[Patients at the end of life in the intensive care unit: cultural aspects of accompaniment]. / Patienten am Lebensende auf der Intensivstation: Kulturelle Aspekte der Begleitung.

The accompaniment of people in the face of death offers insights into dimensions which are mostly not seen in ordinary life. These insights also exist in intensive care in German hospitals and are highly relevant in medical decision making. End-of-life decisions in particular often determine medical, cultural and spiritual aspects concerning medical treatment and therapeutic targets and if necessary new therapy targets. The following article especially illuminates cultural aspects and their characteristics in patients at the end of life in the intensive care unit.

["Scores of Independence for Neurologic and Geriatric Rehabilitation (SINGER)" - development and validation of a new assessment instrument]. / "Selbständigkeits-Index für die Neurologische und Geriatrische Rehabilitation (SINGER)" - Entwicklung und Validierung eines neuen Assessment-Instruments.

In the context of developing and testing a procedure for "Outcome-oriented payment for rehabilitation after stroke", we found that the instruments commonly used to measure the outcomes of rehabilitation after stroke (e. g., Barthel-Index or FIM) were not meeting the special requirements of the new payment system. Therefore the "Scores of Independence for Neurologic and Geriatric Rehabilitation" (SINGER) was developed as a new assessment instrument. This instrument is based on the ICF and measures 20 aspects of "independence in activities of daily living". The characteristic feature of the SINGER is, above all, the way all items are graded in 6 steps: the gradation does not refer to the degree of disability but to the kind and amount of help required for the respective activity, i. e.: 0 = totally dependent on professional help; 1 = professional contact help needed; 2 = contact help by (instructed) lay persons sufficient; 3 = preparation or supervision by lay persons still needed; 4 = independent with assistive device or still slow; 5 = independent without assistive device. For experienced personnel in neurologic rehabilitation, these gradations are "intuitively plausible". A manual moreover describes each grade in detail for each item so that the instrument can be used in rehabilitation facilities without extensive training. The SINGER has been tested and validated in a pilot study (n = 100) and in 2 subsequent studies with large case numbers in neurologic rehabilitation (n = 1058 and n = 700 patients after stroke in all categories of severity). Factor analyses showed that the instrument contains 2 dimensions which can be interpreted as "physical activities" and "activities of communication and cognition". Each of these 2 dimensions can be split into 2 sub-dimensions that can be assigned to the tasks of therapeutical professions in care/Occupational Therapy, physiotherapy, logopedics, and neuro- psychology. The test criteria of reliability, sensitivity, convergent validity, floor and ceiling effects as well as sensitivity to change show good to very good results. Particular emphasis can be given to the high degree of interrater reliability and the wide range of possible applications in clinical practice as well as in research. A limitation of the instrument to be taken into account is the fact that the SINGER has not yet been tested and validated in geriatric rehabilitation facilities.

[Palliative care oriented therapy for all patients : recommendations of an expert circle]. / Palliativmedizinisch orientierte Therapieansätze für alle Patienten : Empfehlungen eines Expertenkreises.

BACKGROUND: Since 2011 palliative care has been a compulsory part of the German medical study course (so-called Q13 palliative and pain medicine). Palliative care content does not, however, as often taught, have to focus only on patients in the so-called palliative stages of disease. The aim of this investigation was to encourage a discussion concerning the integration of palliative care aspects into general medical treatment. METHODS: For data collection an open discussion of the main topics by experts in palliative medical care was used. The main outcome measures and recommendations included responses regarding current practices related to expert opinions, national and international literature and one case report. The literature search was performed using the databases "PubMed", "Medline" and "Google" (1990-2011). RESULTS: As an important consensus, the following recommendations for optimization of inpatient and outpatient care were: (1) integration of aspects of palliative care into medical curricula of all disciplines, (2) palliative care content should be extended to the general optimization of therapy for all patients, (3) palliative medicine should be part of the everyday medical practice in all disciplines and (4) palliative medicine should not be isolated as "death medicine" or medicine of the dying patient. CONCLUSIONS: Palliative care treatment is increasingly becoming integrated into medical education and into medical curricula of all disciplines. Palliative ideas and goals are focussed on patients in the so-called palliative stages of disease. Furthermore, palliative medicine is often described as the medicine of dying patients. As a result of this study it seems to make sense to extend palliative care aspects to all patients and to all patient care. The extent to which such opportunities exist and such health care is economically feasible remains to be the subject of further clinical studies.

