KMT1E-mediated chromatin modifications at the FcγRIIb promoter regulate thymocyte development.

This work examines the role the lysine methyltransferase KMT1E (Setdb1) in thymocyte development. We have developed and described a T cell-specific conditional knockout of Setdb1. A partial block was seen at the double-positive to single-positive transition, causing reduced numbers of single-positive T cells in the thymus and periphery. Knockout thymocytes had reduced numbers of CD69(+) and T-cell receptor TCRß(+) cells and increased numbers of apoptotic cells in the double-positive compartment, suggesting an alteration in the selection process. Transcriptional profiling of thymocytes revealed that Setdb1 deletion derepresses expression of FcγRIIb, the inhibitory Fc receptor. We demonstrate that a KMT1E-containing complex directly interacts with the FcγRIIb promoter and that histone H3 at lysine 9 tri-methylation at this promoter is dependent on Setdb1 expression. Derepression of FcγRIIb causes exacerbated signaling through the TCR complex, with specifically increased phosphorylation of ZAP70, affecting selection. This work identifies KMT1E as a novel repressor of FcγRIIb and identifies an underappreciated role of FcγRIIb in fine tuning thymocyte development.

Interdisciplinary clinical management of high grade arteriovenous malformations and ruptured flow-related aneurysms in the posterior fossa.

Posterior fossa arteriovenous malformations are rare entities and treatment modalities technically challenging. In recent years new therapeutic options have emerged through microsurgical and endovascular means. Based on a series of six cases we describe combined interdisciplinary treatment strategies and report the outcome in a midterm follow-up interval of 12 months. Clinical case data were collected during acute phase and follow-up including standardized angiographic control intervals during follow-up and assessment of the outcome. Treatment options included endovascular techniques as well as microsurgical techniques. All reported cases had SAH based on ruptured flow-related aneurysms in posterior fossa AVM; three out of six had multiple aneurysms. In one case we observed a de novo formation of two flow-associated distal aneurysms in an interval of ten years. Two patients were treated only endovascularly, one patient only surgically and three patients with combined methods. Five out of six patients had a good outcome (GOS 4 or 5). One died in the acute phase. Infratentorial AVMs are rare but characterized by a high risk of rupture and SAH, especially in conjunction with flow related aneurysms, which are predictors of poor outcome. The anatomic conditions of the posterior fossa may lead quickly to life-threatening complications due to mass effects. The present study indicates that treatment strategies in the acute phase should focus on flow-related aneurysms, followed by an elective AVM embolization and ectomy whenever possible. An experienced interdisciplinary team and the combination of techniques contribute to a reduction of complications and to a better outcome.

Migraine and delayed ischaemic neurological deficit after subarachnoid haemorrhage in women: a case-control study.

The aim of the present case-control study was to investigate the role of migraine as a potential risk factor for a delayed ischaemic neurological deficit (DIND) after subarachnoid haemorrhage (SAH). A telephone interview was performed in patients or their relatives to determine the prevalence of migraine. Thirty-six women aged <60 years had SAH with Hunt & Hess grade I-III and DIND (group A). This group was compared with an age-matched group of 36 female SAH patients, Hunt & Hess grade I-III without DIND (group B). The two populations were also characterized regarding hypertension, smoking, diabetes mellitus and alcohol use. A significant difference was only found for the prevalence of migraine with 47% in group A and 25% in group B (P < 0.05; odds ratio: 2.68, confidence interval: 0.99-7.29). Migraineurs revealed similar prevalences of risk factors independently of the presence of DINDs. This retrospective study suggests that women with migraine have a higher risk to develop a DIND than women without migraine.

Intracranial tuberculomas mimicking a malignant disease in an immunocompetent patient.

