imidazo[1,2-b]pyridazine (IZP) 7 was identified as a promising hit compound. Through iterative modification of each of the substituents of the IZP scaffold, the cellular potency was improved while maintaining selectivity over the JH1 domain. These studies led to the discovery of the JH2-selective TYK2 inhibitor 29, which provided encouraging systemic exposures after oral dosing in mice. Phosphodiesterase 4 (PDE4) was identified as an off-target and potential liability of the IZP ligands, and selectivity for TYK2 JH2 over this enzyme was obtained by elaborating along selectivity vectors determined from analyses of X-ray co-crystal structures of representative ligands of the IZP class bound to both proteins.

Antibacterial, cytotoxicity and physical properties of laser--silver doped hydroxyapatite layers.

Hydroxyapatite layers with silver doping from 0.06 at.% to 14 at.% were prepared by laser deposition. The films' physical properties such as morphology, composition, crystallinity, Young's modulus and microhardness were measured. Films were amorphous or polycrystalline in dependence on deposition temperature (from RT to 600 °C). Antibacterial properties were tested using Escherichia coli and Bacillus subtilis cells. The antibacterial efficacy changed with silver doping from 4% to 100%. Cytotoxicity was studied by a direct contact test. Depending on doping and crystallinity the films were either non-toxic or mildly toxic.

Nasal prosthesis supported with self-tapping implants with bioactive surface--a case report.

Nasal prosthesis using dental implants and magnetic abutments is a method of choice in replacement of missing hard and soft facial tissues. Nose form, coloration, and texture must be as indiscernible from the surrounding natural tissues as possible. Rehabilitation efforts can be successful only when patients can appear in public without fear of attracting unwanted attention. This case report evaluates on a step-by-step basis the materials and methods including implants insertion.

Oestrogens and Alzheimer's disease.

In the last decade, several reports suggest that oestrogen replacement therapy (ORT=ERT=estrogen replacement therapy) might prevent or delay Alzheimer's disease. Oestrogens influence and modulate brain structure and brain function. There are substantial arguments that the postmenopausal oestrogen loss might, together with other factors, accelerate the appearance of Alzheimer's disease. The evidence is suggestive, but not compelling, that ORT can reduce the relative risk to suffer from Alzheimer's disease. Furthermore, recent findings are consistent with the hypothesis that oestrogens might ameliorate the symptomatology in early stages of Alzheimer's disease. However, it has to be remembered that in most clinical trials the number of oestrogen users was quite small, and, usually, oestrogen use was not randomised. The aim of the present review is to discuss the data available today in view of their clinical relevance.

Effect of plasma-sprayed hydroxyapatite coating on the osteoconductivity of commercially pure titanium implants.

Formation of a calcium phosphate layer was studied on the surfaces of plasma-sprayed hydroxyapatite (PSHA) and sandblasted commercially pure (cp) titanium in simulated body fluid with ion concentrations similar to those of human blood plasma. The PSHA surface induced the formation of calcium phosphate surface layers, while the precipitation of calcium phosphate on sandblasted cp titanium was not detected. Histologic evaluation of in vivo tests demonstrated that implants with a PSHA coating enabled the growth of bone tissue into gaps with a depth of up to 1 mm without significant formation of intermediate fibrous tissue. In comparison to sandblasted cp titanium, implants with PSHA coating exhibited greater tolerance to unfavorable conditions during healing, such as gaps at the interface or primary instability of the implant. In the case of good primary stability of the implant, filling of the gap with fibrous tissue was observed for sandblasted cp titanium implants over the greater part of the surface of gaps with a depth of 0.3 mm. Direct contact of cp titanium implants with bone was achieved only when the press-fit implantation model was used.

[Psychiatric complications of pharmacotherapy--a review]. / Psychiatrische Komplikationen internistischer Medikamente--eine Ubersicht.

Various commonly used drugs with somatic indications may give rise to a host of partially serious psychiatric side-effects. This overview details important prescribed drugs of daily use and their psychiatric complications. The problems of elderly patients are particularly considered. Also, polypharmacy will be given special attention.

[Depression in old age]. / Depressionen im Alter.

