[COVID-19 and the central and peripheral nervous system]. / COVID-19: Auswirkungen auf das zentrale und periphere Nervensystem.

The health effects of coronavirus disease 2019 (COVID-19) caused by the infection of SARS-CoV­2 (severe acute respiratory syndrome coronavirus 2) are becoming increasingly clear as the pandemic spreads. In addition to the lungs, other organs are also affected, which can significantly influence morbidity and mortality. In particular, neurological symptoms involving the central nervous system can lead to acute or long-term consequences. The mechanisms of this neuropathogenesis of SARS-CoV­2 infection and its relation to acute and chronic neurological symptoms are the subject of current studies investigating a potential direct and indirect viral infection of the nervous system. The following review summarizes the current status of neuropathological manifestations, molecular pathogenesis, possible infection pathways in the nervous system, and systemic effects. In addition, an overview of the Germany-wide CNS-COVID19 registry and collaborations is presented, which should contribute to a better understanding of the neurological symptoms of COVID-19.

A single high dose of dexamethasone affects the phosphorylation state of glutamate AMPA receptors in the human limbic system.

Glucocorticoids (GC) released during stress response exert feedforward effects in the whole brain, but particularly in the limbic circuits that modulates cognition, emotion and behavior. GC are the most commonly prescribed anti-inflammatory and immunosuppressant medication worldwide and pharmacological GC treatment has been paralleled by the high incidence of acute and chronic neuropsychiatric side effects, which reinforces the brain sensitivity for GC. Synapses can be bi-directionally modifiable via potentiation (long-term potentiation, LTP) or depotentiation (long-term depression, LTD) of synaptic transmission efficacy, and the phosphorylation state of Ser831 and Ser845 sites, in the GluA1 subunit of the glutamate AMPA receptors, are a critical event for these synaptic neuroplasticity events. Through a quasi-randomized controlled study, we show that a single high dexamethasone dose significantly reduces in a dose-dependent manner the levels of GluA1-Ser831 phosphorylation in the amygdala resected during surgery for temporal lobe epilepsy. This is the first report demonstrating GC effects on key markers of synaptic neuroplasticity in the human limbic system. The results contribute to understanding how GC affects the human brain under physiologic and pharmacologic conditions.

Scrapie diagnosis in a goat and four Santa Inês sheep from the same herd in Brazil / Diagnóstico de scrapie em um caprino e quatro ovinos Santa Inês de um mesmo rebanho no Brasil

Scrapie is a fatal and progressive transmissible spongiform encephalopathy (TSE) of natural occurrence in sheep and goats. The suspicion of scrapie may be based on clinical signs; however, the detection of pathological features of the prionic protein (PrP) in target tissues is necessary to diagnose the disease. The presence of an abnormal protein form (PrPSc) in lymphoreticular and nervous tissues is an important characteristic in diagnosis. This paper reports a case of scrapie in a flock of 55 Suffolk crossbred sheep, 19 Santa Inês sheep and 21 goats in the Mato Grosso state, midwestern Brazil. The animals were euthanized after the confirmation of a scrapie case with clinical signs in a Suffolk sheep in the same farm...

Scrapie é uma encefalopatia espongiforme transmissível (EET) progressiva e fatal de ocorrência natural em ovinos e caprinos. A suspeita de scrapie é baseada nos sinais clínicos, porém a manifestação patológica da proteína priônica (PrP) nos tecidos-alvo é necessária para a confirmação da doença. A presença de uma forma anormal da proteína (PrPSc) em tecido linforreticular e tecido nervoso constitui uma característica importante para o diagnóstico. Este trabalho é o relato de um foco de scrapie ocorrido em rebanho com 55 ovinos mistos Suffolk, 21 caprinos e 19 ovinos Santa Inês, na região Centro-Oeste do Brasil. Os animais foram eutanasiados após a confirmação de um caso de scrapie com sinais clínicos em um ovino Suffolk nessa propriedade...