We present the unusual occurrence of multiple systemic and two central nervous system tuberculomas in an immunocompetent young patient. A large left frontal epidural tuberculoma with transcalvarian extension was removed surgically and chemotherapy was initiated. The patient remained on a chemotherapy with INH, RMP, and EMB and was followed clinically and with MRI scans for 24 months. Findings. The clinical presentation and neuroimaging studies initially suggested malignant disease. Surgical resection of the left frontal lesion was required to relieve the mass effect. The histological evaluation showed a granulomatous inflammation with epithelial and Langhans giant cells, but no acid-fast bacilli. Cultures of the specimens yielded a mixed infection with Corynebacterium species and Staphylococcus epidermidis. Based on the histological findings, chemotherapy for tuberculosis was initiated. Subsequently, Mycobacterium tuberculosis was cultured from the surgical specimen and sputum. Interpretation. Parenchymal CNS tuberculosis with or without extracerebral manifestations may present as a space-occupying lesion. Because a tuberculoma is rarely suspected especially if there is atypical morphology, biopsy is required to establish the diagnosis and expedite specific treatment.

Head injury by gunshots from blank cartridges.

BACKGROUND: Blank cartridge handguns are generally underestimated in their capacity to inflict serious and potentially life threatening injuries. The predominant reasons for these injuries are suicide or suicide attempts, followed by accidental injuries. METHODS: A series of 26 gas gunshots to the neurocranium is presented. The injury pattern relevant to neurosurgical practice is illustrated in a case summary of 7 selected cases and the clinical courses as well as outcomes are presented. RESULTS: The injury pattern demonstrates that the energy density of the gas jet and the high temperatures of the exploding gas volume cause extensive soft tissue injuries. In close-range shots the gas jet takes on physical properties of a projectile. In these injuries impression fractures and dislocation of bone fragments are common. CONCLUSIONS: Gas handguns, contrary to public opinion, are dangerous weapons and may inflict potentially fatal injuries to the neurocranium when fired at close range. These weapons are frequently used in criminal or careless activities predominantly by young males. Extensive CNS injuries including hematomas, subarachnoid hemorrhage, foreign body contamination, and increased intracranial pressure are frequently observed.

Ultrasound-guided surgery of deep seated brain lesions.

OBJECTIVE: Computer aided navigation systems have been introduced to optimize the neurosurgical strategies minimizing the damage to the healthy brain tissue. As the loss of cerebrospinal fluid and surgical manipulation alter the position of the lesion in the external reference system, there is a risk of being misguided to deep seated brain tumors. In this context we present our experiences with intraoperative ultrasound which represents a real-time navigation system. PATIENTS AND METHODS: 45 patients with subcortical intracerebral lesions were operated on with the support of ultrasound imaging. Tumor depth from the surface measured 5 (superficial) to 68 mm. The minimum size of a cavernoma was 8 mm. Histopathological diagnoses included 17 cavernomas, 12 metastases and 16 gliomas. Ultrasound localization was achieved by two perpendicular projections and the surgical trajectory of the lesion secured by catheter placement. RESULTS: Intraoperative ultrasound allowed an easy identification of all brain lesions. Additionally, a reliable localization of the tumor margins, including gliomas and metastases, was reached in 23 of 28 (82%) cases. The remaining 17 cavernomas were located all by intraoperative ultrasound, even the deep seated brain lesions of less than 10 mm in diameter could be easily detected. The real-time mode enabled a control of the surgical procedure. Technical problems arose from irregular and vaulted cortex surface, head positioning and surgical manipulation causing air artefacts with distal reduction of the signal intensity. CONCLUSION: Intraoperative ultrasound is a reliable intraoperative guidance tool in the localization of deep seated brain tumors because it operates in real-time, thus increasing the safety of the surgical procedure and of the tumor resection.

GTP bound to chloroplast thylakoid membranes is required for light-induced, multienzyme degradation of the photosystem II D1 protein.

