Orbitofrontal epilepsy: Electroclinical analysis of surgical cases and literature review

Clinical and electrographic data were reviewed on 2 of our patients with orbitofrontal epilepsy who were seizure free at 5-year follow-up, and on 2 similar patients from the literature. One of our patients was lesional, and the other was nonlesional. Interictal EEG discharges were lateralized to the side of invasively recorded orbitofrontal seizures in the nonlesional case. In this case, no clinical manifestations occurred until the orbitofrontal discharge had spread to the opposite orbitofrontal and both mesial temporal areas. Unresponsiveness or arrest of activity were the initial manifestations of complex partial seizures in both cases. The 2 cases from the literature with long-term seizure-free follow-up had little impairment of awareness and displayed vigorous motor automatisms. Interictal epileptiform activity was bifrontally synchronous in 1 case. Ipsilateral frontotemporal discharges were seen in both. Invasive ictal epileptiform activity appeared maximal in the ipsilateral orbitofrontal region in both patients. No consistent electrographic or clinical pattern characterized these 4 cases. Seizures of orbitofrontal origin may be characterized by either unresponsiveness associated with oroalimentary automatisms or limited alteration of awareness and associated with vigorous motor automatisms. Invasive monitoring of the orbitofrontal cortex should be considered in nonlesional cases with complex partial seizures that show nonlocalizing ictal patterns and interictal frontal or frontotemporal epileptiform discharges. Copyright (C) 2004 S. Karger AG, Basel

Population dynamics of epiphytic orchids in a metapopulation context

Background and Aims Populations of many epiphytes show a patchy distribution where clusters of plants growing on individual trees are spatially separated and may thus function as metapopulations. Seed dispersal is necessary to (re)colonize unoccupied habitats, and to transfer seeds from high- to low-competition patches. Increasing dispersal distances, however, reduces local fecundity and the probability that seeds will find a safe site outside the original patch. Thus, there is a conflict between seed survival and colonization. Methods Populations of three epiphytic orchids were monitored over three years in a Mexican humid montane forest and analysed with spatially averaged and with spatially explicit matrix metapopulation models. In the latter, population dynamics at the scale of the subpopulations (epiphytes on individual host trees) are based on detailed stage-structured observations of transition probabilities and trees are connected by a dispersal function. Key Results Population growth rates differed among trees and years. While ignoring these differences, and averaging the population matrices over trees, yields negative population growth, metapopulation models predict stable or growing populations because the trees that support growing subpopulations determine the growth of the metapopulation. Stochastic models which account for the differences among years differed only marginally from deterministic models. Population growth rates were significantly lower, and extinctions of local patches more frequent in models where higher dispersal results in reduced local fecundity compared with hypothetical models where this is not the case. The difference between the two models increased with increasing mean dispersal distance. Though recolonization events increased with dispersal distance, this could not compensate the losses due to reduced local fecundity. Conclusions For epiphytes, metapopulation models are useful to capture processes beyond the level of the single host tree, but local processes are equally important to understand epiphyte population dynamics

Forced Degradation Testing as Complementary Tool for Biosimilarity Assessment

Oxidation of monoclonal antibodies (mAbs) can impact their efficacy and may therefore represent critical quality attributes (CQA) that require evaluation. To complement classical CQA, bevacizumab and infliximab were subjected to oxidative stress by H2O2 for 24, 48, or 72 h to probe their oxidation susceptibility. For investigation, a middle-up approach was used utilizing liquid chromatography hyphenated with mass spectrometry (LC-QTOF-MS). In both mAbs, the Fc/2 subunit was completely oxidized. Additional oxidations were found in the light chain (LC) and in the Fd’ subunit of infliximab, but not in bevacizumab. By direct comparison of methionine positions, the oxidized residues in infliximab were assigned to M55 in LC and M18 in Fd’. The forced oxidation approach was further exploited for comparison of respective biosimilar products. Both for bevacizumab and infliximab, comparison of posttranslational modification profiles demonstrated high similarity of the unstressed reference product (RP) and the biosimilar (BS). However, for bevacizumab, comparison after forced oxidation revealed a higher susceptibility of the BS compared to the RP. It may thus be considered a useful tool for biopharmaceutical engineering, biosimilarity assessment, as well as for quality control of protein drugs

Pyrolyse und Anellierungsverhalten von Hetarenen: Untersuchungen zur Darstellung von Heterofullerenen

