[Intraneural cysts of the peroneal nerve in childhood: report of 2 cases and literature review]. / Quistes intraneurales del nervio ciatico popliteo externo en edad pediatrica presentacion de 2 casos revision de la literatura.

Intraneural cysts are benign lesions filled with mucinous content and located inside the epineurum of the peripheral nerves. Peroneal nerve is the most affected nerve. The entity is rare and its ethiopathology still remains to be definitely elucidated. In 2003 Spinner et al published their articular theory, implicated in the formation and frequent recurrence of these lesions after surgical treatment. The practical application of this theory, nowadays almost universally accepted, generated an important diminution in the recurrence rate after surgical evacuation of this lesions, previously very elevated. Most of the cases of this entity are described in adults. In the present paper we describe two pediatric cases and analyze the clinical aspects of these cysts in pediatric and adults patients. Peroneal intraneural cysts are one of the differential diagnoses in foot drop, and an adequate treatment concludes in a complete remission of the symptoms.

[Nerve reconstruction techniques in traumatic brachial plexus surgery. Part 2: intraplexal nerve transfers]. / Técnicas de reconstrucción nerviosa en cirugía del plexo braquial traumatizadoParte 2: Transferencias nerviosas intraplexuales.

After the great enthusiasm generated in the '70s and '80s in brachial plexus surgery as a result of the incorporation of microsurgical techniques and other advances, brachial plexus surgery has been shaken in the last two decades by the emergence of nerve transfer techniques or neurotizations. This technique consists in sectioning a donor nerve, sacrificing its original function, to connect it with the distal stump of a receptor nerve, whose function was lost during the trauma. Neurotizations are indicated when direct repair is not possible, i.e. when a cervical root is avulsed at its origin in the spinal cord. In recent years, due to the positive results of some of these nerve transfer techniques, they have been widely used even in some cases where the roots of the plexus were preserved. In complete brachial plexus injuries, it is mandatory to determine the exact number of roots available (not avulsed) to perform a direct reconstruction. In case of absence of available roots, extraplexual nerve transfers are employed, such as the spinal accessory nerve, the phrenic nerve, the intercostal nerves, etc., to increase the amount of axons transferred to the injured plexus. In cases of avulsion of all the roots, extraplexal neurotizations are the only reinnervation option available to limit the long-term devastating effects of this injury. Given the large amount of reports that has been published in recent years regarding brachial plexus traumatic injuries, the present article has been written in order to clarify the concerned readers the indications, results and techniques available in the surgical armamentarium for this condition. Since the choice of either surgical technique is usually taken during the course of the procedure, all this knowledge should be perfectly embodied by the surgical team before the procedure. In a previous paper extraplexual nerve transfers were analyzed; this literature review complements the preceding paper analyzing intraplexual nerve transfers, and thus completing the analysis of the nerve transfers available in brachial plexus surgery.

[Nerve reconstruction techniques in traumatic brachial plexus surgery. Part 1: extraplexal nerve transfers]. / Técnicas de reconstrucción nerviosa en cirugía del plexo braquial traumatizadoParte 1: Transferencias nerviosas extraplexuales.

After the great enthusiasm generated in the '70s and '80s in brachial plexus surgery as a result of the incorporation of microsurgical techniques and other advances, brachial plexus surgery has been shaken in the last two decades by the emergence of nerve transfer techniques or neurotizations. This technique consists in sectioning a donor nerve, sacrificing its original function, to connect it with the distal stump of a receptor nerve, whose function was lost during the trauma. Neurotizations are indicated when direct repair is not possible, i.e. when a cervical root is avulsed at its origin in the spinal cord. In recent years, due to the positive results of some of these nerve transfer techniques, they have been widely used even in some cases where the roots of the plexus were preserved. In complete brachial plexus injuries, it is mandatory to determine the exact number of roots available (not avulsed) to perform a direct reconstruction. In case of absence of available roots, extraplexual nerve transfers are employed, such as the spinal accessory nerve, the phrenic nerve, the intercostal nerves, etc., to increase the amount of axons transferred to the injured plexus. In cases of avulsion of all the roots, extraplexal neurotizations are the only reinnervation option available to limit the long-term devastating effects of this injury. Given the large amount of reports that has been published in recent years regarding brachial plexus traumatic injuries, the present article has been written in order to clarify the concerned readers the indications, results and techniques available in the surgical armamentarium for this condition. Since the choice of either surgical technique is usually taken during the course of the procedure, all this knowledge should be perfectly embodied by the surgical team before the procedure. In this first part extraplexual nerve transfers are analyzed, while intraplexual nerve transfers will be analyzed in the second part of this presentation.