[Palliative care and end-of-life patients in emergency situations. Recommendations on optimization of out-patient care]. / Palliativpatienten und Patienten am Lebensende in Notfallsituationen. Empfehlungen zur ambulanten Versorgungsoptimierung.

BACKGROUND: At the end of life acute exacerbations of medical symptoms (e.g. dyspnea) in palliative care patients often result in emergency medical services being alerted. The goals of this study were to discuss cooperation between emergency medical and palliative care structures to optimize the quality of care in emergencies involving palliative care patients. METHODS: For data collection an open discussion of the main topics by experts in palliative and emergency medical care was employed. Main outcome measures and recommendations included responses regarding current practices related to expert opinions and international literature sources. RESULTS: As the essential points of consensus the following recommendations for optimization of care were named: (1) integration of palliative care in the emergency medicine curricula for pre-hospital emergency physicians and paramedics, (2) development of outpatient palliative care, (3) integration of palliative care teams into emergency medical structures, (4) cooperation between palliative and emergency medical care, (5) integration of crisis intervention into outpatient palliative emergency medical care, (6) provision of emergency plans and emergency medical boxes, (7) provision of palliative crisis cards and do not attempt resuscitation (DNAR) orders, (8) psychosocial aspects concerning palliative emergencies and (9) definition of palliative patients and their special situation by the physician responsible for prior treatment. CONCLUSIONS: Prehospital emergency physicians are confronted with emergencies in palliative care patients every day. In the treatment of these emergencies there are potentially serious conflicts due to the different therapeutic concepts of palliative medical care and emergency medical services. This study demonstrates that there is a need for regulated criteria for the therapy of palliative patients and patients at the end of life in emergency situations. Overall, more clinical investigations concerning end-of-life care and unresponsive palliative care patients in emergency medical situations are necessary.

Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.

Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective non-toxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the lower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m2 ; higher doses were not more effective. Levels of gamma-GCS and DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration.

Non-specific effects of childhood vaccinations - A case control study nested into a Health and Demographic Surveillance System in rural Burkina Faso.

INTRODUCTION: Previous studies in African countries have been suggestive of non-specific effects (NSE) of vaccination on child survival. Live vaccines (e.g. measles, MV) have been found to reduce child mortality while inactivated vaccines (e.g. diphtheria-tetanus-pertussis, DTP) have been associated with increased mortality; NSE were often found to be sex-specific. METHODS: A case-control study nested into the Health and Demographic Surveillance System (HDSS) cohort of the Centre de Recherche en Santé de Nouna (CRSN) was conducted in northwestern Burkina Faso. A total of 3,010 children born in 2009-11, were included in the study, 375 cases and 2635 age and village matched controls. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. RESULTS: Most deaths occurred in late infancy, and there were significantly more deaths in males as compared to females (OR 1.29, CI 1.04-1.60). Overall, there was no statistically significant association between vaccine status and mortality. However, among children in the age group 2-8 months, there was a consistent sex-differential pattern for all doses of oral polio vaccine combined with pentavalent vaccine (OPV + Penta), with the vaccines being associated with lower mortality in boys, but not in girls. Routine MV + yellow fever vaccine was associated with reduced mortality, but only before mass vaccination campaigns with meningitis and measles vaccines took place. CONCLUSIONS: The findings of this study provide further support on the existence of NSE of childhood vaccinations in a large population of rural Burkina Faso. More randomized controlled trials are needed to confirm these observations.

