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ZusammenfassungEine 39-jährige Patientin hat sich initial wegen Rückenschmerzen orthopädisch vorgestellt. Nachdem sich in der Magnetresonanztomografie der Lendenwirbelsäule der Verdacht auf eine tumoröse Erkrankung gestellt hatte, war in den weiterführenden Untersuchungen eine pulmonale Raumforderung, eine ausgedehnte mediastinale Lymphadenopathie und ein großer einseitiger Pleuraerguss nachweisbar. Histologisch zeigte sich sowohl in den Proben des Tumors im Wirbelkörper als auch in den Proben der transbronchialen Nadelaspiration eines mediastinalen Lymphknotens ein NUT-Karzinom. Das NUT-Karzinom, das früher als NUT-Mittellinienkarzinom bezeichnet wurde, ist eine sehr seltene, aggressive Tumorentität mit ungünstiger Prognose. Der Tumor wurde zunächst gehäuft in der Mittellinie der oberen Atemwege und des Mediastinums beschrieben, ist aber nicht darauf beschränkt. Das NUT-Karzinom trifft häufig junge Patienten. Aufgrund der Seltenheit existiert bisher keine etablierte Therapie.

Unsere zunehmende Abhängigkeit von Informationstechnik erhöht kontinuierlich die Safety- und Security-Anforderungen bei deren Einsatz. Ein zentrales Problem hierbei sind Schwachstellen von Hard- und Software. Marktkräfte konnten diese Situation bislang nicht grundsätzlich beheben. Eine Gegenstrategie sollte deshalb folgende Optionen erwägen: (1) private und staatliche Förderung offener und sicherer IT‑Produktion, (2) Verbesserung der souveränen Kontrolle bei der Produktion aller kritischen IT‑Komponenten innerhalb eines Wirtschaftsraumes sowie (3) verbesserte und durchgesetzte Regulierung. Dieser Beitrag analysiert Vor- und Nachteile dieser Optionen. Es wird vorgeschlagen, die Sicherheit der Schlüsselkomponenten einer Lieferkette durch weltweit verteilte, offene und ggf. mathematisch bewiesene Komponenten zu gewährleisten. Der beschriebene Ansatz erlaubt die Nutzung existierender und neuer proprietärer Komponenten. Increasing dependence on information technology calls for strengthening the requirements on their safety and security. Vulnerabilities that result from flaws in hardware and software are a core problem which market mechanisms have failed to eliminate. A strategy for resolving this issue should consider the following options: (1) private- and public-sector funding for open and secure production, (2) strengthening the sovereign control over the production of critical IT components within an economic zone, and (3) improving and enforcing regulation. This paper analyses the strengths and weaknesses of these options and proposes a globally distributed, secure supply chain based on open and mathematically proved components. The approach supports the integration of legacy and new proprietary components.

Es besteht eine komplexe Beziehung zwischen der chronisch obstruktiven Lungenerkrankung (COPD) und Diabetes. In mehreren Studien wurde nachgewiesen, dass Diabetes die Progression und Prognose einer COPD verschlechtern kann. Dies kann Folge eines direkten Effekts einer Hyperglykamie auf die Lungenphysiologie, Inflammation oder Anfalligkeit fur bakterielle Infektionen sein. Auf der anderen Seite wurden ausgepragte Hinweise dafur gefunden, dass eine COPD das Risiko fur die Entwicklung eines Typ-2-Diabetes, als Folge inflammatorischer Prozesse oder als Nebenwirkung der Therapie mit hoher dosierten Kortikosteroiden, steigert. Obwohl es bedeutende Hinweise fur eine Verbindung zwischen COPD und Diabetes gibt, sind zusatzliche Studien erforderlich, um diese Interaktion und die daraus resultierenden Implikationen besser zu verstehen.

ZusammenfassungSchlafbezogene Atmungsstörungen (SBAS) als häufige und relevante Komorbidität erfordern sowohl im perioperativen Management als auch in der intensivmedizinischen Behandlung kritisch kranker Patienten besondere Berücksichtigung. Patienten mit SBAS benötigen aufgrund eines erhöhten perioperativen Risikos für kardiale, pneumologische und neurologische Komplikationen eine maßgeschneiderte perioperative Überwachung und Therapie, wobei die aktuellen Empfehlungen primär Patienten mit einer obstruktiven Schlafapnoe betrachten. Die intensivmedizinische Behandlung von kritisch kranken Patienten mit SBAS erfordert ein aufmerksames Management während der Beatmung, in der Weaning- und in der Postextubationsphase, um das Risiko einer prolongierten Beatmung oder eines Weaningversagens zu reduzieren.

ZusammenfassungEin 38-jähriger Patient wurde aufgrund einer zunehmenden Verschlechterung des Allgemeinzustandes und einer Kachexie stationär aufgenommen. Bildmorphologisch ergab sich bei einschmelzenden Rundherden und einer kavernösen Formation der Verdacht auf eine Mykobakteriose, sodass die Indikation zu einer Bronchoskopie gestellt wurde. In der Bronchoskopie gelang tatsächlich der Nachweis einer nicht tuberkulösen Mykobakteriose. Als Zufallsbefund zeigte sich im Mittellappenbronchus eine weißliche polypöse Schleimhautveränderung. Histologisch war ein Granularzelltumor (GZT) nachweisbar. Der GZT ist ein seltener Tumor, der an verschiedenen anatomischen Lokalisationen auftreten kann. In der Lunge kann er klinisch durch eine bronchiale Obstruktion manifest werden, bildgebend als Rundherd oder Infiltrat bzw. Atelektase oder als Zufallsbefund in einer Bronchoskopie auffallen. Therapie der 1. Wahl ist die chirurgische Entfernung.