Facial-zygomatic triangle: a relationship between the extracranial portion of facial nerve and the zygomatic arch.

BACKGROUND: This study was conducted to clarify the relationships between the extracranial portion of the facial nerve (EFN) and the zygomatic arch (ZA). METHOD: Four cadaveric heads (8 parotid regions), examined under 3-40x magnification, were dissected from lateral to medial to expose the EFN. FINDINGS: In a vertical plane just anterior to the tragus, the distance from the superior edge of the ZA to the facial nerve (FN) is, on average, 26.88 mm. The FN then courses superiorly and anteriorly, crossing the ZA 18.65 mm anterior to the tragus on average. Thus, three points can be used to depict a triangle: A, at the level of the anterior border of the tragus, just above the superior edge of the ZA; B, 26 mm below A; and C, 18 mm anterior to A. This so called facial-zygomatic triangle represents the area where surgical dissection can be performed with no risk of damaging the FN. Thus, the closer one stays to the tragus, the lesser the risk of damaging the FN below the ZA. If the incision is carried out on a vertical plane closer to the tragus, the skin can be safely cut up to 2 cm below the ZA. CONCLUSION: The facial-zygomatic triangle is a very useful superficial landmark to avoid FN damage when working below the ZA.

Human high-affinity Fc IgG receptor (Fc gamma RI)-mediated phagocytosis and pinocytosis in COS cells.

The high-affinity receptor (Fc gamma RI) for the constant (Fc) portion of immunoglobulin G (IgG) is one of three Fc IgG receptor classes (Fc gamma Rs) found on mononuclear phagocytes. The functional specialization of each of the Fc gamma R classes is not well understood. Previous studies utilizing anti-Fc gamma R monoclonal antibodies (mAbs) as opsonins suggest that Fc gamma RI, like the other Fc gamma Rs expressed by macrophages, is able to mediate phagocytosis. The ability of Fc gamma RI to mediate pinocytosis, however, had not been certain, since it binds, but does not mediate, internalization of monomeric IgG in the monocytoid U937 cells. We studied Fc gamma RI-mediated internalization by introducing it into the Fc gamma R-negative fibroblastic COS cells. We found, using electron microscopy and fluorescence microscopy, that COS cells expressing Fc gamma RI are able to phagocytose IgG-coated zymosan particles and sheep red blood cells (SRBC), as well as pinocytose cross-linked IgG. There was no intracellular accumulation of monomeric IgG. Chimeric receptors which retain the extracellular domains of Fc gamma RI but lack the entire wild-type transmembrane and intracellular regions of the receptor mediated both phagocytosis and pinocytosis with equal or increased efficiency when compared to the wild-type receptor. Control COS cells transfected with CD2 rosetted, but did not phagocytose, SRBC. Attachment of phagocytic targets to COS cells is therefore not sufficient for phagocytosis. Taken together, this suggests that the extracellular domain of Fc gamma RI is sufficient for it to mediate phagocytosis and pinocytosis in this system.

Effects of eliminating tension by means of epineural stitches: a comparative electrophysiological and histomorphometrical study using different suture techniques in an animal model / Avaliação dos efeitos da eliminação da tensão através de ancoramento epineural: estudo experimental comparando resultados eletrofisiológicos e histomorfométricos após diferentes técnicas de reparo no nervo

Epineural stitches are a means to avoid tension in a nerve suture. We evaluate this technique, relative to interposed grafts and simple neurorraphy, in a rat model. METHOD: Twenty rats were allocated to four groups. For Group 1, sectioning of the sciatic nerve was performed, a segment 4 mm long discarded, and epineural suture with distal anchoring stitches were placed resulting in slight tension neurorraphy. For Group 2, a simple neurorraphy was performed. For Group 3, a 4 mm long graft was employed and Group 4 served as control. Ninety days after, reoperation, latency of motor action potentials recording and axonal counts were performed. Inter-group comparison was done by means of ANOVA and the non-parametric Kruskal-Wallis test. RESULTS: The mean motor latency for the simple suture (2.27±0.77 ms) was lower than for the other two surgical groups, but lower than among controls (1.69±0.56 ms). Similar values were founding in both group 1 (2.66±0.71 ms) and group 3 (2.64±0.6 ms). When fibers diameters were compared a significant difference was identified between groups 2 and 3 (p=0.048). CONCLUSION: Good results can be obtained when suturing a nerve employ with epineural anchoring stitches. However, more studies are needed before extrapolating results to human nerve sutures.