DNA methylation influences the decatenation activity of topoisomerase II.

Methylation of cytosine in CpG sequences of the DNA in mammalian cells is involved in the regulation of events like gene expression, genomic imprinting, transcription, and DNA replication. Changes in the DNA methylation pattern influence the DNA conformation. Therefore, certain proteins are disturbed in their interaction with DNA. In this paper, we investigate the influence on the decatenation activity of topoisomerase II, an essential enzyme that modulates DNA topology. We compare the decatenation activity of topoisomerase II for a mitochondrial parasite DNA, that we had methylated to different degrees, and found the decatenation to be methylation dependent. Thus, changes in the methylation pattern are a mechanism for the disturbance of certain topoisomerase II activities and may, therefore, be an event in topoisomerase II related mutagenicity and carcinogenicity.

Genotoxicity of several clinically used topoisomerase II inhibitors.

DNA topoisomerase II is an essential nuclear enzyme that modulates DNA topology during multiple cellular processes such as DNA replication and chromosome segregation. Several important clinical antitumor drugs and antibiotics act through inhibition of topoisomerase II. There are a number of different steps in the action of topoisomerase II, all of which are potential targets for inhibition through drugs and also for cellular and genetic toxicity as well as for mutagenesis. We have investigated and compared the genotoxicity and mutagenicity of the mechanistically different topoisomerase II inhibitors m-amsacrine, mitoxantrone, etoposide, genistein, ICRF 193, and berenil using the in vitro micronucleus test, single cell gelelectrophoresis (comet assay) and the mutation assay (tk-locus) in L5178Y mouse lymphoma cells. All six compounds induced micronuclei and all except berenil were mutagenic. M-amsacrine, mitoxantrone, etopside and genistein induced DNA migration in the comet assay, whereas ICRF 193 was only weakly positive and berenil was negative in this test. Our results are in good agreement with the compounds' proposed mechanisms of interaction with topoisomerase II.

Are topoisomerase II inhibitor-induced micronuclei in vitro a predictive marker for the compounds' ability to cause secondary leukemias after treatment?

The inhibition of topoisomerase II (topo II) is a very powerful principle of chemotherapy and topo II inhibiting drugs are the backbone of most chemotherapeutic strategies. However, secondary malignomas can occur after treatment. Typically, secondary acute myeloid leukemia (t-AML) after treatment with topo II inhibitors has a shorter latency period than t-AML following alkylator therapy. Fragments originating from chromosome breakage as well as whole chromosomes which are not correctly distributed during mitosis give rise to micronuclei in the next interphase. Micronucleus formation has become an important endpoint in genotoxicity testing. In an effort to test the suitability of the micronucleus assay for predictive purposes, we have analyzed three human tumor cell lines for cell growth as well as micronucleus induction after treatment with four clinically used topo II inhibitors. Micronuclei were induced at levels of low toxicity by etoposide, mitoxantrone, daunorubicin and idarubicin. The induction of micronuclei was a more sensitive indicator of drug effects than reduction in cell growth. Thus, micronucleus induction may assist in the prediction of the potency of a chemotherapeutic agent for induction of secondary malignomas.

Phase II study of topotecan (NSC 609 699) in patients with recurrent or metastatic soft tissue sarcoma.

BACKGROUND: New drugs are needed for treatment of unresectable or metastatic soft tissue sarcoma. Topotecan, a semisynthetic derivative of the alkaloid, camptothecin, exerts its cytotoxic effect through inhibition of topoisomerase I. PATIENTS AND METHODS: Thirty-two adult patients with locally advanced or metastatic soft tissue sarcoma entered this phase II study of topotecan, administered at 1.5 mg/m2/day IV x 5 days every 3 weeks. All had measurable disease and none had received previous chemotherapy. RESULTS: There were 3 partial responses (10.3%; 95% CI 2.2-27.4%) in 29 evaluable patients. Grade 3 or 4 neutropenia occurred in 25 patients, and there was a 17% incidence of infection/neutropenic fever leading to one toxic death. CONCLUSIONS: Topotecan, in this dose and schedule, has low activity in adult soft tissue sarcoma.