Atemwegsinfektionen sind eine der haufigsten Ursachen fur die Vorstellung von Patienten beim Hausarzt oder in einer Klinik. Im hausarztlichen Bereich ist es nicht einfach, ohne aufwandige Diagnostik zwischen einer Pneumonie, anderen tiefen Atemwegsinfektionen oder anderen Ursachen der Erkrankung zu differenzieren. Bei der Diagnostik im ambulanten Bereich sollte danach stratifiziert werden, ob Risikofaktoren (schwere internistische oder neurologische Begleiterkrankungen, Antibiotikavortherapie, instabiler klinischer Zustand) vorliegen. Im ambulanten Bereich sind als Diagnostik bei fehlenden Risikofaktoren die klinische Untersuchung, Bestimmung des CRB-65-Scores und Thorax-Rontgenaufnahmen sinnvoll, jedoch kein Labor und keine Mikrobiologie. Im ambulanten Bereich sollte auch an wichtige Differentialdiagnosen der ambulant erworbenen Pneumonie („community-acquired pneumonia“, CAP) gedacht werden. Bei hospitalisierten Patienten umfasst die Diagnostik die klinische Untersuchung, die Bestimmung des CRB-65-Scores, eine ausfuhrliche Anamnese, Thorax-Rontgenaufnahme, Labor, Sauerstoffsattigung und die Entnahme von zwei Blutkulturen. Ein Legionellenantigentest im Urin und die Mikrobiologie eines purulenten Sputums sind optional. Die Entscheidung uber eine stationare Aufnahme wird durch den CRB-65-Score objektiviert. Bei hohem Risiko sollte die Aufnahme auf einer Intensivstation erwogen werden.

ZusammenfassungFrauen leiden häufig im Zusammenhang mit reproduktiven Ereignissen, also vor der Menstruation, während und nach der Schwangerschaft und in den Wechseljahren an affektiven Erkrankungen. Dieses liegt an den komplexen Zusammenhängen zwischen weiblichen Geschlechtshormonen und Neurotransmittern, aber natürlich auch an den Einflüssen belastender oder sich verändernder Lebensumstände. Affektive Symptome können in diesen Zusammenhängen erstmals manifest werden, und in Symptomausprägung oder Schwere variieren. Wochenbetterkrankungen betreffen fast 20% aller Frauen und bergen das Risiko der Schädigung des Kindes durch Vernachlässigung, durch komorbide Zwangssymptome und im extremen Fall durch Infantizid. Die Ursachen der Wochenbettdepression, die sich meist sechs Wochen nach der Geburt manifestiert, sind nicht geklärt. Die Therapie umfasst psychopharmakologische und psychotherapeutische Interventionen, erstere in Abhängigkeit davon, ob die Patientin stillen kann oder möchte. Die Perimenopause ist im Leben einer Frau die Zeit mit dem höchsten Depressionsund Angsterkrankungsrisiko. Hier sind die Zusammenhänge zwischen hormonellen Veränderungen und der psychischen Symptomatik gut belegt. Behandlungsstrategien beinhalten demnach sowohl hormonelle als auch psychopharmakologische, in manchen Fällen auch psychotherapeutische Interventionen.

BACKGROUND AND PURPOSE Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families. METHODS The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools. RESULTS The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease. CONCLUSIONS Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP.

Anchorage of pedicle screw instrumentation in the elderly spine with poor bone quality remains challenging. In this study, micro finite element (µFE) models were used to assess the specific influence of screw design and the relative contribution of local bone density to fixation mechanics. These were created from micro computer tomography (µCT) scans of vertebras implanted with two types of pedicle screws, including a full region-or-interest of 10 mm radius around each screw, as well as submodels for the pedicle and inner trabecular bone of the vertebral body. The local bone volume fraction (BV/TV) calculated from the µCT scans around different regions of the screw (pedicle, inner trabecular region of the vertebral body) were then related to the predicted stiffness in simulated pull-out tests as well as to the experimental pull-out and torsional fixation properties mechanically measured on the corresponding specimens. Results show that predicted stiffness correlated excellently with experimental pull-out strength (R2 > 0.92, p

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

The goal of this study was to examine the development of the reticulum, rumen, omasum and abomasum in six calves from birth to 100 days of age by means of six serial ultrasonographic examinations. The examinations were carried out in standing animals using a 5 MHz-transducer as described previously. The calves were primarily fed milk until examination 4 and then they were weaned. The reticulum was assessed for its shape and contractility, the rumen for its size and content, the omasum for its size, content and motility and the abomasum for its size and content before and after the ingestion of milk. The reticulum was seen in all calves starting at examination 2 and had biphasic and triphasic contractions; the latter were associated with eructation. The rumen was always imaged in all calves as early as Day 1 and its visible size increased progressively in all intercostal spaces (ICSs) during the study period. The omasum was best imaged in the 8th or 9th ICS; it was seen medial to the liver dorsally and usually medial to small intestines ventrally. Its visible size in these two ICSs increased progressively but omasal motility was not apparent. In newborn calves the abomasum was the largest compartment and dominated the abdominal cavity. It was visible from the 5th ICS to the flank. Except for examination 2, the mean visible abomasal length was significantly larger after feeding than before. Lateral abomasal extension to the left was greater than to the right at examinations 1-4, but was much smaller than to the right at examinations 5 and 6 because of progressive expansion of the rumen. Abomasal extension into the right hemiabdomen changed little during the study period.

Postoperative delirium in elderly patients is a frequent complication and associated with poor outcome. The aim of this parallel group study was to determine whether monitoring depth of anaesthesia influences the incidence of postoperative delirium.Patients who were planned for surgery in general anaesthesia expected to last at least 60 min and who were older than 60 yr were included between March 2009 and May 2010. A total of 1277 patients of a consecutive sample were randomized (n=638 open, n=639 blinded) and the data of 1155 patients were analysed (n=575 open, n=580 blinded). In one group, the anaesthesiologists were allowed to use the bispectral index (BIS) data to guide anaesthesia, while in the other group, BIS monitoring was blinded. Cognitive function was evaluated at baseline, 1 week, and 3 months after operation.Delirium incidence was lower in patients guided with BIS. Postoperative delirium was detected in 95 patients (16.7%) in the intervention group compared with 124 patients (21.4%) in the control group (P=0.036). In a multivariate analysis, the percentage of episodes of deep anaesthesia (BIS values20) were independently predictive for postoperative delirium (P=0.006; odds ratio 1.027). BIS monitoring did not alter the incidence of postoperative cognitive dysfunction (7th day P=0.062; 90th day P=0.372).Intraoperative neuromonitoring is associated with a lower incidence of delirium, possibly by reducing extreme low BIS values. Therefore, in high-risk surgical patients, this may give the anaesthesiologist a possibility to influence one precipitating factor in the complex genesis of delirium. Clinical trial registration ISRCTN Register: 36437985. http://www.controlled-trials.com/ISRCTN36437985/.