A aproximação através de pontos epineurais é uma forma de se reduzir a tensão numa neurorrafia. Neste estudo esta técnica é avaliada através da sua comparação com a interposição de enxertos e neurorrafia simples num modelo experimental utilizando o rato. MÉTODO: Vinte ratos foram utilizados e divididos em 4 grupos. No Grupo 1, após a ressecção de 4 mm, os cotos do nervo foram aproximados através de pontos de ancoramento epineurais e suturados com tensão. No Grupo 2, uma neurorrafia simples foi realizada após secção do nervo. No Grupo 3, um enxerto de 4 mm foi utilizado para o reparo e o Grupo 4 foi utilizado como controle. Noventa dias após, os nervos foram novamente expostos e a medida da latência do potencial de ação motor e a contagem axonal foram realizados. A comparação entre os grupos foi realizada através da comparação entre as médias (ANOVA) e com o teste não-paramétrico de Kruskal-Wallis. RESULTADOS: A média da latência motora na sutura simples (2,27±0,77 ms) foi menor em relação aos outros dois grupos onde o nervo foi seccionado e reparado e maior que o grupo controle (1,69±0,56 ms). Resultados semelhantes foram identificados nos grupos 1 (2,66±0,71 ms) e 3 (2,64±0,6 ms). Uma diferença significativa diâmetros das fibras foi identificada quando comparados os grupos 2 e 3 (p=0,048). CONCLUSÃO: Resultados equiparáveis aos obtidos com enxerto podem ser obtidos quando a neurorrafia é realizada com pontos epineurais de ancoramento com tensão, mas estudos adicionais são necessários antes desses resultados serem extrapolados para o reparo de nervo em seres humanos.

The prolactin receptor and severely truncated erythropoietin receptors support differentiation of erythroid progenitors.

Activation of the erythropoietin receptor is essential for the survival, proliferation, and differentiation of erythroid progenitors. To understand the role of erythropoietin receptor (EpoR) activation in erythroid differentiation, we infected primary erythroid progenitors with high-titer retrovirus encoding the non-hematopoietic prolactin receptor. The infected progenitors responded to prolactin in the absence of Epo by generating fully differentiated erythroid colonies. Therefore, differentiation of erythroid progenitors does not require an intracellular signal generated uniquely by the EpoR; the EpoR does not have an instructive role in erythroid differentiation. We also infected primary erythroid progenitors with retrovirus encoding chimeric receptors containing the extracellular domain of PrlR and the intracellular domain of either the wild-type or truncated EpoRs. A chimeric receptor containing only the membrane-proximal 136 amino acids of the EpoR cytoplasmic domain efficiently supported prolactin-dependent differentiation of erythroid progenitors. Substitution of the single cytoplasmic domain tyrosine in this receptor with phenylalanine (Y343F) eliminated its ability to support differentiation. The minimal EpoR cytoplasmic domain required for erythroid differentiation is therefore the same as that previously reported to be sufficient to support cell proliferation (D'Andrea, A. D., Yoshimura, A., Youssoufian, H., Zon, L. I., Koo, J. W., and Lodish, H. F. (1991) Mol. Cell. Biol. 11, 1980-1987; Miura, O., D'Andrea, A. D., Kabat, D., and Ihle, J. N. (1991) Mol. Cell. Biol. 11, 4895-4902; He, T.-C., Jiang, N., Zhuang, H., Quelle, D. E., and Wojchowski, D. M. (1994) J. Biol. Chem. 269, 18291-18294).

The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit.