[Analgesia of the axilla using a paravertebral catheter in the lamina technique]. / Analgesie der Achselhöhle durch Paravertebralkatheter in Laminatechnik.

A 62-year-old female suffered from therapy-resistant pain in the axilla after lymphadenectomy. The pain ranged from 8-10 on the numeric rating scale (NRS) despite multimodal pain therapy (non-steroid anti-rheumatics, opioids, physiotherapy, acupuncture). A paravertebral trial injection was performed preoperatively on the laminae of the thoracic vertebrae Th 2-Th 4. As the patient responded well, a paravertebral catheter was inserted close to Th 4 directly before the revision operation took place the following day. The case study describes the possibilities of eliminating pain segmentally in the axilla and an alternative technique to a paravertebral block (lamina technique).

Glutathione S-transferase activity and glutathione S-transferase mu expression in subjects with risk for colorectal cancer.

The glutathione S-transferases (alpha, mu, and pi), a family of Phase II detoxication enzymes, play a critical role in protecting the colon mucosa by catalyzing the conjugation of dietary carcinogens with glutathione. We investigated the efficacy of using the glutathione S-transferase (GST) activity of blood lymphocytes and GST-mu expression as biomarkers of risk for colorectal cancer. GST activity was measured in the blood lymphocytes of control individuals (n = 67) and in the blood lymphocytes (n = 60) and colon tissue (n = 34) of individuals at increased risk for colon cancer. Total GST activity was determined spectrophotometrically with the use of 1-chloro-2,4-dinitrobenzene as a substrate. The ability to express the um subclass of GST was determined with the use of an ELISA. Although interindividual variability in the GST activity of blood lymphocytes was greater than 8-fold (range, 16.7-146.8 nmol/min/mg), the GST activity of blood lymphocytes and colon tissue within an individual was constant over time and was unrelated to sex, age, or race. The GST activity of blood lymphocytes from high-risk individuals was significantly lower than that of blood lymphocytes from control individuals (P < or = 0.004). No association was observed between the frequency of GST-mu phenotype and risk for colorectal cancer. Blood lymphocytes from high-risk individuals unable to express GST-mu had lower levels of GST activity than did those from control subjects with the GST-mu null phenotype; however, this difference was significant in male subjects only (P < or = 0.006). Analysis of paired samples of blood lymphocytes and colon tissue indicated a strong correlation between the GST activity of the two tissue types (Spearman's rank correlation, r = 0.87; P < or = 0.0001). The GST activity of blood lymphocytes may be used to identify high-risk individuals with decreased protection from this Phase II detoxication enzyme who may benefit from clinical trials evaluating GST modulators as chemopreventive agents for colorectal cancer. The GST activity of blood lymphocytes may also be used in colorectal cancer chemoprevention trials to monitor the responsiveness of colon tissue to regimens that modify Phase II detoxication enzymes.

Preclinical and clinical evaluation of broccoli supplements as inducers of glutathione S-transferase activity.

Previous studies suggest that cruciferous vegetables may provide protection against carcinogen exposure by inducing detoxification enzymes. ICR(Ha) mice were gavaged with broccoli tablets (1 g/kg), and colon tissues were collected after treatment. Glutathione S-transferase (GST) activity was assayed and peaked on days 1 and 2 after treatment, respectively (P = 0.03). Elevations in GST activity were attributed to the increased expression of mu and pi. These data supported a clinical assessment of broccoli supplements. Twenty-nine subjects at increased risk for colorectal cancer were randomized to group 1 (no cruciferous vegetables) or group 2 (broccoli supplements, 3 g/day) for 14 days. Blood samples and colon biopsies were obtained pre- and postintervention. No significant difference was observed between the GST activities of the control and broccoli supplementation groups posttreatment. Mean lymphocyte GST activity was 107% of baseline in the broccoli supplementation group (range, 79-158%) and 102% of baseline in the control group (range, 75-158 percent;). Correlation of the GST activities of blood lymphocytes and colon mucosa taken simultaneously suggested that the GST activity of blood lymphocytes may be used as a biomarker of the responsiveness of colon tissue to chemopreventive regimens. Future clinical studies evaluating cruciferous vegetables should consider using concentrated dietary supplements in subjects with a previous history of colorectal cancer.