Effects of hormones on the prostate in adult and aging men and animals.

Literature on the effect of steroid hormones (androgens, estrogens, and other steroids), of peptide hormones (e.g., prolactin), and growth factors (e.g., EGF, FGF, TGF-beta), on the effect of castration and of experimental hormone application on the prostate is reviewed. Androgens have inductive, repressive, and interactive effects. They counterbalance an agonistic effect on proliferation and an antagonistic effect on cell death; they may influence DNA synthesis and induce the synthesis of substances with mitogenic effects on the prostate. Estrogens exert direct and indirect effects on the prostate. They suppress the secretion of gonatropins, thus repressing testicular androgen secretion. They stimulate the fibromuscular stroma and induce squamous metaplasia of the epithelium. Estrogens may also be involved in the onset of benign prostatic hyperplasia. Prolactin is preferentially bound in the diseased human prostate. An abundance of information has been gained on EGF, FGF, TGF-beta, and other growth factors. They may be involved in the development of prostatic hyperplasia. Castration leads to a striking reduction in prostatic size in a short period of time due to autophagic and heterophagic processes. In castrated individuals, the prostate is enriched in androgen-independent cells. Experimental hormone application involves the substitution of androgens as well as anti-androgens, long-term application of different hormones, and application of combinations of drugs. The results of several studies are described. Further directions in the field of prostate research should concentrate on the role of growth factors in prostate development and pathology and on the effect of certain lectins on prostate diseases. We think that the investigation of interactions between steroid hormones and growth factors in normal and pathological neovascularization of the prostate is important.

A phase I study of recombinant human interferon alpha-2b combined with 5-fluorouracil and cisplatin in patients with advanced cancer.

To determine the maximum tolerated dose (MTD) of escalating doses of interferon-alpha-2b (IFN, Intron A) with 5-fluorouracil (5-FU) and cisplatin (DDP) in patients with advanced cancer, 15 patients were accrued between May 1990 and July 1991. Primary sites were unknown (3), colorectal (3), head and neck (2), lung (2), gynecologic (1), gallbladder (1), sarcoma (1), anal canal (1) and pancreas (1). IFN was given s.c. on days 1-5 and then three times weekly with DDP (75 mg/m2, day 1) and 5-FU [750 mg/m2, days 1-5, continuous infusion (CI) on a 28-day cycle. The first two patients treated at level I (3 x 10(6) U/m2 s.c.) experienced possible neurotoxic deaths [massive cerebrovascular accident (CVA) and metabolic encephalopathy], and patient 3 had a grade 4 toxicity of performance status decline. Analysis of these events led us to exclude the enrollment of patients on i.v. morphine and of those with prior exposure to DDP. This resulted in grade 3 toxicity in terms of nausea, vomiting, fatigue and leukopenia but in no further CNS event. All patients were evaluable for toxicity but only ten were evaluable for response. Only two partial responses were seen, one in a patient with an unknown primary tumour and one in a patient with head and neck cancer. The combination of IFN is possible with 5-FU and DDP. The recommended dose of IFN is 2 x 10(6) U/m2 s.c. in patients with no prior exposure to DDP or i.v. morphine, given together with 5-FU (750 mg/m2, days 1-5, CI) and DDP (75 mg/m2, day 1) on a 28-day cycle.

Studies on the binding of Urtica dioica agglutinin (UDA) and other lectins in an in vitro epidermal growth factor receptor test.

Urtica dioica agglutinin (UDA), a GlcN-Ac-specific lectin from the rhizomes of Urtica dioica, was found to inhibit the binding of (125)I-labelled epidermal growth factor (EGF) to its receptor (EGF-R) on A431 epidermoid cancer cells at concentrations of 500ng/ml to 100µg/ml. The effects of other lectins such as wheat germ agglutinin (WGA), which possesses the same sugar specificity, and the mannose-specific agglutinin from Canavalia ensiformis (Con A) were less pronounced. The inhibitory effect of UDA could be antagonized by the GlcN-Ac trimer (N,N',N″-triacetylchitotriose), suggesting hat UDA may be the major antiprostatic compound of Urtica dioica drug, acting by blocking the EGF-R in prostate tissues.