Ziel der vorliegenden Arbeit war die Untersuchung des Anellierungsverhaltens der fünf- und sechsgliedrigen Hetarene und deren Benzo- und Dibenzoderivate. Der Einfluß von Stickstoff, Sauerstoff und Schwefel als Heteroatom auf die Produktbildung bei Pyrolysereaktionen wurde analysiert. Zu diesem Zweck wurden Fluß-Pyrolysen durchgeführt, da unter den sich hierbei ergebenden Bedingungen bimolekulare Sekundärreaktionen überwiegen und somit vorwiegend größere Produkte gebildet werden sollten. Das Heteroatom prägt das Anellierungsverhalten deutlich, die Ringgröße und die Anellierung haben nur einen geringeren Einfluß auf die gebildeten Produkte. Schwefelhaltige Fragmente zeigen eine Anellierung unter Bildung schwefelhaltiger PAKs, wohingegen stickstoffhaltige Fragmente überwiegend Substitutionsreaktionen unter Bildung von Cyanoderivaten eingehen. Sauerstoffhaltige Fragmente neigen zur Bildung leichtflüchtiger Produkte wie CO. Ein weiterer Aspekt war die Synthese von Fullerenen und Heterofullerenen. Fullerene wurden bei der Pyrolyse von PAKs nachgewiesen. Daher sollte hier die Möglichkeit der Darstellung von Heterofullerenen mittels Fluß-Pyrolyse untersucht werden. Bei keiner der durchgeführten Pyrolysen ergaben sich Hinweise für die Bildung der gewünschten Verbindungen. Lediglich bei der Pyrolyse von Benzo[b]thiophen wurde im Direkteinlaß-Massenspektrum ein Signal gefunden, das als M?+-Signal eines Heterofullerens der Konstitution C58S interpretiert werden könnte. Über die Bildung verschiedener Heterofullerene durch Verdampfung von Graphit in hetero-atomhaltiger Atmosphäre wurde in der Literatur berichtet. In dieser Arbeit konnten nur die Untersuchungen, in denen keine Heterofullerene nachgewiesen wurden, bestätigt werden

The level of interleukin-1after intravesical klh instillation in patients with superficial transitional cell cancer of the urinary bladder

Ova studija potvrđuje mišljenje da instilacija KLH-a stimulira produkciju citokina, koji se zatim izlučuju putem mokraće. Interleukin 1(IL-1) koji proizvode aktivirani makrofagi, domino-efektom stimulira niz imunih reakcija. lnstilacijski program započinje 5 do 7 dana nakon TUR-a primarnoga površnog karcinoma mjehura. Taj program obuhvaća intravezikalnu instilaciju 20 mg KLH-a, razvodnjenoga u 20 ml fiziološke otopine, jedanput tjedno, ukupno 6 puta, a zatim jedanput mjesečno tijekom godine dana. Nakon instilacije KLH-a u mjehur, IL-alfa izlučuje se u mokraći. U svrhu analize korišten je specifični enzimski imunosorbent esej (ELISA). ELISA za IL-1 a, utemeljen u našem laboratoriju, pokazuje graničnu vrijednost otkrivanja od 5 pg/ml. Taj IL-la ELISA varira od 3 do 7% unutar naših mogućnosti mjerenja, a 5 do 15% od serije do serije. U terapijskoj skupini sekrecija IL-la varira u rasponu od 0 do 30.905 pg/24h, dok u kontrolnoj skupim taj se raspon kreće između 0 (razdoblje sakupljanja) i 2.472 pg/4h. Sekrecija IL-la nakon instilacije KLH-a u mjehur bolesnika s karcinomom, značajno raste, uz napomenu da visina te sekrecije znatno varira od bolesnika do bolesnika. Maksimum je izlučivanja postignut tijekom 4 do 8 sati nakon mstilacije, nakon čega to izlučivanje postupno opada. Pritom se pokazala neuobičajeno izražena razlika u količini izlučenoga IL-la tijekom 24 sata u kontrolnoj skupini, od skupine kojoj je instiliran KLH. Osam od 14 bolesnika (57%) koliko ih je reagiralo na KLH, imali su nakon šestotjedne terapije veću koncentraciju IL-la u mokraći nego oni bolesnici koji tijekom 12 mjeseci nisu reagirali na KLH, uz napomenu da razlike nisu bile statistički značajne. Smatra se da sekrecija IL-1 alfa u mokraći predstavlja biološki odgovor mjehura na antigenski stimulus KLH-a. U primjercima mokraće nije nađen IL-2. Preostaje da se dodatnim ispitivanjima utvrdi prisustvo IL-2 citokina, uz napomenu da je možda količina citokina bila ispod granice detekcije koju zahtijeva ELISA. Potrebno je utvrditi stimulira li intravezikalno instiliran Keyhole limpet haemocyanin (KLH) lokalni odgovor stanica sluznice mokraćnoga mjehura u bolesnika s površnim karcinomom mjehura.Our study confirms the theory that instillation of KLH stimulates production of cytokines, resulting in their secretion in urine. Interleukin- 1 (IL-1) stimulates the immune cascade through a domino effect and is produced mainly by activated macrophages. The instillation program was started 5-7 days after TUR of primary superficial cell carcinoma. Twenty mg KLH in 20 ml of 0.9% NaCl was instilled into the bladder each week for 6 consecutive weeks and then monthly for one year. When KLH is instilled into the bladder, IL-1alpha is secreted in the urine. A specific enzyme-linked immunosorbent assay (ELISA) was used for analysis. The ELISA for IL-1a was established in our laboratory and showed a detection limit of 5 pg/ml. This IL-1a ELISA deviation amounts to 3-7% within a series of measurements, and 5-15% from series to series. In the therapy group the IL-1a secretion ranged from 0 to 30,905 pg/24 h and in the control group from 0 (collection period) to 2,472 pg/4 h. IL 1a production increased significantly after KLH instillation in bladder cancer patients; however, the level varied considerably from patient to patient. Maximum production was achieved within a period of 4-8 h, decreasing within 24 h. There was a striking difference between the amount of IL-1a produced over the 24-hour period in the control group and that of the KLH group. 8 of 14 patients (57%) who responded to KLH therapy, had higher urine IL-1a levels after 6 weeks of KLH treatment than those who failed to respond within 12 months, but the levels were not of statistical significance. The secretion of IL-1a in urine is the biological response of the bladder to the antigen stimulus of KLH. No IL-2 was detected in the urine samples. It remains to be determined whether no IL-2 cytokine was present, or whether the amount was smaller than the minimal detection limit required for the ELISA