At least 4% of elderly patients living in the community suffer from a major depressive disorder and some 15% from less severe forms of depressive illness. However, physical and psychiatric comorbidity is high in elderly patients and the incidence of depression may reach 40% to 50% in common medical disorders such as diabetes mellitus or cardiac insufficiency. Therefore, elderly patients who are hospitalised or living in senior citizen homes suffer more frequently from depressive disorders, with prevalence rates up to 50%. The phenomenology and etiology of geriatric depression are very heterogeneous. Depression often presents atypically, e.g., behind a mask of complaints about physical symptoms or anxiety. Diagnostic and therapeutic measures follow the same standards as in younger adults, yet age-related differences must be taken into consideration. Thus, psychopharmacological management must be adapted to the altered metabolism of drugs in the elderly. Also, psychological treatment strategies should respect the distinctive psychosocial situation of elderly patients.

[Diagnosis and therapy of alcohol-withdrawal symptoms in the elderly: a case report]. / Der Alkoholentzug im fortgeschrittenen Lebensalter. Diagnose und Therapie anhand eines Fallbeispiels.

The incidence and prevalence of alcoholism in the elderly population are tendentially underestimated. There are some reasons for this fact. The pathway to the diagnosis of alcoholism may be considerably compromised in the often comorbid or multimorbid patient. To live up to an advanced age seems to be a good argument against chronic substance abuse. Elderly people and their relatives are often still more reluctant to report about socially stigmatizing disorders. On top of that, the amount of social control is reduced after the end of employment and upon entering retirement. Yet, if alcohol-withdrawal symptoms occur, e.g., following an admission of the addicted patient to a hospital, the missed diagnosis of alcoholism means a delay of the correct interpretation of such complications and of the necessary treatment. Aged patients with reduced physical and mental reserve capacity are at special risk of developing further serious complications. Progressive, sometimes irreversible decay of the cognitive functions in long lasting delirious states or, as an aftermath of withdrawal, epileptic seizures are of particular importance.

[Ethical aspects of the treatment of mentally and physically seriously ill patients--a case report of an elderly female schizophrenic patient with jaundice]. / Medizinethische Aspekte der Behandlung psychisch und körperlich schwer Erkrankter. Fallbeispiel einer betagten schizophrenen Patientin mit cholestatischem Ikterus.

The treatment of elderly patients with combined psychiatric and physical illness often implicates special challenges for physicians. A psychiatric disorder may significantly complicate diagnostic and therapeutic measures for somatic diseases. The realisation of planned procedures may be delayed or even become impossible in non-compliant subjects. Respect of the patient's will conflicts with the assessment of his/her judgement and protection of his/her supposed interests. Such considerations need an abstraction of the destructive, illness-bound will of these patients in the light of ethical and medical options. The increasing responsibility of physicians in such cases is limited by an often controversial legal frame. We present such practice-relevant problems which we encountered in the treatment of an 83-year-old woman with cholestatic jaundice of clinically unknown origin and chronic schizophrenia.

[Suicide of psychiatric inpatients assisted by euthanasia advocacy groups. Cases of assisted suicide?]. / Suizide in der stationären Psychiatrie unter Beihilfe einer Sterbehilfevereinigung. Fälle aktiver Sterbehilfe?

The debate on passive and active euthanasia has met a controversial echo both in the German-speaking media and in professional publications within recent years. This discussion, however, largely excluded mentally ill patients. Also, euthanasia advocacy groups have usually distanced themselves from euthanasia in psychiatric patients. We report here two cases from our hospital in which inpatients with affective disorders committed assisted suicide during a hospital pass. We discuss these events under the assumption that these are cases of questionable active euthanasia in mentally ill patients whose judgement was considerably compromised by their disorder.

Catatonia under medication with risperidone in a 61-year-old patient.

This report describes the case of a 61-year-old female schizophrenic patient with status post-frontal lobotomy some 35 years ago with prominent paranoid delusions. This woman developed severe catatonia under medication with a serotonergic/dopaminergic neuroleptic, risperidone, at a dose of up to 5 mg daily. The catatonic disorder was dose-dependent and subsided immediately after switching the medication to another atypical antipsychotic, clozapine. Given the negative history for catatonia in this patient, the temporal coincidence of administration of risperidone and catatonia is a novel finding.

