[How many potential organ donors are there really? : Retrospective analysis of why determination of irreversible loss of brain function was not performed in deceased patients with relevant brain damage]. / Wie viele potenzielle Organspender gibt es wirklich? : Retrospektive Analyse zu nichterfolgter Diagnostik des irreversiblen Hirnfunktionsausfalls bei verstorbenen Patienten mit relevanter Hirnschädigung.

BACKGROUND: No systematic study has previously been undertaken in Germany to ascertain why irreversible brain death determination (BDD) has not been carried out. OBJECTIVE: A comprehensive analysis of reasons for unperformed BDD in deceased patients with acute, severe brain damage could improve the identification of potential organ donors. METHOD: Using the Transplantcheck program of the German Organ Transplantation Foundation (DSO) an analysis of the data from 2016 was undertaken in participating hospitals in Saxony, Saxony-Anhalt and Thuringia (Region East of the DSO), regarding why a BDD was not initiated in deceased patients with primary or secondary brain damage. RESULTS: In 128 of the 144 Region East hospitals, 7889 deceased patients with primary or secondary brain damage were detected. In 7389 patients a BDD was out of the question for a variety of reasons. In 232 patients organ donation was not considered due to an advance directive. In 195 cases treatment was limited based on the patient's infaust neurological prognosis without the possibility of organ donation being discussed with relatives. In 73 cases initiation of BDD was indicated but not performed. CONCLUSION: The number of potential organ donors in Region East of the DSO could be significantly increased by identifying patients where BDD is indicated. By consistent evaluation of patients' wills in terms of organ donation before treatment is withdrawn in patients with poor neurological prognosis, additional potential organ donors could be identified. Furthermore, involving neurointensive care physicians in the care of all patients with brain damage could improve the prognostic assessment.

Motor-cognitive dual-task performance: effects of a concurrent motor task on distinct components of visual processing capacity.

Dual tasking, or the simultaneous execution of two continuous tasks, is frequently associated with a performance decline that can be explained within a capacity sharing framework. In this study, we assessed the effects of a concurrent motor task on the efficiency of visual information uptake based on the 'theory of visual attention' (TVA). TVA provides parameter estimates reflecting distinct components of visual processing capacity: perceptual threshold, visual processing speed, and visual short-term memory (VSTM) storage capacity. Moreover, goodness-of-fit values and bootstrapping estimates were derived to test whether the TVA-model is validly applicable also under dual task conditions, and whether the robustness of parameter estimates is comparable in single- and dual-task conditions. 24 subjects of middle to higher age performed a continuous tapping task, and a visual processing task (whole report of briefly presented letter arrays) under both single- and dual-task conditions. Results suggest a decline of both visual processing capacity and VSTM storage capacity under dual-task conditions, while the perceptual threshold remained unaffected by a concurrent motor task. In addition, goodness-of-fit values and bootstrapping estimates support the notion that participants processed the visual task in a qualitatively comparable, although quantitatively less efficient way under dual-task conditions. The results support a capacity sharing account of motor-cognitive dual tasking and suggest that even performing a relatively simple motor task relies on central attentional capacity that is necessary for efficient visual information uptake.

Inpatient treatment of patients with acute idiopathic peripheral facial palsy: A population-based healthcare research study.

OBJECTIVES: To determine the inpatient management for patients with acute idiopathic facial palsy (IFP) in Thuringia, Germany. DESIGN: Population-based study. SETTING: All inpatients with IFP in all hospitals with departments of otolaryngology and neurology in 2012, in the German federal state, Thuringia. MAIN OUTCOME MEASURES: Patients' characteristics and treatment were compared between departments, and the probability of recovery was tested. RESULTS: A total of 291 patients were mainly treated in departments of otolaryngology (55%) and neurology (36%). Corticosteroid treatment was the predominant therapy (84.5%). The probability to receive a facial nerve grading (odds ratio [OR=12.939; 95% confidence interval [CI]=3.599 to 46.516), gustatory testing (OR=6.878; CI=1.064 to 44.474) and audiometry (OR=32.505; CI=1.485 to 711.257) was significantly higher in otolaryngology departments, but lower for cranial CT (OR=0.192; CI=0.061 to 0.602), cerebrospinal fluid examination (OR=0.024; CI=0.006 to 0.102). A total of 131 patients (45%) showed a recovery to House-Brackmann grade≤II. A pathological stapedial reflex test (Hazard ratio [HR]=0.416; CI=0.180 to 0.959) was the only independent diagnostic predictor of worse outcome. Prednisolone dose >500 mg (HR=0.579; CI 0.400 to 0.838) and no adjuvant physiotherapy (HR=0.568; CI=0.407 to 0.794) were treatment-related predictors of worse outcome. CONCLUSIONS: Inpatient treatment of IFP seems to be highly variable in daily practice, partly depending on the treating discipline and despite the availability of evidence-based guidelines. The population-based recovery rate was worse than reported in clinical trials.

Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration.

BACKGROUND AND PURPOSE: There is an urgent need for early predictive markers for the course of disease in prodromal α-synucleinopathies such as idiopathic rapid eye movement (REM) sleep behaviour disorder. Autonomic cardiac/vascular dysfunction is a prominent feature in advanced α-synucleinopathies, but its diagnostic value as an early neurodegenerative marker remains unclear. The latter may be complicated since synuclein-mediated neurodegeneration may involve central and peripheral components of the autonomic nervous system. METHODS: The diagnostic value of autonomic symptoms and central and peripheral autonomic markers of blood pressure and heart rate regulation were prospectively evaluated in 20 subjects with idiopathic REM sleep behaviour disorder and 20 age-matched healthy controls. RESULTS: Although subjects with REM sleep behaviour disorder showed no clinical autonomic symptoms, blood pressure (P ≤ 0.035) and heart rate response (P ≤ 0.065) were slightly diminished during orthostatic challenge. Autonomic dysregulation was distinctively reflected in lower resting heart rate (all components, P ≤ 0.05) and blood pressure variability (low frequency component, P ≤ 0.024) indicating peripheral cardiac/vascular denervation. In contrast, baroreflex sensitivity and central cardiac autonomic outflow (sympathovagal balance) were well preserved indicating intact central autonomic regulation. Heart rate variability [very low frequency component, receiver operating characteristic (ROC) area under the curve (AUC) 0.80, P ≤ 0.001] and blood pressure variability (low frequency component ROC AUC 0.73, P ≤ 0.01) but not baroreflex sensitivity and sympathovagal balance showed an excellent diagnostic accuracy in identifying subjects with REM sleep behaviour disorder and healthy controls. CONCLUSIONS: Cardiac/vascular dysfunction in prodromal α-synucleinopathy arises from peripheral rather than from central autonomic degeneration. Autonomic indices encoded in heart rate and blood pressure variability are precise functional markers of early synuclein-mediated neurodegeneration.

Perceived cognitive impairments after critical illness: a longitudinal study in survivors and family member controls.

BACKGROUND: Many former intensive care unit (ICU) patients report difficulties in cognitive functions especially in their daily life. We aimed to measure perceived cognitive impairments in daily life in survivors of critical illness and their family member controls (FMC). METHODS: Perceived cognitive impairments were assessed two times after ICU discharge using an adapted German version of the "Functional Assessment of Cancer Therapy - Cognitive Function" questionnaire. After 3 months, 127 former patients and 52 FMC participated and 103/127 patients and 36/52 FMC were followed up after 6 months. Baseline information was obtained retrospectively. RESULTS: We found no significant differences between the patient sample and FMC, 3 and 6 months after ICU discharge. Based on questionnaire ratings, cluster analysis divided patients and FMC into a cognitively 'impaired' and a 'non-impaired' cluster. Questionnaire scales differed significantly prior to ICU admission as well as 3 and 6 months after ICU discharge between both clusters. While differences between patients and FMC were less pronounced in the 'non-impaired' cluster, patients were significantly more impaired than FMC at 3 and 6 months after ICU discharge in the 'impaired' cluster. DISCUSSION: A substantial part of former patients were affected by post-ICU cognitive impairment in daily life. Pre-existing cognitive impairments were a risk factor. These patients would probably profit from tailored neurorehabilitative therapy. Therefore, an efficient tool to identify potential patients for neurorehabilitation is needed. The questionnaire revealed good psychometric properties. We recommend a comprehensive validation of the questionnaire in this patient population.

[Supraorbital approach to treat a fronto-orbital fracture with pneumocephaly, a minimal invasive technique]. / Abord supraorbitaire pour traiter une fracture frontale avec pneumocéphalie, une technique peu invasive.