We recently showed that a retrovirally transduced prolactin receptor (PrlR) efficiently supports the differentiation of wild-type burst-forming unit erythroid (BFU-e) and colony-forming unit erythroid (CFU-e) progenitors in response to prolactin and in the absence of erythropoietin (Epo). To examine directly whether the Epo receptor (EpoR) expressed by wild-type erythroid progenitors was essential for their terminal differentiation, we infected EpoR-/- progenitors with retroviral constructs encoding either the PrlR or a chimeric receptor containing the extracellular domain of the PrlR and intracellular domain of EpoR. In response to prolactin, both receptors were equally efficient in supporting full differentiation of the EpoR-/- progenitors into erythroid colonies in vitro. Therefore, there is no requirement for an EpoR-unique signal in erythroid differentiation; EpoR signaling has no instructive role in red blood cell differentiation. A synergistic interaction between EpoR and c-kit is essential for the production of normal numbers of red blood cells, as demonstrated by the severe anemia of mice mutant for either c-kit or its ligand, stem cell factor. We show that the addition of stem cell factor potentiates the ability of the PrlR to support differentiation of both EpoR-/- and wild-type CFU-e progenitors. This synergism is quantitatively equivalent to that observed between c-kit and EpoR. Therefore, there is no requirement for an EpoR-unique signal in the synergistic interaction between c-kit and EpoR.

Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction.

The erythropoietin receptor (EpoR) is essential for production of red blood cells; a principal function of EpoR is to rescue committed erythroid progenitors from apoptosis. Stat5 is rapidly activated following EpoR stimulation, but its function in erythropoiesis has been unclear since adult Stat5a-/-5b-/- mice have normal steady-state hematocrit. Here we show that Stat5 is essential for the high erythropoietic rate during fetal development. Stat5a-/-5b-/- embryos are severely anemic; erythroid progenitors are present in low numbers, show higher levels of apoptosis, and are less responsive to Epo. These findings are explained by a crucial role for Stat5 in EpoR's antiapoptotic signaling: it mediates the immediate-early induction of Bcl-X(L) in erythroid cells through direct binding to the Bcl-X promoter.

Genetic analysis of BRCA1 function in a defined tumor cell line.

Retrovirally expressed, wild-type BRCA1 decreased the gamma radiation (IR) sensitivity and increased the efficiency of double-strand DNA break repair (DSBR) of the BRCA1-/- human breast cancer line, HCC1937. It also reduced its susceptibility to DSB generation by IR. By contrast, multiple, clinically validated, missense mutant BRCA1 products were nonfunctional in these assays. These data constitute the basis for a BRCA1 functional assay and suggest that efficient repair of double-strand DNA breaks is linked to BRCA1 tumor suppression function.

Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor.

von Hippel-Lindau (VHL) disease is a pleomorphic familial tumor syndrome that is characterized by the development of highly vascularized tumors. Homozygous disruption of the VHL gene in mice results in embryonic lethality. To investigate VHL function in the adult we have generated a conditional VHL null allele (2-lox allele) and null allele (1-lox allele) by Cre-mediated recombination in embryonic stem cells. We show here that mice heterozygous for the 1-lox allele develop cavernous hemangiomas of the liver, a rare manifestation of the human disease. Histologically these tumors were associated with hepatocellular steatosis and focal proliferations of small vessels. To study the cellular origin of these lesions we inactivated VHL tissue-specifically in hepatocytes. Deletion of VHL in the liver resulted in severe steatosis, many blood-filled vascular cavities, and foci of increased vascularization within the hepatic parenchyma. These histopathological changes were similar to those seen in livers from mice heterozygous for the 1-lox allele. Hypoxia-inducible mRNAs encoding vascular endothelial growth factor, glucose transporter 1, and erythropoietin were up-regulated. We thus provide evidence that targeted inactivation of mouse VHL can model clinical features of the human disease and underline the importance of the VHL gene product in the regulation of hypoxia-responsive genes in vivo.

Tyrosine residues within the intracellular domain of the erythropoietin receptor mediate activation of AP-1 transcription factors.

Binding of erythropoietin (Epo) to the Epo receptor (EpoR) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of AP-1 transcription factor(s). While Epo is known to activate c-fos gene expression, the mechanism of AP-1 activation is unknown. Here we show that AP-1 activation by Epo requires tyrosine kinase activity and also de novo protein synthesis. Using a mutant EpoR containing no cytosolic tyrosine residues, and a set of eight mutants containing a single cytosolic tyrosine residue, we show that multiple EpoR tyrosines, thought to activate multiple intracellular signal transduction proteins, can mediate AP-1 activation. An EpoR containing only tyrosine 343 or tyrosine 464 supports a maximal level of AP-1 activation. We also show that AP-1 activation does not require maximal STAT5 activation and may occur via a STAT5-independent signaling pathway.

Cytokine receptor signal transduction and the control of hematopoietic cell development.