Summary Background Treatment guidelines for aphasia recommend intensive speech and language therapy for chronic (≥6 months) aphasia after stroke, but large-scale, class 1 randomised controlled trials on treatment effectiveness are scarce. We aimed to examine whether 3 weeks of intensive speech and language therapy under routine clinical conditions improved verbal communication in daily-life situations in people with chronic aphasia after stroke. Methods In this multicentre, parallel group, superiority, open-label, blinded-endpoint, randomised controlled trial, patients aged 70 years or younger with aphasia after stroke lasting for 6 months or more were recruited from 19 inpatient or outpatient rehabilitation centres in Germany. An external biostatistician used a computer-generated permuted block randomisation method, stratified by treatment centre, to randomly assign participants to either 3 weeks or more of intensive speech and language therapy (≥10 h per week) or 3 weeks deferral of intensive speech and language therapy. The primary endpoint was between-group difference in the change in verbal communication effectiveness in everyday life scenarios (Amsterdam–Nijmegen Everyday Language Test A-scale) from baseline to immediately after 3 weeks of treatment or treatment deferral. All analyses were done using the modified intention-to-treat population (those who received 1 day or more of intensive treatment or treatment deferral). This study is registered with ClinicalTrials.gov, number NCT01540383. Findings We randomly assigned 158 patients between April 1, 2012, and May 31, 2014. The modified intention-to-treat population comprised 156 patients (78 per group). Verbal communication was significantly improved from baseline to after intensive speech and language treatment (mean difference 2·61 points [SD 4·94]; 95% CI 1·49 to 3·72), but not from baseline to after treatment deferral (−0·03 points [4·04]; −0·94 to 0·88; between-group difference Cohen's d 0·58; p=0·0004). Eight patients had adverse events during therapy or treatment deferral (one car accident [in the control group], two common cold [one patient per group], three gastrointestinal or cardiac symptoms [all intervention group], two recurrent stroke [one in intervention group before initiation of treatment, and one before group assignment had occurred]); all were unrelated to study participation. Interpretation 3 weeks of intensive speech and language therapy significantly enhanced verbal communication in people aged 70 years or younger with chronic aphasia after stroke, providing an effective evidence-based treatment approach in this population. Future studies should examine the minimum treatment intensity required for meaningful treatment effects, and determine whether treatment effects cumulate over repeated intervention periods. Funding German Federal Ministry of Education and Research and the German Society for Aphasia Research and Treatment.

Objectives: We aimed to identify clinical characteristics and to assess effectiveness of different initial antibiotic regimens in adult patients with community-acquired pneumonia (CAP) caused by Haemophilus influenzae. Methods: Characteristics were compared between patients with H. influenzae monoinfection versus CAP of other and unknown aetiology enrolled by the German prospective cohort study CAPNETZ. Impact of initial antibiotic treatment on "early clinical response" according to FDA criteria and overall clinical cure were analysed. Results: H. influenzae was found in 176 out of 2790 patients with pathogen detection (6.3%). Characteristics significantly associated with a H. influenzae CAP (p

Die pontozerebellare Hypoplasie (PCH) Typ 2 ist eine seltene autosomal-rezessive Erkrankung, radiologisch charakterisiert durch eine zerebellare und pontine Hypoplasie, welche sich klinisch in der fruhen Sauglingszeit mit einer Entwicklungsretardierung, pyramidalen/extrapyramidalen Bewegungsstorung sowie einer progressiven sekundaren Mikrozephalie manifestiert. Wir berichten uber ein 3 1/2 Monate altes Madchen, bei dem die Diagnose PCH2 aufgrund der Klinik und den charakteristischen MRT-Veranderungen gestellt und molekulargenetisch gesichert wurde.

Das Lungenkarzinom ist eine der haufigsten Krebserkrankungen und die haufigste Krebstodesursache. Mit der Einfuhrung innovativer Substanzen ist die Moglichkeit einer individualisierten Therapie gegeben, die eine Verbesserung von Prognose und Lebensqualitat verspricht. Die Wirksamkeit dieser Therapeutika basiert auf spezifischen molekularen Eigenschaften des Lungenkarzinoms und stellt neue Anforderungen an die pathohistologische Diagnostik. Neben dem Histotyp haben sich molekulare Alterationen, insbesondere EGFR-Mutationen, als pradiktive Marker erwiesen. Die histologische Typisierung umfasst daher nicht nur die Unterscheidung von SCLC und NSCLC, sondern die Subtypisierung der NSCLC unter Einbezug immunhistologischer und molekularer Untersuchungen. Zusammenfassend werden Kriterien und Neuerungen der pathohistologischen Begutachtung des Lungenkarzinoms unter Berucksichtigung von TNM-Klassifikation, Grading, Tumorregression, immunhistologischen Expressionsmustern, Mutationsanalysen und der Einteilung neuroendokriner Tumoren dargestellt. Erganzend werden die Kernpunkte der neuen interdisziplinaren Konsensusklassifikation zur Klassifikation des Adenokarzinoms vorgestellt.