We describe a supraorbital approach through an upper eyebrow skin incision to treat a fronto-orbital fracture with pneumocephaly in a 84-year-old cardiac patient. The clinical and cosmetic results are excellent. This case is illustrated by pre- and postoperative CT-scan and MRI as well as pictures showing the minimal invasive technique.

[Emotional impact of facial palsy]. / Emotionale Auswirkungen einer Fazialisparese.

Facial palsy is not only a movement disorder but leads also to an emotional and communicative disorder in chronic stage but also in some patients already during the acute phase of the disease. The present review describes the current knowledge of the neurobiological and psychological fundamentals on the relation of facial movement and its emotional context. So far there is not much knowledge on the impact of a facial palsy on the interaction between facial movement, emotional processing and communicative skills of the patient. The emotional contagion seems to be reduced in patients with facial palsy. The ability to express emotions seems also to be reduced. Moreover, the patients feel to be perceived negatively. In fact, most of the expressions of patients with facial palsy are allocated with a negative affect even when the patients are smiling. Patients with facial palsy react with negative stress, anxiety and depression. The patients avoid social contacts. In turn, this reinforces the communicative disorder. The otorhinolaryngologist can use the Facial Disability Index as a simple questionnaire to detect such dysfunctions. Diagnostics that are necessary to develop a therapy program are presented in this review. Standardized therapy concepts that are not only treat the movement disorder but also the emotional context is missing so far. Finally, the review will give an outlook on potential therapy strategies.

The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis.

Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1(G93A) NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1(G93A) NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1(G93A) motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1(G93A) , providing evidence that ER stress plays a major role in ALS.

Heart rate variability - a potential early marker of sub-acute post-stroke infections.

OBJECTIVE: Infection is the most relevant complication after acute ischemic stroke. Activity of the autonomic nervous system seems to control post-stroke immunodepression. We investigated heart rate variability (HRV) indices that reflect autonomic readjustments as predictors of post-stroke infection. MATERIALS AND METHODS: Forty-three patients with acute ischemic stroke were enrolled in a prospective study. The predictability of sub-acute infections (day 4 ± 1 after admission) was investigated in 34 patients without acute infection by means of HRV indices obtained in the acute period (48 h after admission). RESULTS: Sub-acute infection could be predicted in patients without clinical or paraclinical (white blood cell count and C-reactive protein) signs of infection in the acute period at (i) day: increased HFnorm, reduced LFnorm and LF/HF; (ii) night: reduced LF and VLF (P < 0.05). CONCLUSIONS: HRV indices are candidates for early markers of developing post-stroke infections, preceding routine blood samples. Thus, HRV-based early diagnosis of post-stroke infection should be investigated in more detail as it may have implications as a novel tool for timely and appropriate treatment. A corresponding continuous HRV-based risk assessment using the ECG provided by the routine stroke monitoring system would be possible without any additional burden for patients and staff.

Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice.

Prostate cancer mortality results from metastasis to bone and hormone-independent tumor growth. Models to study these progressive changes are lacking. Here we describe the propagation of advanced human prostate cancer by direct transfer of surgical samples from patients into immune-deficient male SCID mice. Explants from six of eight patients formed prostate tumors and two showed unique cytogenetic, biologic and molecular features that were retained through six or more passages. One grew in an androgen-independent fashion, whereas the second formed tumors that regressed following castration then regrew. Micrometastatic disease was detected in the hematopoietic tissues of half of the recipient mice. Thus selected specimens of advanced human prostate cancer can be propagated in SCID mice in a manner that recapitulates the clinical transition from androgen-sensitive to androgen-independent growth, accompanied by micrometastasis.

Minimally invasive endoscopic unilateral transsphenoidal surgery for pituitary adenomas.

