Early progressive encephalopathy in boys and MECP2 mutations.

MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.

Posterior cruciate ligament architecture: evaluation under microsurgical dissection.

PURPOSE: Our objective was to verify the fiber anatomy of the posterior cruciate ligament (PCL) and to measure the main dimensions and the femoral and tibial attachment site distances of the ligament after microsurgical dissection. We hypothesized that PCL anatomy is more complex than the 2 traditionally characterized bands. TYPE OF STUDY: This is a purely anatomic description of microdissections of the PCL, focused on the fine anatomy of the ligament. MATERIALS AND METHODS: Twenty-four fresh-frozen cadaveric knees were dissected using magnifying loupes and an operative microscope, being careful to avoid creating artificially separated bundles. The main dimensions of the PCL were measured using a micrometer. RESULTS: The anterior, central, posterior-longitudinal, and posterior-oblique were the 4 fiber regions identified based on their orientation and the osseous sites of their insertions. These were partially separable anatomically but were functionally distinct. The anterior and central fiber regions made up the bulk of the ligament, while the remaining 15% consisted of the posterior fiber regions. During manual joint motion, the behavior of these fiber regions was observed. The anterior fiber region appeared to be the most nonisometric and remained in tension mainly between 30 degrees and 90 degrees of flexion. The posterior fiber regions appeared to be the most isometric (especially the posterior-oblique) and remained in tension mainly in extension and partially in deep flexion. The central fiber region appeared to have an intermediate behavior and remained in tension mainly between 30 degrees and 120 degrees of flexion. Additionally, it appeared to be the widest of all fiber regions. CONCLUSIONS: These findings should be of interest and help in interpreting some of the anatomy encountered during arthroscopic examination of the PCL, both from the anterior and posterior lateral portals. Furthermore, this information should prove useful in selecting treatment for the PCL.

Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti.

IKK gamma/NEMO is the essential regulatory subunit of the I kappa B kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for NF-kappa B activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikk gamma/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikk gamma+/- females eventually recover, Ikk gamma- males die in utero. These symptoms and inheritance pattern are very similar to those of incontinentia pigmenti (IP), a human genodermatosis, synthenic with the IKK gamma/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKK gamma/NEMO expression but normal expression of IKK catalytic subunits. This unique self-limiting disease, the first to be genetically linked to the IKK signaling pathway, is dependent on X-chromosome inactivation. We propose that the IKK gamma/NEMO-deficient cells trigger an inflammatory reaction that eventually leads to their death.

MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration.

Exposure of eukaryotic cells to extracellular stimuli results in activation of mitogen-activated protein kinase (MAPK) cascades composed of MAPKs, MAPK kinases (MAP2Ks), and MAPK kinase kinases (MAP3Ks). Mammals possess a large number of MAP3Ks, many of which can activate the c-Jun N-terminal kinase (JNK) MAPK cascade when overexpressed, but whose biological function is poorly understood. We examined the function of the MAP3K MEK kinase 1 (MEKK1) in proinflammatory signaling. Using MEKK1-deficient embryonic stem cells prepared by gene targeting, we find that, in addition to its function in JNK activation by growth factors, MEKK1 is required for JNK activation by diverse proinflammatory stimuli, including tumor necrosis factor alpha, IL-1, double-stranded RNA, and lipopolysaccharide. MEKK1 is also essential for induction of embryonic stem cell migration by serum factors, but is not required for activation of other MAPKs or the IkappaB kinase signaling cascade.

Nerve and vessel injuries during high tibial osteotomy combined with distal fibular osteotomy: a clinically relevant anatomic study.