ZusammenfassungDie bipolare Erkrankung ist eine sowohl in der Allgemeinbevölkerung als auch in klinischen Populationen häufig vorkommende Erkrankung. Dennoch bleiben mehr als 50% der bipolaren Patienten länger als fünf Jahre nach Auftreten der ersten Symptome unbehandelt, 36% sogar länger als zehn Jahre. Bei 73% der Patienten mit einer bipolaren Erkrankung wird initial eine andere psychiatrische Diagnose gestellt. Im Durchschnitt vergehen acht Jahre zwischen dem Auftreten der ersten Symptome und der Diagnose. Den Patienten geht dadurch wertvolle Zeit bis zum Beginn einer störungsspezifischen Therapie verloren. Bei Auftreten der Erkrankung in der Adoleszenz vergeht noch mehr Zeit, bis die zutreffende Diagnose gestellt wird. Im nachfolgenden Beitrag werden Diagnostik und Differenzialdiagnostik der bipolaren Störung unter besonderer Berücksichtigung klinischer Alltagsfragen dargestellt.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Background Respiratory infection and failure is a commonly encountered problem in intensive care unit (ICU) patients. However, despite the accumulating body of evidence to suggest that herpes simplex virus type 1 (HSV-1) is associated with pneumonia, the exact role played by this virus in this process is still not fully understood. Therefore, to identify patients at risk, we have conducted a case–control study to characterize patients with HSV-1-positive pneumonia. Patients and methods Between 2007 and 2009, all patients with suspected viral pneumonia were tested for the presence of herpes viruses using a PCR assay approach with respiratory specimens. To identify possible associations, risk factors, and impact of HSV, HSV-1-positive ICU patients (n = 51) were compared to age-, gender-, and department- and season-matched HSV-negative patients (n = 52). Results HSV-positive patients differed significantly from the HSV-negative ones only in terms of time of mechanical ventilation (13 vs. 6 days, respectively; p = 0.002). Subgroup analysis in the patients aged >60 years and in those without bacterial detection revealed a similar trend (p = 0.01 and p = 0.004, respectively). Mortality did not differ between the groups or between the HSV-1-positive patients treated with aciclovir and those who were not. A viral load >10E+05 geq/ml was associated with mechanical ventilation (20/21 vs. 17/29; p = 0.004), acute respiratory distress syndrome (ARDS; 19/21 vs. 18/29; p = 0.005), sepsis (18/21 vs. 14/29; p = 0.008), detection of a bacterial pathogen in the same specimen (10/21 vs. 4/29; p = 0.01) and longer ICU stay (25 vs. 30 days; p = 0.04). Conclusion Despite several associations with high viral load, the clinical outcome of HSV-1-positive ICU patients did not differ significantly from the clinical outcome of HSV-negative patients. This finding indicates that HSV-1 viral loads in respiratory specimens are a symptom of a clinically poor condition rather than a cause of it. Longitudinal and therapy studies are therefore needed to distinguish between HSV-1 as a causative pathogen and HSV-1 as a bystander of pneumonia/ARDS.

PURPOSE: The study was performed to evaluate an intensified breast cancer screening program for women at risk of familial breast cancer. MATERIAL UND METHODS: 157 women were included in the study. Criteria for inclusion were: proven mutation of the BRCA 1-gene (n = 33), BRCA 2-gene (n = 14), heterozygous risk of ≥ 20 % or lifetime risk for developing breast cancer of ≥ 30 % (n = 110). Results were evaluated separately for healthy women and women with a history of breast or ovarian cancer. The study protocol consisted of 6-monthly clinical examinations as well as ultrasound and yearly mammography and MR-mammography. RESULTS: 12 women were diagnosed with breast cancer during the observation period (1. 11. 1999-31. 10. 2007); 75 % of the carcinomas were pT1-lesions, 89 % were pN0-lesions. The sensitivity of clinical examination was 25 % (mammography 27 %, ultrasound 58 %, MR-mammography 100 %). The positive predictive value was 75, 38, 50 and 60 % and specificity was 99,8, 99,6, 99,0, 97,6 %, respectively. These data are in accordance with the results of other national and international studies. The detection rate of carcinoma and positive predictive value were highest for carriers of BRCA 1-gene mutations. CONCLUSION: Based on the published data, implementing intensified screening programs for women at risk of familial breast cancer leads to the detection of carcinoma at an early stage. MR-mammography was shown to be the most sensitive method with acceptable positive predictive value. Further studies need to be performed to determine the perfect interval between examinations.

Ein wesentliches Problem im Management von pulmonalen Infektionen ist, dass klinische Symptome wie Husten, Auswurf, Fieber und Dyspnoe nicht spezifisch sind fur eine exakte Diagnose „respiratorische Infektion“ und vor allem nicht fur die Notwendigkeit einer antibiotischen Therapie. Ein idealer Biomarker fur bakterielle pulmonale Infektionen sollte eine fruhzeitige Diagnose ermoglichen, einen prognostischen Wert haben und therapeutische Entscheidungen erleichtern. Die beiden klinisch verwendeten Biomarker sind das C-reaktive Protein (CRP) und das Procalcitonin (PCT). Das CRP ist sehr unspezifisch und sowohl bei bakteriellen und viralen Infektionen erhoht. PCT ist aktuell der einzige Biomarker, der fur bakterielle pulmonale Infektionen spezifisch genug ist. In mehreren Interventionsstudien konnte nachgewiesen werden, dass durch eine PCT-Steuerung Haufigkeit und Dauer einer antibiotischen Therapie signifikant reduziert werden konnen bei gleicher klinischer Heilungsrate.