Phase II trial of 10-EDAM in advanced soft tissue sarcoma. A study of the Canadian Sarcoma Group and the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Inoperable locally recurrent soft tissue sarcomas (STS) are incurable with chemotherapy. Therefore the National Cancer Institute of Canada Clinical Trials Group are performing phase II studies in an attempt to find better drugs. PATIENTS AND METHODS: Thirty-one evaluable patients with incurable soft tissue sarcoma were treated with the antifol 10-EDAM at a dose of 80 mg per m2/week. RESULTS: Mucositis was the most common toxicity. Only 41% of patients received > or = 90% of the planned dose time because of dose modification mainly for grade 1 mucositis. Two patients died after neutropenic episodes. Toxicity otherwise was generally mild (< grade 2). One patient had a pathologically confirmed complete response but relapsed after four months. Another had a partial response lasting 16 weeks. Eleven other patients had stabilization of disease. CONCLUSIONS: In this study, 10-EDAM was not found to be an effective agent to treat advanced soft tissue sarcoma.

Search for the antiprostatic principle of stinging nettle (Urtica dioica) roots.

While searching for the antiprostatic active principle of the roots of Urtica dioica we ethanol-precipitated a polysaccharide mixture from an aqueous root extract and obtained chemically defined acidic polysaccharides with molecular masses of 15-210kDa. The chemical structures of these compounds have been determined. Some polysaccharides stimulated T lymphocytes in vitro while others influenced the complement system or triggered the release of TNF-α. The crude polysaccharide extract showed a prolonged antiinflammatory activity in the rat paw edema test for 22 hr, which is comparable to the pharmacological efficacy of indometacin. We have reisolated the isolectin mixture (UDA) originally detected in Urtica roots by Peumans et al. (1984). This mixture displayed immunomodulatory effects on T lymphocytes in a dose-dependent manner. In addition, UDA also directly inhibited cell proliferation and blocked binding of epidermal growth factor to its receptor on a tumor cell line, as determined by a [(125)I]-EGF binding assay. These investigations suggest that Urtica polysaccharides and also the N-acetyl-glucosamine specific lectin UDA play a major role in the antiprostatic activity of the drug and phytopreparations containing it.

A phase I study of escalating interferon alpha-2a combined with 5-fluorouracil and leucovorin in patients with gastrointestinal malignancies.

On the basis of preclinical data showing synergy between 5-fluorouracil (5-FU), leucovorin (LV) and IFN-alpha-2a, a phase I study was carried out to determine the maximum tolerable dose (MTD) of IFN-alpha-2a with this combination in patients with gastrointestinal malignancies. The treatment consisted of 370 mg/m2 5-FU and 200 mg/m2, LV on days 1 to 5, and IFN-alpha-2a on days 1 to 5 of the first week of chemotherapy and on days 1, 3, 5 of each subsequent week, on a 28-day cycle. Six patients with colorectal, 3 with pancreas, 2 with oesophagus, 2 with hepatocellular and one with gastric cancer were treated. At level III (5 x 10(6) U/m2) all patients experienced grade 3 or 4 toxicity during the first 56 days of treatment and the MTD was declared level II. Grade 3 toxicity comprised of anorexia, mucositis, diarrhoea, and fatigue; in one instance, grade 4 neutropenia occurred. Ten patients were evaluable for response, one patient with an oesophageal cancer had a minor response and one patient with rectal cancer and liver metastases had a radiological complete response lasting 3 months. The recommended dose for this schedule in phase II studies is 5-FU 370 mg/m2, LV 200 mg/m2, and IFN-alpha-2a 4 x 10(6) U/m2.