Apnea syndrome in a patient with Alzheimer dementia under chlormethiazole treatment: a clinical experience report.

Sleep apnea syndromes in conjunction with dementia have attracted considerable interest among geropsychiatrists in recent years. This clinical case report describes a demented and delirious elderly patient with a history of alcoholism who developed a sleep apnea syndrome under treatment with chlormethiazole. The risk of chlormethiazole treatment may be underestimated in vulnerable patients, e.g. those suffering from severe respiratory diseases or dementia. Alternative treatments for delirious states need to be evaluated instead.

[Treatment of anxiety and panic attacks in geriatric psychiatry]. / Behandlung von Angst und Panikattacken in der Gerontopsychiatrie.

For the treatment of anxiety disorders and panic attacks in elderly patients a multidimensional approach including pharmacotherapy, psychotherapy and behavioral modification is crucial. More than in younger patients side effects of drugs have to be taken into account. For the long-term treatment only a few psychotropic drugs are recommended. Useful substances are antidepressants including tricyclics and the newer class of SSRI. Buspirone may also play a role in the long-term pharmacotherapy of anxiety disorders. Neuroleptics, benzodiazepines and betablockers should only be prescribed after careful evaluation; by and large, they are of minor significance in the long-term strategy due to significant adverse effects. The pharmacological treatment should always be accompanied by psychotherapy. In particular, behavioral therapy and behavioral modification strategies are of benefit.

[Diagnostic and therapeutic procedures in intraabdominal injuries.]. / Diagnostické a lécebné postupy u nitrobrisního poranení

The authors evaluated the diagnostic and therapeutic procedure in 25 patients with blunt and in 12 with penetrating abdominal injuries hospitalized between Jan. 1, 1995 and Aug. 30, 1997 at the intensive care unit of the Surgical Clinic Prague 10. The diagnostic algorithm included in addition to the basic clinical examination also computed tomography. The most frequently injured organ in blunt injuries was the spleen (12 times) and liver (11 times). Twenty-three patients were operated. In casualties with penetrating injuries there were 8 with piercing wounds and 4 with shotgun wounds. The most frequently injured organ was the small intestine (4 times). Two patients of the group died. Key words: blunt and penetrating abdominal injuries, diagnosis, treatment.

Identification and characterization of novel somatostatin antagonists.

The study of the five somatostatin receptor subtypes (SSTx, where x is the subtype number) has been hampered by the lack of high affinity antagonists. Potent and selective antagonists would increase our understanding of SST structure, function, and regulation. In this study, the identification of novel disulfide-linked cyclic octapeptide antagonists of somatostatin is described. The antagonists contain a core structure of a DL-cysteine pair at positions 2 and 7 of the peptides. Substitution of a D-cysteine at position 2 with an L-cysteine converts the full antagonist into a full agonist. All somatostatin receptor subtypes are coupled to inhibition of adenylate cyclase. The functional properties of these peptides have been determined in radioligand binding assays, in functional coupling of the SST2 subtype to yeast pheromone response pathway, and in cAMP accumulations. One peptide antagonist [Ac-4-NO2-Phe-c(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)-D-Tyr-NH2] displays a binding affinity to SST2 comparable with that observed for the native hormone (Ki = 0.2 nM) and reverses somatostatin-mediated inhibition of cAMP accumulation in rat somatomammotroph GH4C1 cells, cells transfected with the SST2 and SST5 subtypes, as well as somatostatin-stimulated growth of yeast cells expressing the SST2 subtype. This class of somatostatin antagonists, which are the first to be described, should be useful for determination of somatostatin's diverse functions in vivo and in vitro.

Pharmacological characterization of the rat A2a adenosine receptor functionally coupled to the yeast pheromone response pathway.