History and clinical findings A 73-year-old woman in renal failure for the past 22 years had been on haemodialysis for 16 years. Because of hyperphosphataemia and peptic ulcers she had been on aluminium-containing antacids with a total intake over time of about 8 kg "pure" aluminium. Over the past 11 years she had biphasic symptoms of death anxieties and depression. She also had amnesic aphasia and some extrapyramidal symptoms as well as generalized convulsive seizures and recurrent falls. Investigations Cranial computed tomography merely revealed signs of a microangiopathy and an age-related decrease in brain volume. The EEG showed intermittent changes while the CSF and ECG were unremarkable. There was no benzodiazepine or ethanol in the blood. Treatment and course After excluding stroke with secondary epilepsy, uraemic encephalopathy was assumed to be the cause of the severe organic psychiatric syndrome. In the last few days before her death the patient had disturbance of consciousness and of breathing. She died during grotesque tossing movements, thought to be due to a brain stem stroke. Autopsy revealed high-grade myocardial hypertrophy caused by the hypertension, contracted kidney of vascular cause, hyperplasia of the parathyroid and calcification of the renal parenchyma as a sign of secondary parathyroidism. The CNS showed severe dialysis-associated encephalopathy with characteristic argyrophilic, aluminium-induced lysosomal intracytoplasmic inclusions in the choroid plexus epithelium, cortical glia and numerous neuron populations. Laser microprobe mass analysis (LAMMA) confirmed manifold increase in subcellular aluminium content, especially in the neuronal cytoplasm, also demonstrated by atom absorption spectrometry. Additional distinct deposition of beta A4-amyloid, typical of Alzheimer's disease, was probably age-related rather than associated with the dialysis and the aluminium uptake. Conclusion Dialysis-associated encephalopathy must be taken into account as a possible cause of aetiologically uncertain neuropsychiatric symptoms in patients on chronic haemodialysis.

History and admission findings A 75-year-old woman was admitted because of weakness and paraesthesias in both legs. 15 years earlier a chest radiogram had shown numerous round foci of uncertain cause. Physical examination confirmed muscular weakness in all limbs, especially the legs, as well as abnormal superficial and deep sensory perception. Investigations Electromyography registered a patchy pattern of intentional muscular activity and marked denervation activity but largely normal nerve conduction. There was no evidence of inflammatory disease in the laboratory tests, including the CNS. DIAGNOSIS, COURSE AND TREATMENT: The neurological findings indicated progressive axonal sensorimotor polyneuropathy. A paraneoplastic cause was suspected, but search for a primary tumour was unsuccessful. The patient developed a urinary infection from which she died in septic shock. A carcinoid-like well-differentiated carcinoma of the breast with hematogenous metastases to liver, spleen and lung was discovered at autopsy. It also revealed severe systemic AA-type amyloidosis, involving liver, spleen heart and kidneys. In addition there was a severe progressive axonal neuropathy and marked neurogenic atrophy of the peripheral skeletal musculature. No amyloid deposition was seen. Conclusion In case of amyloidosis and polyneuropathy of uncertain cause a paraneoplastic pathogenesis should be considered in the differential diagnosis, even in the absence of proven malignancy.

The aim of the present study was to investigate the prognostic value, in patients with community-acquired pneumonia (CAP), of procalcitonin (PCT) compared with the established inflammatory markers C-reactive protein (CRP) and leukocyte (WBC) count alone or in combination with the CRB-65 (confusion, respiratory rateor=30 breaths x min(-1), low blood pressure (systolic value90 mmHg or diastolic valueor=60 mmHg) and ageor=65 yrs) score. In total, 1,671 patients with proven CAP were enrolled in the study. PCT, CRP, WBC and CRB-65 score were all determined on admission and patients were followed-up for 28 days for survival. In contrast to CRP and WBC, PCT levels markedly increased with the severity of CAP, as measured by the CRB-65 score. In 70 patients who died during follow-up, PCT levels on admission were significantly higher compared with levels in survivors. In receiver operating characteristic analysis for survival, the area under the curve (95% confidence interval) for PCT and CRB-65 was comparable (0.80 (0.75-0.84) versus 0.79 (0.74-0.84)), but each significantly higher compared with CRP (0.62 (0.54-0.68)) and WBC (0.61 (0.54-0.68)). PCT identified low-risk patients across CRB classes 0-4. In conclusion, procalcitonin levels on admission predict the severity and outcome of community-acquired pneumonia with a similar prognostic accuracy as the CRB-65 score and a higher prognostic accuracy compared with C-reactive protein and leukocyte count. Procalcitonin levels can provide independent identification of patients at low risk of death within CRB-65 (confusion, respiratory rateor=30 breaths x min(-1), low blood pressure (systolic value90 mmHg or diastolic valueor=60 mmHg) and ageor=65 yrs) risk classes.

PURPOSE: To assess interobserver agreement (IOA) in the diagnosis of pulmonary infiltrates on chest X-rays for patients with community-acquired pneumonia (CAP). MATERIALS AND METHODS: From 7/2002 to 12/2005, 806 adults with CAP were included in the multicenter study “CAPNETZ” (7 hospitals). Inclusion criteria were clinical signs of pneumonia and pulmonary opacification on chest X-rays. Each X-ray was reevaluated by two radiologists from the university hospital in consensus reading against the interpreter at the referring hospital in regard to: presence of infiltrate (yes/no/equivocal), transparency (≤/> 50 %), localization, and pattern of infiltrates (alveolar/interstitial). The following parameters were documented: digital or film radiography, hospitalization, fever, findings of auscultation, microbiological findings. RESULTS: The overall IOA concerning the detection of infiltrates was 77.7 % (n = 626; CI 0.75 - 0.81), the infiltrates were not verified in 16.4 % (n = 132) by the referring radiologist with equivocal findings in 5.9 % (n = 48). The IOA of the different clinical centers varied between 63.2 % (n = 38, CI 0.48 - 0.78) and 92.3 % (n = 65, CI 0.86 - 0.99). The IOA for the diagnosis of infiltrates was significantly higher for inpatients with 82.6 % (n = 546; CI 0.80 - 0.85) than for outpatients with 55.2 % (n = 80; CI 0.47 - 0.63), p 50 % was 95.1 % (n = 215; CI 0.92 - 0.98) versus 80.4 % (n = 403; CI 0.77 - 0.84) for infiltrates with a transparency > 50 % (p < 0.0001). In patients with positive auscultation, the IOA was higher (p = 0,034). Chest X-rays of patients with antibiotic therapy or an alveolar infiltrate showed more equivocal findings compared to patients without these features. CONCLUSION: There is considerable interobserver variability in the diagnosis of pulmonary infiltrates on chest radiographs. The IOA is higher in more opaque infiltrates, positive auscultation and inpatients.