Endotoxin-mediated activation of cytokine production in human PBMCs by collagenase and Ficoll.

Endotoxin-induced early inflammatory reactions may inhibit the function and survival of isolated cells or cell aggregates after transplantation. By the chromogenic Limulus amebocyte lysate assay we found rather high but variable endotoxin concentrations in the chemicals used for islet isolation, i.e. collagenase and Ficoll. Liberase, a special collagenase preparation from Boehringer, was nearly endotoxin-free. Correlating to the endotoxin content, collagenase and Ficoll had the capacity to induce interleukin-1beta release from human peripheral blood mononuclear cells. Because collagenase and density gradient media are needed in most cell isolation procedures from solid organs, each lot of these chemicals should be tested for endotoxin contamination. In pancreatic islet transplantation, the use of endotoxin-free chemicals may diminish early local inflammatory reactions at the graft site and thereby reduce the number of islets needed for successful islet transplantation.

Cytokine mRNA expression in peripheral blood cells of immunosuppressed human islet transplant recipients.

The macrophage derived cytokines interleukin-beta (IL-1beta), and tumor necrosis factor alpha (TNFalpha), and the T-cell derived cytokine interferon gamma (IFNgamma) have been implicated to play an important role in early attack on islet cells during human islet transplantation (ITx). Therefore, the aim of this study was to investigate the influence of the current immunosuppressive induction therapy in clinical islet transplantation on mRNA expression of these cytokines in blood cells, compared to lipopolysaccharide (LPS) induced cytokine release in vitro and to plasma levels. The cytokine release correlated to lymphocyte counts and significantly decreased after ATG, and partially recovered 2 weeks after ITx. Unexpectedly, there was no correlation between mRNA expression for IL-1beta in total blood and the number of lymphocytes and monocytes remaining after anti thymocyte globulin (ATG)-therapy. Even when the blood was nearly totally depleted from mononuclear cells, high amounts of IL-1beta mRNA could be detected. However, IL-1beta secretion could not be stimulated in vitro. Our results show that application of ATG during ITx might contribute to graft survival during the early posttransplant period by suppression of the synthesis of monocyte derived cytokines IL-1beta and TNFalpha.

A morphometric study of nerve fiber atrophy in rat spinal roots.

A morphometric study of atrophy of nerve fibers was made in the ventral and dorsal roots of rats, four to 48 weeks (wk) after transection of their sciatic nerves and with regeneration prevented. The pathophysiological events of fiber atrophy may be summarized as follows: wasting of the axon caliber coincides with a loss of neurofilaments with relative preservation of microtubules. This leads to non-circularity of the fiber, evident from four wk on. The caliber of the circular profile is also reduced. Adaptive changes in myelin sheath structure follow. Thinner fibers with relatively thick sheaths are first detectable after eight wk and prominent after 24 to 48 wk. This change may indicate passive slippage of the sheath, but sheath remodelling in adjustment to a changed internodal geometry appears more likely.

Isolated angiitis of the central nervous system: lack of inflammation after long-term treatment.

A case of isolated angiitis of the CNS was observed for 5 years. Initial response to cyclophosphamide was followed by relapse on therapy interruption. After renewed treatment, clinical stabilization was achieved despite progressive stenoses shown by angiography. The patient died of cyclophosphamide-induced myelodysplastic syndrome. Autopsy revealed lack of inflammation, vascular scarring, and amyloid angiopathy. We conclude that cure from isolated angiitis of the CNS is possible and that the risk of overtreatment should be minimized.

Depletion of colonic detoxication enzyme activity in mice with dextran sulphate sodium-induced colitis.