The rat A2a adenosine receptor, a G protein-coupled receptor, was functionally expressed in the yeast Saccharomyces cerevisiae. High affinity binding sites for A2a adenosine agonists were detected in yeast membranes containing the endogenous Grx protein Gpa1. Agonist saturation binding isotherms using [3H]5'-N-ethylcarboxamidoadenosine indicated that the A2a adenosine receptor expressed in yeast cell membranes displays pharmacological properties equivalent to those observed when the receptor is expressed in human embryonic kidney 293 cell membranes. The rank order of potency of various agonists in [3H]5'-N-ethylcarboxamidoadenosine competition binding assays performed with yeast cell membranes was comparable to that seen for the receptor expressed in mammalian cell membranes. Adenosine agonist-dependent growth response of yeast strains expressing the A2a adenosine receptor was elicited via activation of the yeast pheromone-response pathway. Induction of a pheromone-responsive FUS1-HIS3 reporter gene in far1 his3 cells permits cell growth in medium lacking histidine. The sensitivity of the bioassay was increased by deletion of the STE2 gene, which encodes the yeast alpha-mating pheromone receptor. The growth response was dose dependent, and agonists of varying affinities displayed a rank order of potency comparable to that observed in competition binding assays. Agonist-activated growth assays performed in liquid culture gave ED50 values for various adenosine agonists consistent with reported Kd alpha values. Yeast strains expressing a single receptor/G protein complex will be useful as a model system for the study of receptor/G protein interactions in vivo.

Identification of a critical aspartate residue in transmembrane domain three necessary for the binding of somatostatin to the somatostatin receptor SSTR2.

To determine which residues within the rat somatostatin receptor subtype SSTR2 may be interacting with the lys9 of somatostatin-14 (S-14), mutant SSTR2 receptors were created by mutating asp89 or asp122. [125I Tyr11]S-14 binding to D89A and D89E mutants suggests that asp89 is not directly involved in S-14 binding. Binding studies with the charge switch mutants, asp9S-14, and D122K, suggest that asp122 may be interacting with the lys9 of S-14. [125I Tyr11]asp9S-14 displayed saturable binding to D122K with an affinity comparable to that seen with [125I Tyr11]S-14 and WT SSTR2. These data suggest that the interaction between lys9 of S-14 and the TM3 asp122 of SSTR2 represents one contact site between S-14 and SSTR2.

Rat somatostatin receptor type 1 couples to G proteins and inhibition of cyclic AMP accumulation.

The pharmacology, signal transduction, and coupling to G proteins of the rat somatostatin (SRIF) receptor (SSTR)1 have been characterized in transfected Chinese hamster ovary (CHO) (K1 strain) cells. The expressed receptor exhibited saturable, high affinity binding of several radioiodinated SRIF analogues. Three different radioligands were used to determine the pharmacological properties of this SSTR subtype. [125I-Tyr11]SRIF-14 (125I-S-14), [Leu8,D-Trp22,125I-Tyr25]SRIF-28 (125I-S-28), and cyclo(D-Trp-Lys-Abu-Phe-MeAla-125I-Tyr) (125I-peptide C) displayed the following rank order of affinity (Kd) for the SSTR1 subtype: 125I-S-14 > or = 125I-S-28 > 125I-peptide C. Competition of 125I-S-14 with S-14, S-28, or peptide C displayed the same rank order of potency. Chemical cross-linking of specifically bound 125I-S-28 to membranes from CHO cells expressing the receptor indicated that the molecular weight of the SSTR1 expressed in CHO cells is approximately 70,000, suggesting that it is heavily glycosylated. Previous reports have suggested that the human SSTR1 [Mol. Pharmacol. 42:28-34 (1992)] couples poorly to G proteins. The coupling of the rat SSTR1 to G proteins was demonstrated by three independent methods. (a) Binding of 125I-S-14 to the SSTR1 subtype was inhibited in a dose-dependent fashion by incubation of membranes with guanosine-5'-O-(3-thio)triphosphate. (b) Treatment of cells with pertussis toxin decreased binding by 80%. (c) Immunoprecipitation of 125I-S-14 binding was observed with antiserum specific for Gi alpha 1,2, but not with antiserum specific for Gs alpha, in membranes from transfected cells. In CHO cells transfected with the SSTR1 cDNA, SRIF inhibited forskolin-stimulated cAMP accumulation by up to 50%, in a dose-dependent fashion (ED50 = 1.1 nM). Pertussis toxin treatment decreased both the efficacy and the potency of the SRIF-mediated inhibition of cAMP accumulation (from 50% to 22%), compared with control untreated cells. These data suggest that the rat SSTR1 inhibits cAMP accumulation by coupling to pertussis toxin-sensitive G proteins.