Neoadjuvant chemotherapy with cytosine arabinoside by continuous infusion and cisplatin for resectable squamous cell carcinoma of the esophagus.

The combination of cisplatin and cytosine arabinoside has been shown in experimental models to be synergistic. We conducted a pilot study of cytosine arabinoside and cisplatin in unresectable or metastatic cancer of the esophagus in five patients and found significant activity, also on visceral metastasis. Therefore, we decided to examine this combination in the neoadjuvant setting. Since January 1989, eight patients with squamous cell carcinoma esophageal cancer were treated with two cycles of cytosine arabinoside (50 mg/m2) by continuous infusion for 4 days and by cisplatin (100 mg/m2) on the 5th day. Their ages ranged from 54-79 years. One patient had Stage I, three had Stage II, and four had Stage III disease. Responses assessed by endoscopy and computed tomographic (CT) scan prior to surgery were three with partial response, three with minor response, and two with no response. Only six patients were surgically resectable after chemotherapy. Toxicity consisted of grade 3 (one patient) and grade 4 (two patients) neutropenia, grade 3 (three patients) anemia, and grade 3 (two patients) and grade 4 (three patients) thrombocytopenia. All patients had subjective improvement of dysphagia 4 weeks after chemotherapy. Median survival of the whole group was 7.5 months. We concluded that there was no evidence of synergy of these drugs given in this manner in esophageal carcinoma since the response rate was no different from that achieved with cisplatin alone.

Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients.

Twenty-three adult patients with chronic pain due to cancer completed a double-blind, randomized, two-phase crossover trial comparing plasma morphine concentrations and analgesic efficacy of oral morphine sulfate solution (MSS) and controlled-release morphine sulfate tablets (MS Contin [MSC], Purdue Frederick, Inc., Toronto, Ontario, Canada). MS Contin was given every 12 hours to all patients except those whose daily morphine dose could not be equally divided into two 12-hour doses with the tablet strengths available. MSS was given every 4 hours. Patients received both of the test drugs for at least 5 days, and, on the final day of each phase, peripheral venous blood samples for morphine analysis were obtained. Eighteen patients received MSC every 12 hours, and five received it every 8 hours. The same total daily morphine dose was given in both phases. In the 18 patients who received MSC every 12 hours, the daily morphine dose was 183.9 +/- 140.0 mg (mean +/- SD). In this group, the mean area under the curve (AUC) with MSC was 443.6 +/- 348.4 ng/ml/hour, compared with 406.8 +/- 259.7 ng/ml/hour for MSS (P greater than 0.20). Mean maximum morphine concentrations (Cmax) for MSC and MSS were 67.9 +/- 42.1 and 58.8 +/- 30.3 ng/ml, respectively (P greater than 0.05). Mean minimum morphine concentrations (Cmin) were 17.0 +/- 17.7 and 18.3 +/- 15.0, respectively (P greater than 0.30). There was a significant difference (P less than 0.001) between the two drugs in time required to reach maximum morphine concentration (Tmax). Mean Tmax after MSC occurred at 3.6 +/- 2.3 hours. After MSS, it occurred at 1.3 +/- 0.4 hours. In the five patients who received MSC every 8 hours, the findings paralleled those in the principal group, with no significant differences between MSC and MSS in Cmax or Cmin and a highly significant difference between the two in Tmax. However, in this small group of patients, the AUC with MSC was significantly (P = 0.04) greater than that with MSS. All patients had very good pain control throughout the study and both formulations were well tolerated. There were no significant differences between MSC and MSS in pain scores or side effects. Under the conditions of this study there was no clinically significant difference in bioavailability between MSC and oral MSS. When given on a 12-hourly basis in individually titrated doses, the MSC provided therapeutic plasma morphine concentrations throughout the dosing interval.

Hepatic malignancies: improved treatment with intraarterial Y-90.