Affective mixed states in bipolar disorders are a current matter of scientific debate and represent a complex clinical picture with coexisting manic and depressive symptoms. Treatment of mixed states is regarded as an important challenge. As diagnostic uncertainties complicate systematic clinical evaluations of this patient group, generally accepted clinical treatment guidelines are lacking yet. In this review the significance as well as the problems and risks of new treatment options are discussed.

Freehand positioning of the femoral drill guide is difficult during hip resurfacing and the surgeon is often unsure of the implant position achieved peroperatively. The purpose of this study was to find out whether, by using a navigation system, acetabular and femoral component positioning could be made easier and more precise. Eighteen patients operated on by the same surgeon were matched by sex, age, BMI, diagnosis and ASA score (nine patients with computer assistance, nine with the regular ancillary). Pre-operative planning was done on standard AP and axial radiographs with CT scan views for the computer-assisted operations. The final position of implants was evaluated by the same radiographs for all patients. The follow-up was at least 1 year. No difference between both groups in terms of femoral component position was observed (p > 0.05). There was also no difference in femoral notching. A trend for a better cup position was observed for the navigated hips, especially for cup anteversion. There was no additional operating time for the navigated hips. Hip navigation for resurfacing surgery may allow improved visualisation and hip implant positioning, but its advantage probably will be more obvious with mini-incisions than with regular incision surgery.

Summary We report a case of cutaneous alternariosis in a 69-year-old male patient. During hospitalization for treatment of the skin disorder, acute myeloid leukaemia was diagnosed. He received multiple chemotherapeutic agents but the leukaemia remained refractory to therapy and the patient died. The clinical picture, diagnosis and treatment of cutaneous alternariosis will be discussed and a review of the literature regarding patients with haematological diseases will be given. Zusammenfassung Wir berichten ubet einen Fall einer kutanen Alternariose bei einem 69-jahrigen mannlichen Patienten. Wahrend seines stationaren Aufenthaltes zur Behandlung seiner Hauterkrankung, wurde eine akute myeloische Leukamie diagnostiziert. Er erhielt Polychemotherapie, aber die Leukamie blieb therapierefraktar, und der Patient verstarb. Das klinische Bild, die Diagnose und die Behandlung der kutanen Alternariose wird besprochen und ein Review der Literatur wird beigefugt uber Alternariosen bei hamatologischen Erkrankungen.

Summary Background : Mutations within the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease. Aims : To investigate the clinical impact of the three common NOD2/CARD15 mutations in patients with Crohn's disease. Methods : We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 3020insC) in 180 patients with Crohn's disease, 70 patients with ulcerative colitis and 97 controls. In patients with Crohn's disease, prevalence of NOD2/CARD15 mutations were correlated to clinical and demographical parameters. Results : In Crohn's disease patients, 35.6% carried at least one mutant allele of NOD2/CARD15 mutations compared with 14.3% of patients with ulcerative colitis (P = 0.006) and to 15.5% of controls (P = 0.0001). Genotype phenotype analyses revealed that NOD2/CARD15 mutations determined younger age at disease diagnosis (P = 0.03), ileal disease location (P = 0.01) and ileocecal resections (P = 0.0002). Interestingly, reoperation with resection of the anastomosis was significantly more frequent in patients with NOD2/CARD15 mutations (P = 0.01). Conclusions : Our investigations support the current hypothesis that NOD2/CARD15 mutations are associated with a phenotype of Crohn's disease with younger age at diagnosis, ileal involvement, ileocecal resections and a high risk of postoperative relapse and reoperation. NOD2/CARD15 mutations might therefore be used to identify high risk patients for relapse prevention strategies.

Chlamydia pneumoniae, a major cause of community-acquired pneumonia, primarily infects the respiratory tract. Chronic infection of nonrespiratory sites, such as the vascular wall, the brain or blood monocytes, requires evasion from the lungs and spreading via the bloodstream. The cell types involved in dissemination are insufficiently characterised. In this study, New Zealand White rabbits were infected intratracheally with C. pneumoniae, and lung manifestation and systemic dissemination were monitored by polymerase chain reaction and immunohistochemistry. Infection of the lungs was characterised by an early phase dominated by granulocytes and a late phase dominated by alveolar macrophages (AM). Granulocytes, AM and alveolar epithelial cells acted as host cells for chlamydiae, which remained detectable for up to 8 weeks. AM transported the pathogen to the peribronchiolar lymphatic tissue, and subsequently C. pneumoniae entered the spleen and the aorta via dissemination by peripheral blood monocytes. In conclusion, Chlamydia pneumoniae-infected alveolar macrophages transmigrate through the mucosal barrier, and give the pathogen access to the lymphatic system and the systemic circulation. Infected peripheral blood monocytes are the vector system within the bloodstream and transmit the infection to the vascular wall. This is the first description of granulocytes acting as a reservoir for Chlamydia pneumoniae early in infection.

The transmembrane HER-2 receptor is 185 kD of molecular weight and is encoded by the proto oncogene HER-2 on the long arm of chromosome 17 (17 q 12-21). Over-expression of HER-2 is found in about one third of all breast carcinomas. Determining the HER-2 status is a prerequisite for the use of the monoclonal antibody trastuzumab (Herceptin) in the therapy of metastatic breast cancer. Various test assays for HER-2 either on the protein level (immunhistochemistry [IHC], enzyme-linked immunosorbent assay [ELISA], western blot) or on the gene level (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], polymerase chain reaction [PCR], and southern blot) are available. However, IHC and FISH are most often applied. For routine HER-2 testing a combination of both methods is recommended. IHC should be used for screening, followed by FISH only in those cases scored as 2 + by the HercepTest. In future, CISH may represent a useful alternative to FISH. In CISH fluorescent dyes are replaced by chromogenes, facilitating the use of light microscopes and the filing of slides. Quantitative analysis of the shed extracellular domain of HER-2 (HER-2 ECD) in the patients' serum by ELISA is helpful for clinical use. With HER-2 ECD as a surrogate marker of the tumor volume monitoring of adjuvant therapies and tumor recurrence would be feasible. However, more prospective studies with higher numbers of patients are required for validation of these new methods.