Antibody response to intravesical klh instillation in patients with superfical transitional cell cancer of the urinary bladder

Analizirana je bila dinamika specifične produkcije KLH-antitijela nakon intrakutane i intravezikalne instilacije KLH-a. U razmatranju je bilo 9 bolesnika, i to 7 muškaraca i 2 žene, u dobi od 45 do 75 (prosječna vrijednost 68.6 god.), svi s primamim površnim karcinomom mjehura. Ti su bolesnici nakon kompletne resekcije tumora bili imunizirani intrakutanom injekcijom 1 mg Keyhole limpet haemocyanin (KLH). Postupak je nastavljen intravezikalnom aplikacijom 20 mg KLH-a u 20 ml fiziološke otopine jedanput tjedno, tijekom sljedećih 6 tjedana, a zatim tijekom godine dana, jedanput mjesečno i konačno, svaka 2 mjeseca tijekom sljedeće 2 godine. Antitijela prema KLH-u bila su u serumu ovih bolesnika određivana pomoću posebno razvijenoga i direktno povezanoga imunosorbentnoga eseja (ELISA: prema H. von Kammer. Max Planck Institute for Biophysical Chemistry, Göttingen, Njemačka). Primjerak krvi uzet je za ispitivanje titra antitijela prije postupka i 8 tjedana nakon postupka. Titar KLH-antitijela u bolesnika s karcinomom mjehura signifikantno je porastao nakon terapije KLH-om (Mann Whitney test P=0.02), uz napomenu da je ta razina u većem rasponu varirala od bolesnika do bolesnika. Od tih je 9 bolesnika 6 (67%) pokazivalo povišeni serumski titar antitijela prema KLH-u, dok su 4 bolesnika (44.4%) bila bez tumora tijekom promatranja koje je trajalo od 10 do 45 mjeseci (srednja vrijednost 30.7 mjeseci). Jedan bolesnik koji nije imao povišeni titar antitijela prema KLH-u bio je također bez recidiva, dok su daljnja 2 bolesnika doživjela recidiv tumora, i to nakon aplikacije KLH-a. Dva su bolesnika pokazala recidiv tumora, unatoč povišenom titm antitijela. Ni u jednoga bolesnika s recidivom nakon primjene KLH-a, nije bilo progresije tumora. Četvorica od 5 bolesnika (80%) bez recidiva pokazivali su pozitivni kožni test. Od bolesnika pak s recidivom tumora 50% ih je imalo negativni kožni test. Recidiv tumora imalo je 44.4% bolesnika tretiranih s KLH-om. Stupanj recidiva iznosio je 1.6, dok je vrijeme pojave recidiva bilo 8.75 mjeseci. Instilacija KLH-a nije uzrokovala značajnije negativne posljedice. Pozitivni kožni test i odgovor antitijela na KLH više su registrirani u bolesnika s pozitivnim odgovorom, tj. u onih koji nakon terapije nisu više imali tumor nego u onih bolesnika koji su bili bez odgovora. Produkcija antitijela na KLH čini se daje biološki odgovor na antigenski stimulus KLH-a.The dynamics of the specific KLH-antibody production after intracutaneous and intravesical instillation was analysed. Nine patients (male n=7; female n=2 mean 68.6 years, range 47-75) with primary superficial carcinomas of the bladder, were intracutaneously immunized with 1 mg Keyhole Limpet Haemocyanin (KLH) after the complete resection of tumors. Treatment consisting of 20 mg KLH in 20 ml saline introduced intravesically was continued once a week during the next 6 weeks, then once a month during one year and finally once every two months during the next 2 years. Antibodies against KLH in patients\u27 sera were determined by means of specially developed direct enzyme-linked immunosorbent assay (ELISA: according to H. von der Kammer, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany). Blood was taken for antibody-titer examination before the treatment and 8 weeks after the treatment. The KLH-antibody titer increased significantly after KLH therapy (Mann-Whitney-Test P=0.02) in bladder cancer patients, however the level varied considerably from patient to patient. Six out of 9 patients (67%) presented increased serum antibody titers to KLH after immunotherapy, 4 patients (44.4%) remained free of tumor during the established follow-up period of 10-45 months (median 30.7 months). One patient without increased antibody titer to KLH was free of tumor. Two patients however, suffered from tumor recurrence after the KLH course. Two patients presented tumor recurrence in spite of increased antibody titers. No evidence of tumor progression occurred in patients with recurrence after KLH therapy. Four out of 5 patients (80%) without tumor recurrence presented positive skin test. In patients with tumor recurrence, 50% of them had a negative skin test. 44.4% KLH-treated patients had tumor recurrence. The recurrence rate was 1.6. Time span of recurrence was 8.75 months. KLH instillation did not induce major side effects. Positive skin test reactivity and KLH antibody response were more commonly seen in responding patients (i.e. those who remained tumor-free after the therapy) than in non-responders. The production of KLH antibodies apparently is the biological response to the antigen stimulus of KLH