Even though light is the driving force in photosynthesis, it also can be harmful to plants. The water-splitting photosystem II is the main target for this light stress, leading to inactivation of photosynthetic electron transport and photooxidative damage to its reaction center. The plant survives through an intricate repair mechanism involving proteolytic degradation and replacement of the photodamaged reaction center D1 protein. Based on experiments with isolated chloroplast thylakoid membranes and photosystem II core complexes, we report several aspects concerning the rapid turnover of the D1 protein. (i) The primary cleavage step is a GTP-dependent process, leading to accumulation of a 23-kDa N-terminal fragment. (ii) Proteolysis of the D1 protein is inhibited below basal levels by nonhydrolyzable GTP analogues and apyrase treatment, indicating the existence of endogenous GTP tightly bound to the thylakoid membrane. This possibility was corroborated by binding studies. (iii) The proteolysis of the 23-kDa primary degradation fragment (but not of the D1 protein) is an ATP- and zinc-dependent process. (iv) D1 protein degradation is a multienzyme event involving a strategic (primary) protease and a cleaning-up (secondary) protease. (v) The chloroplast FtsH protease is likely to be involved in the secondary degradation steps. Apart from its significance for understanding the repair of photoinhibition, the discovery of tightly bound GTP should have general implications for other regulatory reactions and signal transduction pathways associated with the photosynthetic membrane.

[Hypertension-induced organ damage]. / Hypertoniebedingte Organschäden.

Until now, an occasional blood pressure of below 140 mmHg systolic and less than 90 mmHg diastolic at rest has been regarded as normal. However, the most recent recommendations set the range for normotension lower: below 130/85 mmHg. Therapeutic targets will have to be adjusted accordingly. Raised diastolic and/or systolic blood pressure accelerates the process of arteriosclerosis and causes baromechanical effects. These result in disturbances of organ perfusion (brain, heart, kidney, peripheral organs) and left ventricular hypertrophy, cardiac failure, haemorrhagic insult and hypertensive encephalopathy. Echocardiography is particularly well suited for revealing and quantifying the results of hypertension at an early stage. Prompt, adequate antihypertensive therapy prevents or decreases hypertension-induced organ damage. Early diagnosis of hypertension and consistent blood pressure normalisation are, therefore, indispensable. The proportion of undiagnosed and inadequately treated hypertension patients is too high, in fact it is clearly increasing. The author presents specific proposals for improving antihypertensive treatment in order to reduce or prevent avoidable hypertension-induced organ damage. Above all, society must heighten its awareness of health and sharpen its own sense of responsibility.

Ganglioglioma of the neurohypophysis with secretion of vasopressin.

A patient with a ganglioglioma of the neurohypophysis developed the syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present the case and describe its microscopic and ultrastructural features. Malignant neoplasms were thought to be the main cause of ectopic production of vasopressin. Head trauma, infection, or drugs, however, can also induce hypersecretion of vasopressin. Mechanical compression of the pituitary stalk can lead to an excessive antidiuretic hormone (ADH) release by affecting the inhibitory system. Primary neuroendocrine tumors of the hypothalamic-neurohypophyseal system are extremely rare. We demonstrate the presence of vasopressin in the tumor cells by immunocytochemistry. This represents the first case of SIADH caused by a tumor of the neurohypophysis.

Influence of sleep apnea on 24-hour blood pressure.

OBJECTIVE: To study the influence of obstructive sleep apnea (OSA) on 24-h BP. SETTING: Sleep laboratory of the Medical Department, Neukölln Hospital, Berlin, Germany. METHODS: In 93 subjects, noninvasive 24-h BP monitoring was performed with BP recordings made at 15-min intervals. Apnea severity was evaluated by means of a portable device that allows calculation of an oxygen desaturation index (ODI). A normal 24-h BP profile (dipping) was defined by a night/day BP ratio of 0.9. RESULTS: ODI was related to systolic and diastolic daytime (p<0.001) and nighttime BP (p<0.001) as well as systolic and diastolic BP night/day ratios (p<0.001). Multiple regression analysis showed that age and ODI were independently related to daytime BP. When subjects were grouped according to apnea severity, daytime BP increased as ODI increased: 127/80+/-10/11 mm Hg in habitual snorers (ODI 0 to 5), 135/87+/-15/9 mm Hg in mild OSA (ODI 6 to 30), and 140/90+/-13/10 mm Hg in severe OSA (ODI >30) (p values <0.05 for comparisons of OSA groups with habitual snorers). Compared to subjects with mild OSA or habitual snorers, BP night/day ratios were greater in patients with severe OSA (p values <0.05). Accordingly, hypertension and nondipping increased as ODI increased. CONCLUSION: OSA is associated with hypertension independent of the confounding factors of age and obesity. Nondipping is related to apnea severity. These alterations might contribute to the increased mortality in patients with severe OSA.