Based on our clinical experience and an anatomical study, we examined the conditions under which injury to the popliteal artery, tibial nerve or peroneal nerve and its branches may occur during high tibial osteotomy. In 250 high tibial osteotomies performed in our department, we observed the following intraoperative complications. (1) The popliteal artery was severed in 1 patient and repaired by the same surgical team using a microsurgical technique. (2) A tibial nerve paresis also occurred in 1 patient. (3) In 3 patients, temporary palsy of the anterior tibialis muscle was documented. (4) In 4 other patients, palsy of the extensor hallucis longus occurred. To investigate the causes of these complications in the popliteal artery, tibial nerve and branches of the peroneal nerve, we dissected the neurovascular structures surrounding the area of the osteotomy in 10 cadaveric knees and performed a high tibial osteotomy in another 13 cadaveric knees. We concluded the following. (1) The popliteal artery and tibial nerve are protected, at the level of the osteotomy, behind the popliteus and tibialis posterior muscles. Damage can occur only by placing the Hohman retractor behind the muscles. The insertion of the muscles is very close to the periosteum and can be separated only with a scalpel. (2) The tibialis anterior muscle is innervated by a group of branches arising from the deep branch of the peroneal nerve. In two-thirds of the dissected knees, we found a main branch close to the periosteum, which can be damaged by dividing the muscle improperly or due to improper placement and pressure of the Hohman retractor. This may explain the partially reversible muscle palsy. (3) The extensor hallucis longus is also innervated by 2-3 thin branches, arising from the deep branch of the peroneal nerve, but in 25% of the specimens, only one large branch was found. This branch is placed under tension by manipulating the distal tibia forward. Thus, it may be damaged by the Hohman retractor during distal screw fixation, tensioned by hyperextension or directly injured during midshaft fibular osteotomy.

Development in a Windows environment of a radiation treatment planning system for personal computers.

A new personal computer (PC) radiotherapy treatment planning system (RTPS) is presented. The PC-based RTPS is designed to run in the Microsoft Windows 3.11 environment (and later versions), for computers equipped with 486 or Pentium processors. The algorithm used by the new PC-based program for dose calculation belongs to the 'radiological pathlength' category and it was previously implemented on VAX 711 computers at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, NY, within EXTREP-III RTPS. The EXTREP-III program is a two-dimensional RTPS (with restricted three-dimensional capabilities), developed and used in clinical practice at MSKCC during the 1980s. The PC-based program is implemented in the Visual Basic (version 3.0) language and supports features commonly available in most photon-mode RTPSs: dose calculation for fixed, isocentric and rotational irradiation techniques, dose corrections for both internal inhomogeneities and external inhomogeneities (boluses and compensators), association of machine-specific beams with various wedges and blocks, etc. The graphic interface of the PC-based RTPS is completely new and is designed to meet the requirements of fast and accurate planning. The user interface consists of an event-oriented button-based console which allows users to perform planning and to have isodose charts overlaid on patient computed tomography images initially loaded in the program. The PC-based RTPS tests, performed in order to assess its accuracy and speed of computation, show good results. The acceptable computation times obtained, the good accuracy in dose computation and the user-friendly interface of the program are sufficient reasons to consider the PC-based RTPS a good quality-price ratio tool for radiation treatment planning in cancer therapy.

Difficulties and early results of the endoscopic carpal tunnel release using the modified Chow technique.

In reporting on the preliminary results of our series of 76 patients, this paper aims to identify potentially complicating aspects of endoscopic carpal tunnel release (ECTR) using the two-portal Chow technique, and to recommended solutions, based on our early experience, which enhance the ease and safety of this minimally invasive technique. Of the first 24 patients, 16 cases required conversion to an open procedure. Based on these initial cases, we developed certain modifications of the Chow technique which precluded any need for open conversion in the 60 remaining cases. During a follow-up interval ranging from 4 to 24 months, there was no recurrence of carpal tunnel symptoms, and the average time to resumption of work activity was 14 days. The complication rate was 5% and included one case of transient hypesthesia, one case of extended hematoma, and one hypersensitive scar. All complications resolved at subsequent follow-up. In our experience, correct positioning of the hand, proper injection of local anesthetic, use of magnifying loupes, and correct use of instruments are essential for a safe and successful procedure.

Derepressed hyphal growth and reduced virulence in a VH1 family-related protein phosphatase mutant of the human pathogen Candida albicans.

Mitogen-activated protein (MAP) kinases are pivotal components of eukaryotic signaling cascades. Phosphorylation of tyrosine and threonine residues activates MAP kinases, but either dual-specificity or monospecificity phosphatases can inactivate them. The Candida albicans CPP1 gene, a structural member of the VH1 family of dual- specificity phosphatases, was previously cloned by its ability to block the pheromone response MAP kinase cascade in Saccharomyces cerevisiae. Cpp1p inactivated mammalian MAP kinases in vitro and acted as a tyrosine-specific enzyme. In C. albicans a MAP kinase cascade can trigger the transition from the budding yeast form to a more invasive filamentous form. Disruption of the CPP1 gene in C. albicans derepressed the yeast to hyphal transition at ambient temperatures, on solid surfaces. A hyphal growth rate defect under physiological conditions in vitro was also observed and could explain a reduction in virulence associated with reduced fungal burden in the kidneys seen in a systemic mouse model. A hyper-hyphal pathway may thus have some detrimental effects on C. albicans cells. Disruption of the MAP kinase homologue CEK1 suppressed the morphological effects of the CPP1 disruption in C. albicans. The results presented here demonstrate the biological importance of a tyrosine phosphatase in cell-fate decisions and virulence in C. albicans.