BACKGROUND: The increased risk of colonic malignancies in individuals with ulcerative colitis has prompted a search for early biomarkers of disease progression. AIM: To characterize Phase II detoxication enzyme expression during acute and chronic colitis. The mouse model of dextran sulphate sodium (DSS)-induced colitis represents a relevant system with which to sequentially evaluate the spectrum of biochemical changes associated with colorectal cancer risk. METHODS: Acute and chronic colitis were induced in Swiss Webster mice by administering DSS in the drinking water (5%) for 1-4 cycles. Each cycle consisted of 7 days DSS and 14 days of water. The glutathione S-transferase (GST) activity, gamma-glutamylcysteine synthetase (gamma-GCS) activity and glutathione content of the colonic tissues were determined at various time points throughout the experiment. Alterations in GST isozyme expression were confirmed by Western and Northern blot. RESULTS: GST activity was reduced significantly in the colon by the end of Cycle 1 (84% of control values). Specific activities continued to decrease with subsequent cycles of DSS exposure. By the end of Cycle 4, glutathione levels and gamma-GCS activity had reached 29% and 56% of control, respectively. CONCLUSIONS: These data suggest that detoxication enzyme depletion is associated with both acute and chronic colitis and may be an important event in the progression of ulcerative colitis to colon cancer.

Monoamine oxidase types A and B in the human adrenal gland and pheochromocytoma.

The distribution of the two types of monoamine oxidase within the human adrenal gland was studied. As demonstrated by histochemical techniques, the zona reticularis of the adrenal cortex contains the type A enzyme and the zonas glomerulosa and fasciculata contain little enzyme activity. Biochemical analysis showed that the adrenal medulla contains both types of monoamine oxidase. It is suggested that the type B enzyme is present in chromaffin cells and the type A enzyme is present in vascular and other neural elements. Pheochromocytoma, a tumor of the adrenal medulla, apparently does not contain the B type enzyme.

Long-term management of acute respiratory failure in metabolic myopathy.

OBJECTIVE: To describe how patients cope with the proposal of treatment with intermittent artificial ventilation after acute respiratory failure due to progressive respiratory muscle weakness. DESIGN: Case series, follow-up study. SETTING: Neurological intensive care unit (ICU). PATIENTS: 7 consecutive patients with metabolic myopathy treated for acute respiratory failure between 1983 and 1992. INTERVENTIONS: Intermittent positive pressure ventilation (IPPV) via tracheostomy. MEASUREMENTS AND RESULTS: Symptoms of chronic hypoventilation preceded acute respiratory failure for months. With one exception, patients were mainly disabled from respiratory muscle weakness and sleep-related breathing disorders. IPPV was recommended to prevent recurrent respiratory failure. Two of three patients who accepted home IPPV returned to full-time jobs. One patient, who decided against IPPV, died from CO2 narcosis several months after discharge. All patients adhered to the respiratory regimen once instituted. CONCLUSIONS: Acute respiratory failure in chronic myopathy is heralded by daytime drowsiness. IPPV, or at least regular monitoring of waking and sleeping partial pressure of carbon dioxide, is highly recommended even if weaning is successful. IPPV improved quality of life. The treatment strategy at discharge from the ICU should be optimal, as patients are reluctant to modify regimens.

Cooperative approach to the treatment of cervical cancer.

This study covers 20 years' experience in the treatment of carcinoma of the cervix. Improved results and a decreased rate of major complications are seen as a result of a cooperative approach in treatment planning and careful dosimetry. Comparisons are made with large treatment centers as well as with national survival rates. Preliminary results with improved radiotherapeutic techniques continue to show improvement in survival rates.

Indicators of dysautonomia in severe Guillain-Barré syndrome.