Structured patient education for out-patients with hypertension in general practice: a model project in Germany.

In a model project, office-based physicians in two regions of Germany provided a structured treatment and teaching programme for out-patients with hypertension. The project was carried out in co-operation with the German Hypertension League and designed to evaluate the practicability and efficacy of the implementation in routine primary health care. A total of 111 primary health care practices in two German districts who had participated in a training course were interviewed. In 43 of these offices documented data of all patients who had received the standardised treatment and teaching were evaluated. The programme was well received by the physicians of which 81% rated the training course and 93% the teaching material as 'very good' or 'good'. A total of 466 patients were trained. Data collected on 272 patients (22 weeks after the intervention) demonstrated the efficacy of the programme at treatment level: reduction of body weight (2 kg, P < 0.001) and blood pressure (from systolic 158+/-18 to 148+/-17 mm Hg, P < 0.001; diastolic 91 +/-9 to 86+/-9, P < 0.001). Sixty-five per cent of patients learned for the first time how to perform blood pressure self-monitoring during the programme. The number of blood pressure readings by the patients' increased significantly from 1+/-3 measurements per week before, to 8+/-7 measurements per week after the programme (P < 0.001). The results of the study demonstrate the practicability and efficacy of the implementation of the programme for patients with hypertension into routine primary health care.

Comparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertension.

The efficacy of spirapril, 6 mg once daily, was compared with enalapril, 5-20 mg once daily, in the control of mild-to-moderate hypertension in a placebo-controlled, parallel-group study. A total of 251 patients participated in the study, all of whom underwent a 4-week washout period on placebo. Thereafter, 100 patients were randomized to spirapril, 6 mg once daily, 101 patients to enalapril, 5-20 mg once daily, and 50 patients remained on placebo. Sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were measured at 2-weekly clinic visits. Blood pressure profiles during peak and trough plasma drug concentrations (2-4 hours and 24-26 hours postdose, respectively) were determined at baseline and 4 and 8 weeks after starting the double-blind phase. Compared with placebo, treatment with both spirapril and enalapril resulted in significant reductions (p < 0.001) in DBP and SBP. DBP was reduced to a greater extent with spirapril than with enalapril both at peak (-17.4 mmHg vs. -14.8 mmHg) and trough (-14.7 mmHg vs. -12.4 mmHg). Thus, although the trough/peak DBP ratios for spirapril and enalapril were very similar (84% vs. 82%), actual reductions in DBP were different. Spirapril and enalapril treatment resulted in similar reductions in SBP at both peak and trough levels. Both drugs were well tolerated, and there were very few adverse events or changes in hematological or biochemical parameters during the study. In conclusion, spirapril, 6 mg once daily, as the initial and maintenance dose, is at least as effective and well tolerated as enalapril individually titrated.

Monitoring antihypertensive therapy through blood pressure measurements taken casually, at rest, during exercise, and under outpatient conditions.

To ensure a high degree of patient compliance, and thus, therapeutic safety also, an antihypertensive agent should lower blood pressure for 24 h when taken once a day. A placebo-controlled investigation was carried out in 22 patients with essential arterial hypertension, to ascertain whether this was the case with once daily administration of ramipril. Blood pressure was measured at rest, during exercise, and under outpatient conditions (ambulant blood pressure measurement-ABPM). In our study, ramipril had an excellent 24-h effect and was found to be suitable for administration once a day. ABPM represents the most comprehensive and reliable means of monitoring antihypertensive treatment, particularly since it also provides data about nocturnal blood pressure behavior and additionally enables the most distinctive determination of the trough to peak-ratio.