OBJECTIVE: The aim of this study was to analyse the results of minimally invasive endoscopic unilateral transsphenoidal surgery for pituitary adenomas. METHODS: A series of 83 patients presenting with a pituitary lesion was reviewed retrospectively. Surgical procedures were performed between February 2007 and December 2010. The extent of resection was evaluated on post-operative contrast-enhanced MRI. We also reviewed our complications and compared them with the literature. RESULTS: Our series included 10 micro- and 73 macro-adenomas, with cavernous sinus invasion in 60.3%. Fifty-three per cent were non-secreting. Complete resection of the macro-adenomas was achieved in 22.5% of the cases. Complications were as follows: 2 deaths (2.5%), 2 sinusitis (2.5%), 5 CSF leaks (6.2%), 1 meningitis (1.2%), 16 post-operative anterior lobe insufficiency (19.8%) and 4 persistent diabetes insipidus (4.9%). Thirty-seven patients (44.6%) presented with a compression of optical pathways with an improvement of visual acuity in 94.3%. CONCLUSIONS: Purely endoscopic unilateral endonasal transsphenoidal adenoma resection is minimally invasive surgery leading to a good rate of gross total tumour resection and it is associated with a low complication rate.

The role of interventional neuroradiology in the management of skull base tumours and related surgical complications.

The management of hypervascular skull base tumours is complex and requires a multidisciplinary approach. Skull base surgery may be challenging because of the risk of serious intra-operative bleeding and of potential injuries to lower cranial nerves and/or large cervical vessels. Over the last four decades, advances in neuro-interventional procedures have produced a range of adjunctive endovascular techniques in addition to conventional surgery. Digital subtraction angiography (DSA) allows for a better understanding of tumour vascularisation and its relationship with Surrounding vessels. Tumoural devascularisation and the occlusion of feeding arteries is a useful adjunct to surgery because it allows for the reduction of intra-operative blood loss and induces ischaemic necrosis of the tumour. Finally, surgery-related iatrogenic vascular lesions may be successfully treated with endovascular techniques. Nevertheless, endovascular procedures in the head and neck region are associated with infrequent but potentially serious complications. An extensive and comprehensive knowledge of head and neck vascular anatomy is therefore necessary. This article provides a review of the indications for, and results of, diagnostic, pre-operative and therapeutic endovascular procedures for the management of skull base tumours and related surgical complications.

Hearing outcome after gamma knife radiosurgery for vestibular schwannoma: a prospective Belgian clinical study.

INTRODUCTION: Leksel Gamma Knife (LGK) radiosurgery is a safe and efficient therapeutic approach for vestibular schwannoma (VS) with low side effects. The goal of radiosurgery is not necessarily to cause significant tumour necrosis or to obtain a complete radiographic response, but to halt the tumour's growth permanently through its biological elimination. The 2 major aims of radiosurgery for VS are long-term tumour control and functional hearing preservation. The purpose of this study is to report our experience with LGK radiosurgery in the management of VS and to evaluate the hearing preservation rate after a minimum one-year follow-up. MATERIAL AND METHODS: Between January 2000 and January 2011, 415 patients with unilateral VS underwent LGK radiosurgery at the University Erasmus Hospital of Brussels. There were 349 patients with previously untreated VS (86 grade I, 96 grade II, 141 grade III, 9 grade IVa, 17 unknown grades, according to Koos) and 66 patients with post-operative residual tumour. All patients in our series underwent evaluation with high resolution neurodiagnostic imaging including computed tomography and magnetic resonance imaging, and clinical evaluation as well as audiological tests that included tonal and speech audiometries. The Gardner Robertson (GR) classification is used to report the results of this study. We identified 276 patients treated for VS with LGK, tested and retested with speech and tonal audiometries by the same team, and followed for a minimum of one year. RESULTS: Before LGK, 144 patients had serviceable (85 GR class I and 59 GR class II) hearing; 95 (65.97%) of these patients had preservation of serviceable hearing (Pure tone average < or = 50 db and Speech discrimination > or = 50%) at minimum one-year audiological follow-up. It was observed that 44 of the 85 GR class I patients (51.76%) maintained their level of audition and 66 of these (74.64%) preserved serviceable hearing. In the 34 patients with preradiosurgery non-serviceable hearing (GR class III-IV) 25 of these patients (73.52%) maintained their hearing. The tumour was stable or declining in size in 90.44% of cases. CONCLUSION: LGK radiosurgery provides excellent tumour control in vestibular schwannomas and has low toxicity even after long-term follow-up.

[Non-functioning pituitary adenoma: is there an interest to treat a residue after surgery?]. / Adénome hypophysaire non sécrétant: faut-il traiter un résidu après chirurgie?