Lactose intolerance with adult-onset is due to the inadequate enzymatic activity of lactasephlorizin hydrolase (LPH). It is frequently seen in patients with Crohn disease, but the mechanism remains to be elucidated. Two DNA genotypes, C/C(-13910) and G/G(-22018), located upstream from the LCT locus, the gene encoding for LPH, were recently identified as representing genetic markers for lactose intolerance. We utilized these two DNA genotypes to study their role in inflammatory bowel disease.We investigated the prevalence of these two DNA variants using specific restriction enzyme digest assays in 166 patients with Crohn disease, in 120 healthy first-degree relatives of Crohn disease patients, in 63 patients with ulcerative colitis and in 187 healthy individuals.The analysis revealed a frequency of 21.4% of the 2 genotypes for adult-type hypolactasia in our studied German cohort of healthy individuals, which is higher than previously reported (15%) based on the hydrogen (H2) breath test. This might indicate a higher sensitivity of genotyping, but it has to be confirmed in larger cohorts. No significant difference was detectable in the frequency of the C/C(-13910) and G/G(-22018) genotypes in patients with Crohn disease (C/C(-13910): 21.7%; G/G(-22018): 22.3%) compared to first-degree relatives (C/C(-13910): 21.7%; G/G(-22018): 20.8%), patients with ulcerative colitis (C/C(-13910): 20.3%; G/G(-22018): 20.3%) and healthy individuals (C/C(-13910): 21.4%; G/G(-22018): 21.4%).The C/C(-13910) and G/G(-22018) genotype of adult-type hypolactasia is not associated with susceptibility to the pathogenesis of Crohn disease and ulcerative colitis.

Recurrent focal myositis is a rare entity and can be difficult to diagnose and treat. A long-term follow-up and diagnostic evaluation was carried out in a patient who presented with ankle stiffness secondary to a painful mass within the calf. This process was diagnosed as focal myositis of the peroneal muscles, which recurred over a period of 7 yr. A review of the literature regarding focal myositis, treatment options and a successful conservative therapy regimen, as an alternative to a surgical protocol, are presented. After making the diagnosis with the help of a muscle biopsy, long-term therapy should be considered. Conservative treatment of focal myositis with anti-inflammatory drugs and physical therapy can be successful but recurrence may occur if the medical treatment is interrupted.

The broadening of the classification systems for manic-depressive illness towards a spectrum of bipolar disorders implicates a more differentiated use of pharmacotherapies. However, many questions still remain open. This implies that all consensus guidelines and recommendations have to be considered as preliminary. On the other hand, research in the last decade has developed many new treatment alternatives, both for mood stabilizers and antidepressants as well as antipsychotics. These recommendations, which have been developed in the process of two consensus meetings, try to consider the broadening of the concept of bipolar disorder by differentiating between subgroups according to acute symptomatology and characteristics of the long-term course, e.g., rapid cycling. In particular, the emerging role and new indications of mood stabilizing antiepileptic drugs, atypical antipsychotics, and new antidepressants will be discussed.

Background and purpose Multiple structural white matter abnormalities have been described in patients with juvenile myoclonic epilepsy (JME). In the present study, the question of whether microstructural variations exist between the two subgroups of JME, with and without photoparoxysmal responses (PPR positive and negative), was addressed using diffusion tensor imaging. Methods A selection of 18 patients (eight PPR positive) from a tertiary epilepsy center diagnosed with JME and 27 healthy controls was studied. The following regions of interest were investigated: the ascending reticular activating system, lateral geniculate nucleus, genu of the internal capsule, ventromedial thalamus and inferior cerebellar peduncle. Results Widespread white matter microstructural abnormalities in JME and in particular in PPR positive cases were identified. PPR positive patients demonstrated increased fractional anisotropy in the ascending reticular activating system and ventromedial thalamus compared to PPR negative patients and healthy controls. Reduced fractional anisotropy of the lateral geniculate nucleus was observed in the entire JME group compared to healthy controls. Conclusions Several microstructural variations between PPR positive and negative JME patients have been identified. Our findings highlight the pivotal role of the thalamus in the pathophysiology of primary generalized seizures and suggest that thalamo-premotor connections are both an essential part of epileptic networks and important in the pathogenesis of photosensitivity.

Background Betulinic acid and other triterpenes have shown strong antitumour activity in vitro and in vivo. A triterpene extract of birch bark formed the base of Oleogel-S10 and allowed topical application. Two previous trials have shown efficacy and tolerability in the treatment of actinic keratoses (AKs) with betulin-based Oleogel-S10. Objectives To confirm the efficacy and tolerability/safety of Oleogel-S10 in the treatment of AKs in a multicentre placebo-controlled study. Methods Patients (n = 165) were treated topically for 3 months in a four-arm parallel study design, randomly allocated to A (n = 53) Oleogel-S10 once daily, B (n = 51) Oleogel-S10 twice daily, or C (n = 25) or D (n = 28) placebo (petroleum jelly) once or twice daily, respectively. Clinical efficacy in this double-blind study was assessed by the investigators. Final and baseline biopsies were evaluated by central histopathology. Results Complete clearance of the target lesions was seen in 4% of patients in group A and 7% in group B, but not in the placebo groups. A clearance rate of > 75% was seen for 15% and 18% of patients in groups A and B, respectively, and for 13% in the placebo groups. These differences were not statistically significant. Histopathologically, 43·9% of patients showed a downgrading or clearance of the marker AK with no significant differences between the groups. Treatment with Oleogel-S10 was well tolerated. The tolerability as assessed by the investigator was mostly 'very good' (78·8%), followed by 'good' (18·2%) and only 1·2% assessed it as 'intolerable'. Patient-assessed tolerability was graded mostly 'very good' (56·4%) or 'good' (34·5%). Conclusions Treatment with Oleogel-S10 was well tolerated during a treatment period of 3 months, yet was no better than placebo in terms of efficacy in the treatment of AKs. What's already known about this topic? Previous single open-label trials have shown activity for Oleogel-S10 in actinic keratoses, with a clearance of > 75% of the lesions in 79% and 86% of patients. What does this study add? In this multicentre randomized double-blind trial Oleogel-S10 was highly tolerable but could not demonstrate superiority over placebo treatment.