An improved treatment method for hepatic malignancies with yttrium-90 incorporated into the matrix of glass microspheres was evaluated prospectively. Fifteen patients with 12 metastatic colorectal cancers, one carcinoid, one islet cell tumor, and one hepatoma were treated with three dose levels: 5,000 cGy (5,000 rad), ten patients; 7,500 cGy (7,500 rad), three patients; and 10,000 cGy (10,000 rad), two patients. Mean follow-up was 7 months (range, 2-12 months). Stable disease in the liver was seen in ten patients, four of whom had concurrent progression of extrahepatic disease, which resulted in two deaths. Two additional deaths were not directly related to the malignant process. Progression of liver disease was found in five patients, with three deaths occurring at 7-8 months. No procedural, hematologic, or pulmonary complications occurred. Late gastroduodenal ulceration occurred at 6-8 weeks in three patients who had histories of chronic alcohol abuse. This method of therapy seems to be feasible and efficient. Caution is necessary with high doses or with patients with a history of or predisposition to gastroduodenal ulcers.

Double antibody radioimmunoassay for monitoring metastatic breast cancer.

We previously reported the production of a panel of murine monoclonal antibodies which recognize glycoproteins abnormally expressed in human breast tumours. Using two of these antibodies, a double antibody radioimmunoassay was designed to quantify levels of these breast tumour marker glycoproteins in serum. Marker levels greater than 28 units were considered abnormal. Using this criterion, 63% and 75% of patients with breast cancer stages I and II, respectively, and 88% of those with metastatic disease were found to have elevated marker levels. Thirteen percent of patients with non-malignant breast disease also had elevated marker levels. Elevated marker levels were also detected in patients with non breast neoplasms. One hundred and eleven women with metastatic disease were followed. Eighty-two percent of those with progressive disease and 73% of those where disease regressed had 20% changes in marker levels. These changes in marker levels preceded by up to 6 months changes in disease state. From these results we conclude that this assay may be useful for monitoring the course of disease in breast cancer patients.

Obstruction of the swing phase during gait: phase-dependent bilateral leg muscle coordination.

We have investigated bilateral leg muscle activation following an obstruction of the forward swinging leg during gait. When the holding impulse was released at the beginning of the swing phase, weak gastrocnemius (GM) and biceps femoris (BF) responses appeared in the contralateral, standing leg. When the holding impulse was released at the end of the swing phase, strong tibialis anterior (TA) and rectus femoris (RF) responses appeared in the swinging leg, and GM and BF responses in the standing leg. In the latter condition the TA response was followed by a premature impact associated with a GM activation. The latency between onset of impulse and appearance of the responses was 65-70 ms in both legs. While in the first condition the duration of GM and BF response corresponded to the duration of the impulse, it was independent for the duration of GM and BF response in the latter. It is concluded that different strategies for compensation are at work. In the first condition, body stability is maintained during the obstruction by the standing leg. In the second condition, body support is provided by a premature touchdown of the swinging leg. It is suggested that the appropriate pattern is, in part, released by a spinal generator.

Ambulatory hepatic artery infusion chemotherapy for cancer of the liver.

We have used continuous hepatic arterial infusion chemotherapy to treat 105 patients with cancer of the liver originating from colorectal, other gastrointestinal, and nongastrointestinal sites. The response rate seen in colorectal metastases was two to three times that expected for systemic chemotherapy. The median survival of responders of 16 months was significantly better then for nonresponders (6 months). The median duration of response was 9 months. The results for patients with other tumor types were less encouraging. Although minor problems developed in about 30 percent of the patients, major complications requiring removal of the catheter were not common. Expertise derived from managing many patients and a team approach, with a defined protocol for catheter care and follow-up, contributed to the success of the ambulatory program. However, the role of hepatic arterial infusion chemotherapy remains under debate. At the root of the controversy is the lack of randomized, controlled trials supporting the superiority of hepatic arterial infusion over systemic chemotherapy in the treatment of colorectal liver metastases. This and other issues, including the current liberal use of implanted infusion pumps, should be studied.