Diagnosis of non-functioning pituitary adenoma is generally posted when there is a compression of the ophthalmic nerve or when a hypopituitarism occurred. Surgery will be the first treatment but complete removal can be achieved in less than 50% of the patients. In the great majority of the patients, there is a recurrence and a new treatment is proposed. The question is when we must treat a residue after surgery. We performed a retrospective study reviewing a series of 111 patients with a non-functioning pituitary adenoma. All patients had a pre- and post-operative MRI (1.5 T). A statistical analysis was done to determine the influence of the resection, the age of the patient on the recurrence. A complete removal was achieved for 45 patients and 11 of these present a recurrence. 39 patients out of 66 patients who had a partial removal presented also a recurrence. The mean age of the population is 53 years. The statistical analysis demonstrates that patients with a complete removal had less recurrence. Patient with an age below 60 years had more frequently a recurrence compared with older than 60 years old. In conclusion, treatment for non-functioning pituitary adenoma is a transsphenoidal approach surgery. A complete surgery must be the aim of the neurosurgeon. And when a residue is present, a secondary treatment must be given for patient with an age below 60 years old like radiosurgery or radiation therapy.

Regulated progression of B lymphocyte differentiation from cultured fetal liver.

Lymphoid fetal liver cultures (LFLC) are long-term, nontransformed cultures of early B lymphoid lineage cells which appear developmentally blocked at the pre-B stage in vitro. When injected into severe combined immunodeficient (SCID) mice, cells from LFLC could reconstitute splenic B lymphocytes and serum IgM. T lymphocyte reconstitution was not observed and serum IgG levels were very low. IgG3 was the predominant gamma subisotype in the serum of the LFLC-reconstituted mice, indicating impaired class switching in these B lymphocytes. When thymocytes were coinjected with LFLC, the B lymphocytes were able to class switch fully and respond to T-dependent antigens. These serological responses were heterogeneous. This experimental system allows separation of three B lymphocyte developmental stages: early differentiation in vitro, progression to IgM secretion in vivo, and late differentiation dependent upon mature T lymphocytes in vivo. The unique advantage of this system is the ability to regulate the B lymphocyte developmental pathway in a defined, stepwise manner.

Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene.

To determine the functional importance of Ras in transformation by Abl oncogenes, we used a genetic approach to measure the effect of impaired Ras activity on the ability of Bcr-Abl or v-Abl to transform cells. Expression of the catalytic domain of the GTPase activating protein for Ras (Gap C terminus) impaired soft agar colony formation by fibroblasts expressing v-Abl or Bcr-Abl by 70-80%. To test Ras function in a model that more closely resembles clinical diseases involving Bcr-Abl, double gene retroviruses expressing Bcr-Abl paired with the Gap C terminus or dominant negative Ras were introduced into naive mouse bone marrow cells. Transformation by Bcr-Abl was completely blocked in both situations. Coexpression of normal c-H-Ras accelerated the transforming activity of Bcr-Abl. These findings show that Ras activation is essential for the leukemogenic activity of Abl oncogenes in two distinct model systems. The results genetically define a connection between the Bcr-Abl cytoplasmic tyrosine kinase and Ras and add to the accumulating evidence that deregulation of Ras is a central event in the genesis of a number of molecularly distinct forms of human myeloid leukemia.

Feedback inhibition of immunoglobulin gene rearrangement by membrane mu, but not by secreted mu heavy chains.

Previous work (6-10) has shown that allelic exclusion of Ig gene expression is controlled by functionally rearranged mu and kappa genes. This report deals with the comparison of membrane mu (micron) and secreted mu (microsecond) in promoting such feedback inhibition. Splenic B cell hybridomas were analyzed from transgenic mice harboring a rearranged kappa gene alone or in combination with either an intact rearranged mu gene or a truncated version of the mu gene. The intact mu gene is capable of producing both membrane and secreted forms of the protein, while the truncated version can only encode the secreted form. The role of the microsecond was also tested in pre-B cell lines. Analysis of the extent of endogenous Ig gene rearrangement revealed that (a) the production of micron together with kappa can terminate Ig gene rearrangement; (b) microsecond with kappa does not have this feedback effect; (c) microsecond may interfere with the effect of micron and kappa; and (d) the feedback shown here probably represents a complete shutoff of the specific recombinase by micron + kappa; the data do not address the question of mu alone affecting the accessibility of H genes for rearrangement.