Ultrasonography of a six-year-old Simmental cow revealed an abscess like structure, approximately 15 cm in diameter, in place of the right kidney. The cow had a history of colic for 4 days and was referred to our clinic with a tentative diagnosis of caecal dilatation. The cow voided dark opaque urine with white floccules. Laboratory examination yielded increased haematocrit, leukocytosis with left shift, hyperbilirubinaemia and azotaemia. The diagnosis was confirmed, the caecum emptied surgically and the pus-filled structure at the site of the right kidney removed. A diagnosis of pyonephrosis was made after pathological examination of the pus-filled structure.

Anxiety occurs frequently in patients who are on the waiting-list for a lung-transplantation or have already been transplanted. In this context anxiety is a theme of every interaction of doctor and patient but often remains unrecognized because it hides behind bodily symptoms and mechanisms of defense. Anxiety affects patients' behavior and compliance and may afflict - especially if not recognized - doctors' decisions and thus patients' health and survival. It is therefore necessary to recognize and to openly handle anxiety in the interaction of doctor and patient.

Beside its role in calcium homeostasis, 1,25-D3 modulates multiple immunological functions in cells of the immune system. In tubular epithelial cells, it increases the expression of HLA-DR and ICAM-1 molecules. Since production of chemokines, such as IL-8 and MCP-1, by tubular epithelial cells is crucial for the inflammatory response in acute transplant rejection and interstitial nephritis, we tested whether 1,25-D3 influences the production of IL-8 and MCP-1 by primary human tubular epithelial cells (TEC). For chemokine detection we used enzyme-linked immunosorbent assays. We differentiated between chemokine secretion directed to the apical and basolateral environment by using cell culture inserts as a model for the tubular basement membrane. mRNA of IL-8 and MCP-1 after stimulation of TEC with IL-1α and/or 1,25-D3 was isolated and compared by competitive RT-PCR. We found that basolateral production of IL-8 was higher than luminal secretion. 1,25-D3 (10–8M) alone and in combination with IL-1α suppressed IL-8 production after 48 h. Basolateral compared to luminal MCP-1 secretion was higher after stimulation either with IL-1α alone or combined with 1,25-D3. After 72 h, 1,25-D3 enhanced the IL-1α-stimulated MCP-1 secretion. Increased IL-8 mRNA expression after stimulation with IL-1α was suppressed by coincubation with 1,25-D3, while MCP-1 mRNA synthesis was enhanced by 1,25-D3 alone and in combination with IL-1 α . We conclude that 1,25-D3 differently modulates the expression of CXC-chemokine IL-8 and CC-chemokine MCP-1 by human TEC. The differential effects of 1,25-D3 on renal tubular cytokine secretion have to be considered in therapeutic dials on this hormone, e.g. in renal transplant rejection.

Purpose: To depict the central and peripheral pulmonary vessel anatomy with real-time radial MR scanning without respiratory control. Methods: Three healthy volunteers and one patient with pulmonary embolism proven by spiral CT angiography were studied with a 1.5 T MR imaging system. First, a breath-hold, contrast-enhanced MR angiography was performed for comparison of accuracy. Gradient echo images (T R 16 ms, T E 4 ms, flip angle 18°) were obtained applying a combination of radial scanning and the sliding window reconstruction technique. A dedicated backprojector allowed data reconstruction in real-time with a frame rate of 20 images per second. Scanning was performed during free breathing. Results : The described technique depicted the central and peripheral portions of the normal pulmonary anatomy with comparable image quality as the 3D contrast-enhanced angiography. Visualization of the pulmonary emboli as demonstrated by spiral CT was possible. Conclusion: Real-time radial scanning allows promising image acquisition of the pulmonary vasculature without respiratory control. Further technical improvements and clinical trials are required to evaluate its role in the diagnosis of vascular pathologies.

Objective: Tamoxifen may be responsible for an increased incidence of secondary endometrial cancer in postmenopausal women with breast cancer. The objective of this study was to determine the prevalence of endometrial hyperplasia and neoplasia in postmenopausal women with breast cancer before adjuvant treatment with tamoxifen. Methods: Over a 30-month period 55 postmenopausal women undergoing primary treatment for breast cancer underwent uterine curettage as well as preoperative transvaginal and color Doppler sonography. Results: Three patients (5.5%) had invasive endometrial carcinoma accompanied by atypical hyperplasia. All three of these patients had abnormal sonographic findings. Four patients had endometrial hyperplasia without atypia (three'simple, one complex, three with a polyp). 48 patients (87%) had normal endometrial findings; seven of these patients had an endometrial polyp). Thirty-nine patients (71 %) went on to receive tamoxifen. Conclusions: The increased incidence of endometrial carcinoma in breast cancer patients receiving tamoxifen may be due to a higher incidence of preexistent endometrial hyperplasia or neoplasia. We recommend routine sonographic evaluation of the endometrium in breast cancer patients and histologic evaluation in those with abnormal sonographic findings.

Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs 24.5) and for ovarian cancer (20 vs 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast–ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers (standardized incidence ratio 2.5; 95% CI 0.5–7.4) and especially brothers (29; 7.7–74), although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer. © 1999 Cancer Research Campaign