The cytokine receptor superfamily is characterized by structural motifs in the exoplasmic domain and by the absence of catalytic activity in the cytosolic segment. Activated by ligand-triggered multimerization, these receptors in turn activate a number of cytosolic signal transduction proteins, including protein tyrosine kinases and phosphatases, and affect an array of cellular functions that include proliferation and differentiation. Molecular study of these receptors is revealing the roles they play in the control of normal hematopoiesis and in the development of disease.

Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts.

Erythropoietin (Epo) controls red cell production in the basal state and during stress. Epo binding to its receptor, EpoR, on erythroid progenitors leads to rapid activation of the transcription factor Stat5. Previously, fetal anemia and increased apoptosis of fetal liver erythroid progenitors were found in Stat5a(-/-)5b(-/-) mice. However, the role of Stat5 in adult erythropoiesis was not clear. The present study shows that some adult Stat5a(-/-)5b(-/-) mice have a near-normal hematocrit but are deficient in generating high erythropoietic rates in response to stress. Further, many adult Stat5a(-/-)5b(-/-) mice have persistent anemia despite a marked compensatory expansion in their erythropoietic tissue. Analysis of erythroblast maturation in Stat5a(-/-)5b(-/-) hematopoietic tissue shows a dramatic increase in early erythroblast numbers, but these fail to progress in differentiation. Decreased expression of bcl-x(L) and increased apoptosis in Stat5a(-/-)5b(-/-) early erythroblasts correlate with the degree of anemia. Hence, Stat5 controls a rate-determining step regulating early erythroblast survival.

Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain.

Binding of erythropoietin (Epo) to the Epo receptor (EpoR) is crucial for production of mature red cells. Although it is well established that the Epo-bound EpoR is a dimer, it is not clear whether, in the absence of ligand, the intact EpoR is a monomer or oligomer. Using antibody-mediated immunofluorescence copatching (oligomerizing) of epitope-tagged receptors at the surface of live cells, we show herein that a major fraction of the full-length murine EpoR exists as preformed dimers/oligomers in BOSC cells, which are human embryo kidney 293T-derived cells. This observed oligomerization is specific because, under the same conditions, epitope-tagged EpoR did not oligomerize with several other tagged receptors (thrombopoietin receptor, transforming growth factor beta receptor type II, or prolactin receptor). Strikingly, the EpoR transmembrane (TM) domain but not the extracellular or intracellular domains enabled the prolactin receptor to copatch with EpoR. Preformed EpoR oligomers are not constitutively active and Epo binding was required to induce signaling. In contrast to tyrosine kinase receptors (e.g., insulin receptor), which cannot signal when their TM domain is replaced by the strongly dimerizing TM domain of glycophorin A, the EpoR could tolerate the replacement of its TM domain with that of glycophorin A and retained signaling. We propose a model in which TM domain-induced dimerization maintains unliganded EpoR in an inactive state that can readily be switched to an active state by physiologic levels of Epo.

Derivación lumbo-peritoneal: análisis de 18 casos y revión bibliográfica / Lumbo-peritoneal derivatons: analysis of 18 cases and bibliographic review

Se analizan 18 casos de pacientes derivados con un sistema lumbo-periotoneal (DLP) entre junio de 1991 y junio del 2000 en nuestro servicio. Siete pacientes presentaron hidrocefalia comunicante (4 post-meningiticas y 3 post-HSA), 4 fistulas de liquido cefalorraquídeo (LCR), 4 pacientes hipertensión endocraneana benigna y 2 hidrocefalía normotensiva. Catorce de los 18 casos (83,3 por ciento) resolvieron su problema con la derivación, mientras que los restantes 4 no lo hicieron y requirieron de otro tipo de sistema o tratamiento. Las complicaciones mas frecuentemente observadas fueron dolor radicular y cefaléa a la sedestación. El sistema debió ser revisado en 5 pacientes. El análisis bibligráfico muestran cifras similares a las halladas en esta serie, respecto a indices de reexploraciones y éxitos terapéuticos. En conclusión, la DLP es un metodo de derivación de LCR en las hidrocefalías comunicantes de cualquier etiología, en fístulas de LCR abiertas o cerradas y en hipertensión endocraneana benigna. Presenta indice bajo de fracasos terapéuticos, pero como contralpartida genera una relativamente alta tasa de disfunsiones y complicaciones leves, que suelen requerir reexploraciones quirúrgicas frecuentes.