Hypertension and obstructive sleep apnea. Ambulatory blood pressure monitoring before and with nCPAP-therapy.

We studied 24-h blood pressure (BP) in 17 hypertensive patients with polysomnographic verified moderate to severe obstructive sleep apnea (OSA) before, after 1-3 days and after 4-6 months of treatment with nasal continuous positive airway pressure (nCPAP). BP was recorded using an ambulatory blood pressure monitoring (ABPM) device with oscillometric measurement method (SpaceLabs 90207) over a period of 24 h with intervals of 15 min in daytime and nighttime. Hypertension was defined as mean BP in the daytime period > 135/85 mm Hg; OSA was diagnosed when a full night polysomnography indicated an apnea hypopnea index (AHI) > 10/h. Hypertensive systolic/diastolic daytime BP values decreased significantly from 144.8/94.4 mm Hg at baseline to 138.9/89.4 mm Hg after short-term, and to 136.4/86.9 mm Hg after long-term nCPAP-therapy. Nighttime BP values, too, were reduced significantly from 137.6/87.1 mm Hg at baseline to 129.9/82.3 mm Hg after short-term, and to 128.6/ 79.8 mm Hg after long-term therapy. In addition to these data the heart rate fell significantly from 82.5 b/min to 74.8 b/min after 4-6 months in daytime, and from 70.9 b/min to 63.6 b/min in nighttime. The beneficial effect on diurnal and nocturnal hypertension in patients with nCPAP-therapy of OSA suggests a causal relationship between systemic hypertension and obstructive sleep apnea.

Characterization of a virus variant produced by L cells persistently infected with lymphocytic choriomeningitis virus.

Continuous cultivation of murine L cells infected with lymphocytic choriomeningitis virus strain Armstrong leads to production of L(Arm) cells, which produce a predominantly cell-associated attenuated variant, the L(Arm) virus. The relatively few infectious particles that are released have lost the ability to form plaques on L cells and to cause illness in mice even if inoculated intracerebrally. Based on equal protein M(r)s, antigenicity and protein kinase activity, essentially identical results were obtained for the purified Armstrong and L(Arm) viruses. There was also no difference in production and release of particles with the potential to cause homologous interference. Such particles consisted of two types, one of which was highly susceptible to u.v.-irradiation, the other was highly resistant. In the case of the L(Arm) virus interfering particles, it appears that the u.v.-irradiation-susceptible forms represented infectious virus. Purified L(Arm) virus particles contained considerable quantities of subgenomic forms of (small) S- and (large) L-RNA and their complementary counterparts, which all appeared to be replicated autonomously in an unenriched manner.

[Therapy of arterial hypertension in the elderly. Characteristics of hypertension in aging--use of calcium antagonists]. / Therapie der arteriellen Hypertonie beim älteren Menschen. Besonderheiten der Hypertonie im Alter--Einsatz von Kalziumantagonisten.

In the elderly patient (from 60-65 years) elevated blood pressure (160/99 mmHg or more under conditions of rest) is a risk factor that requires treatment. This also applies to isolated systolic hypertension (systolic BP > or = 160 mmHg at a diastolic pressure < 90 mmHg). Individually tailored antihypertensive treatment can clearly improve the quality of life and prognosis of the elderly hypertensive. In view of the importance of increased peripheralvascular resistance, in the elderly patient, the anti-hypertensive concept should always include a vasodilator. This requirement makes calcium antagonists, in particular those of the dihydropyridine type, when they are well tolerated, highly suitable for treating hypertension in the elderly. An added advantage is the fact that there are virtually no major contraindications. In this connection, substances that exert a uniform effect over 24 hours should be given preference (advantages: single dosage, better tolerability). In addition, the dihydropyridines (calcium antagonists of the nifedipine type) can readily be together with other agents when combination treatment necessary.