Is routine magnetic resonance imaging necessary in patients with clinically diagnosed frozen shoulder? Utility of magnetic resonance imaging in frozen shoulder

BACKGROUND Shoulder magnetic resonance imaging (MRI) is commonly performed in patients with frozen shoulder (FS). However, the necessity of MRI and its diagnostic value is questionable. Therefore, the purpose of the present study was to clarify whether routine MRI could identify additional shoulder pathologies not previously suspected in the clinical examination and if any change in the treatment plan based on these additional MRI findings in FS patients was observed. MATERIALS AND METHODS The medical records of all patients who presented in our outpatient clinic with a diagnosis of FS from January 2017 to December 2018 were retrospectively reviewed. Patient demographics, the number of patients who received a shoulder MRI, changes in the diagnosis or identification of structural shoulder pathologies following MRI examination (if performed), as well as any alternation in the initially suggested treatment plan were recorded. RESULTS A total of 609 patients (male: 241, female: 368) diagnosed with an FS and an average age of 52 ± 10 (range: 18 to 81) years were identified. In 403 of the 609 patients (66%), a shoulder MRI was performed. An additional structural shoulder pathology was identified in 89 of 403 (22%) patients following the shoulder MRI, mostly rotator cuff tears (partial: 46/403 [11.4%], full-thickness: 30/403 [7.4%], rerupture following reconstruction: 10/403 [2.5%]) and labrum tears (3/403 [0.7%]). At minimum 2-year follow-up, 11 of 403 (2.7%) patients were treated surgically for the additional pathology identified on the MRI scan consisting of an arthroscopic rotator cuff reconstruction in 10 patients and a labrum refixation in one patient. Five of the 609 (0.8%) patients were treated for refractory FS by arthroscopic capsulotomy. CONCLUSIONS Although additional pathologies were identified in 22% of the patients, a change in treatment plan due to the MRI findings was only observed in 2.7% (37 MRIs needed to identify 1 patient with FS requiring surgery for the additional MRI findings). Therefore, routine use of shoulder MRI scans in patients with FS but without suspicion of an additional pathology may not be indicated