Long-term cultures of murine fetal liver retain very early B lymphoid phenotype.

Long-term cultures of murine fetal liver have been successfully established using a modification of our in vitro bone marrow culture system (14, 15). Fetal liver cells from midgestation BALB/c embryos were plated onto BAB-14 bone marrow stromal cell-adherent layers. After a 3-5 wk period, cell growth began to increase and these cells were expanded in number on fresh feeder layers. The cultured fetal liver cells were lymphoid in morphology, 5-20% cytoplasmic Ig-positive, but less than 1% surface Ig-positive. Southern blot analysis of the cultured fetal liver cells, as well as cultured bone marrow-derived B cells, demonstrated a population with germline Ig heavy chain loci, possibly representing very early B cell precursors. Abelson murine leukemia virus (A-MuLV) clonal transformants of such cultured fetal liver cells had a phenotypic distribution similar to that seen with fresh fetal liver transformants but distinct from those obtained with the transformation of either cultured or fresh bone marrow. All A-MuLV transformants isolated had rearrangements at the mu heavy chain locus of both chromosomes, irrespective of Ig production. In addition, most mu heavy chain producers had at least one rearranged kappa gene locus. These long-term fetal liver cultures provide large numbers of cells for studying events early in the B lymphocyte lineage. The cultured fetal liver cells retained phenotypic traits similar to fresh fetal liver B cells and distinctive from bone marrow cells cultured under similar conditions.

Distinctive growth requirements and gene expression patterns distinguish progenitor B cells from pre-B cells.

Long-term bone marrow cultures have been useful in determining gene expression patterns in pre-B cells and in the identification of cytokines such as interleukin 7 (IL-7). We have developed a culture system to selectively grow populations of B lineage restricted progenitors (pro-B cells) from murine bone marrow. Pro-B cells do not grow in response to IL-7, Steel locus factor (SLF), or a combination of the two. c-kit, the SLF receptor, and the IL-7 receptor are both expressed by pro-B cells, indicating that the lack of response is not simply due to the absence of receptors. Furthermore, SLF is not necessary for the growth of pro-B cells since they could be expanded on a stromal line derived from Steel mice that produces no SLF. IL-7 responsiveness in pre-B cells is associated with an increase in n-myc expression and is correlated with immunoglobulin (Ig) gene rearrangements. Although members of the ets family of transcription factors and the Pim-1 kinase are expressed by pro-B cells, n-myc is not expressed. Pro-B cells maintain Ig genes in the germline configuration, which is correlated with a low level of recombination activating genes 1 and 2 (Rag-1 and 2) mRNA expression, but high expression of sterile mu and terminal deoxynucleotidyl transferase. Pro-B cells are unable to grow separated from the stromal layer by a porous membrane, indicating that stromal contact is required for growth. These results suggest that pro-B cells are dependent on alternative growth signals derived from bone marrow stroma and can be distinguished from pre-B cells by specific patterns of gene expression.

Independent and opposing roles for Btk and lyn in B and myeloid signaling pathways.

Transphosphorylation by Src family kinases is required for the activation of Bruton's tyrosine kinase (Btk). Differences in the phenotypes of Btk-/- and lyn-/- mice suggest that these kinases may also have independent or opposing functions. B cell development and function were examined in Btk-/-lyn-/- mice to better understand the functional interaction of Btk and Lyn in vivo. The antigen-independent phase of B lymphopoiesis was normal in Btk-/-lyn-/- mice. However, Btk-/-lyn-/- animals had a more severe immunodeficiency than Btk-/- mice. B cell numbers and response to T cell-dependent antigens were reduced. Btk and Lyn therefore play independent or partially redundant roles in the maintenance and function of peripheral B cells. Autoimmunity, hypersensitivity to B cell receptor (BCR) cross-linking, and splenomegaly caused by myeloerythroid hyperplasia were alleviated by Btk deficiency in lyn-/- mice. A transgene expressing Btk at approximately 25% of endogenous levels (Btklo) was crossed onto Btk-/- and Btk-/-lyn-/- backgrounds to demonstrate that Btk is limiting for BCR signaling in the presence but not in the absence of Lyn. These observations indicate that the net outcome of Lyn function in vivo is to inhibit Btk-dependent pathways in B and myeloid cells, and that Btklo mice are a useful sensitized system to identify regulatory components of Btk signaling pathways.