This study sought to establish quantitative criteria for dysautonomia in artificially ventilated patients with Guillain-Barré syndrome (GBS). Such criteria would help to identify patients at risk for cardiovascular complications. This retrospective controlled clinical study compared hourly cardiovascular monitoring data from 36 successive, artificially ventilated GBS patients with that from 11 artificially ventilated control patients with myasthenia. Tolerance limits for daily means, extremes, and variations in heart rate (HR) and blood pressure (BP) were estimated from the most abnormal subgroups of the treatment days of our control patients. These exceeded previously suggested arbitrary cutoff values for dysautonomia. The range in systolic BP was increased in 27 GBS patients, despite an upper limit of normal (85 mmHg) that was double the value suggested in previous work. All 16 patients with mean systolic BP above 165 mmHg also had persistent tachycardia (mean HR > 125 bpm), or were treated with beta-blockers. This pattern of sympathetic hyperactivity was combined with probable vagal hyperactivity (bradycardia < 48 bpm) in 6 patients. Hypotension (minimal systolic BP < 85 mmHg) and unprovoked bradycardia indicated sympathetic hypoactivity in 3 patients. Except in one patient who suffered from asystole on his first day on the ICU, all episodes of bradycardia were preceded by increased daily systolic BP variation (> 85 mmHg), which thus proved to be a sensitive and prognostically valuable indicator of dysautonomia in GBS.

Polyneuropathy associated with chronic hypoxaemia: prevalence in patients with chronic obstructive pulmonary disease.

The prevalence of clinical and electrophysiological signs of peripheral nerve disease was evaluated in 151 patients with chronic obstructive pulmonary disease. Patients with concomitant disorders affecting the peripheral nervous system were excluded. Thirty patients had clinical signs of a mild sensorimotor and distal neuropathy and 13 additional patients had only electrophysiological abnormalities. The rate and the severity of the neuropathy correlated with the severity of chronic hypoxaemia. Three out of 20 patients with mild hypoxaemia (PaO2 less than 15 mm Hg below normal) had polyneuropathy as compared with 15 out of 36 with severe hypoxaemia (PaO2 more than 30 mm Hg below normal (rates different at the 10% level)). PaO2 and age were the only variables discriminating between patients with and without peripheral neuropathy.

Sensitivity and specificity of different conduction block criteria.

OBJECTIVES: To resolve the discrepancy between conduction block criteria derived from healthy controls and stricter criteria suggested by computer simulation of interphase cancellation through altered motor units. METHODS: An EMG database provided control nerves from patients with amyotrophic lateral sclerosis (ALS) or neural muscular atrophy (CMT1) (disease controls) and from subjects without neuromuscular diseases (healthy controls). We estimated normal limits from the healthy controls (criterion A) and from the pooled sample of healthy and disease controls (criterion B). We compared their sensitivity with that of an arbitrary limit of 0.5 (criterion C) in acute (AIDP) and chronic inflammatory demyelinating neuropathy (CIDP) and in multifocal motor neuropathy (MMNP). Specificity was assessed in ALS and CMT1. RESULTS: Limits estimated from healthy controls (criterion A: amplitude ratio of <0.7 in median and peroneal nerves and <0.8 in the ulnar nerve) gave false positive results in 17.3% of the ALS nerves. High scatter of the amplitude ratio of the nerves with distal response amplitudes below 1 mV required amplitude-dependent limits (0.36 for distal responses below 1 mV, 0.56 between 1 and 2 mV, and between 0.67 and 0.73 for higher response amplitudes) for criterion B. It was false positive in 4.3% of the ALS nerves and in 28.3% of the CMT1 nerves. A limit of 0.5 for nerves with distal responses above 1 mV and a limit of 0.36 for smaller responses (criterion D) avoided false positive results in ALS without further impairing sensitivity per patient in MMNP. Sensitivity in AIDP was 34.9% for criterion A, 19.5% for criterion B, and 10.2% for criterion D. Amplitude ratios were more sensitive than area ratios in CIDP and MMNP, but less specific in CMT1. CONCLUSIONS: Limits derived from healthy controls are unspecific in chronic neuromuscular diseases and in nerves with low response amplitudes. Criterion D should be used if motor unit restructuring or conduction delays have to be taken into account. Criterion A may be applicable in early AIDP if the distal response amplitude is above 1 mV.