Anterior cruciate ligament reconstruction with the press-fit technique. 2-5 years followed-up of 42 patients.

42 patients underwent anterior cruciate ligament (ACL) reconstruction with the press-fit technique. The ACL was reconstructed with a bone-tendon-bone graft from the medial third of the patellar tendon. The graft was stabilized without screws in the femur and tibia by press-fit. To imitate the anatomical functioning of the ACL, the femoral bone block was placed with the tendon close to the over-the-top position. The tibial block was then placed in a trough on the tibia, so that the ligament fibres were parallel and tight during extension and slightly inverted during flexion. At evaluation mean 41 (25-61) months postoperatively, the mean Lysholm score was 93 (80-100) points, the mean activity level was 6 (3-10) points, and the mean translation of the tibia head, measured by the KT-1000 arthrometer (side-to-side difference), was 2 (0-7) mm. Only 3 of the patients suffered loss of extension (5 degrees). Patients who underwent reconstruction at least 4 months after the injury had better results than those who were operated earlier. The press-fit method allowed for anatomic substitution of the ACL with a stable graft without the disadvantages associated with screws. This method gave early postoperative functioning of the knee and good mid-term results.

Total knee arthroplasties infected by Brucella melitensis: a case report.

A 74-year-old man with bilateral knee arthroplasties developed Brucella arthritis in both joints after a total joint arthroplasty in his left knee. This complication is the second case reported in the literature to date.

Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability.

The NF-kappaB/Rel transcription factors participate in the activation of immune system regulatory genes and viral early genes including the human immunodeficiency virus type 1 long terminal repeat. NF-kappaB/Rel proteins are coupled to inhibitory molecules, collectively termed IkappaB, which are responsible for cytoplasmic retention of NF-kappaB. Cell activation leads to the phosphorylation and degradation of IkappaBalpha, permitting NG-kappaB/Rel translocation to the nucleus and target gene activation. To further characterize the signaling events that contribute to IkappaBalpha phosphorylation, a kinase activity was isolated from Jurkat T cells that specifically interacted with IkappaBalpha in an affinity chromatography step and phosphorylated IkappaBalpha with high specificity in vitro. By using an in-gel kinase assay with recombinant IkappaBalpha as substrate, two forms of the kinase (43 and 38 kDa) were identified. Biochemical criteria and immunological cross-reactivity identified the kinase activity as the alpha catalytic subunit of casein kinase II (CKII). Deletion mutants of IkappaBalpha delta1 to delta4) localized phosphorylation to the C-terminal PEST domain of IkappaBalpha. Point mutation of residues T-291, S-283, and T-299 dramatically reduced phosphorylation of IkappaBalpha by the kinase in vitro. NIH-3T3 cells that stably expressed wild-type IkappaBalpha (wtIkappaB), double-point-mutated IkappaBalpha (T291A, S283A), or triple-point-mutated IkappaBalpha (T291A, S283A, T299A) under the control of the tetracycline-responsive promoter were generated. Constitutive phosphorylation of the triple point mutant was eliminated in vivo, although tumor necrosis factor-inducible IkappaBalpha degradation was unaffected. In cell lines and in transiently transfected cells, mutation of the CKII sites in IkappaBalpha resulted in a protein with increased intrinsic stability. Together with results demonstrating a role for N-terminal sites in inducer-mediated phosphorylation and degradation of IkappaBalpha, these studies indicate that CKII sites in the C-terminal PEST domain are important for constitutive phosphorylation and intrinsic stability of IkappaBalpha.

Hemoglobin production in human bone marrow cultures is inhibited by lyophilized coagulation factor concentrates.

Transfusion of blood products may be followed by viral hepatitis and aplastic anemia despite improved techniques for prevention. In view of the need for intensive therapy of hemophilia with blood products, the authors investigated the capacity of these concentrates to influence cultures of human bone marrow cells. Factor VIII concentrates contained a heat-stable dialyzable substance(s) that drastically impaired 59Fe incorporation in normal human bone marrow. Factor IX concentrates had less and cryoprecipitate had no such inhibitory activity. These studies may offer information regarding the effects of various blood products on bone marrow function.