Ocular Pathology of Fukuyama Congenital Muscular Dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is one of the congenital muscular dystrophies, showing central nervous system (CNS) and ocular lesions, in addition to muscular dystrophy. It is included in α-dystroglycanopathy, an entity of muscular dystrophies caused by reduced glycosylation of α-dystroglycan (α-DG). Studies of ocular lesions are not so many, compared with those of the muscle and CNS. Clinical ocular manifestations are myopia, strabismus, retinal detachment, and so on. Since the retina has a structure partly resembling the cerebral cortex, pathological findings similar to those found in the brain have been reported. The major observation considered to be involved in the pathogenesis of retinal lesions is abnormalities in the internal limiting membrane formed by Müller cells, which is corresponding to the glia limitans formed by astrocytes in the brain. Fukutin, responsible for FCMD, and α-DG are expressed in Müller cells. Moreover, fukutin may be involved in synaptic functions of retinal neurons through the glycosylation of α-DG. In this chapter, ocular lesions of fetal and child FCMD patients are presented, especially focusing on pathological findings of the retina, and functions of fukutin are discussed

Multiple Functions of <em>Fukutin</em>, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System

Fukuyama congenital muscular dystrophy (FCMD), accompanying central nervous system (CNS) and ocular anomalies, is the second common muscular dystrophy in Japan, and the responsible gene is fukutin. The lesions are mainly caused by fragile basement membrane/cell membrane due to hypoglycosylation of α-dystroglycan (α-DG), and astrocytes play a crucial role for CNS malformation. On the other hand, since fukutin is expressed almost ubiquitously, diverse functions of fukutin, besides the glycosylation of α-DG, can be considered. As for the CNS, fukutin possibly upregulates cyclin D1 expression as a cofactor of activator protein-1 in astrocytoma. Moreover, fukutin may be involved in the phosphorylation of tau, one of the key proteins of dementia represented by Alzheimer’s disease, in glutamatergic neurons. A presynaptic function in GABAergic neurons is also suggested. Owing to the recent advances of molecular and biochemical techniques, new therapeutic strategies are under consideration, even for brain malformation, which begins to be formed during the first trimester in utero. Recovery of hypoglycosylation of α-DG supposed to be a main therapeutic target, but to know various functions and regulation systems of fukutin might be important for developing suitable therapies

Optimal Entry Point for Lateral Mass Screwing

Study Design: Retrospective study of 37 consecutive female patients with cervical spondylotic myelopathy who underwent reconstructed computed tomography (CT) scanning of the cervical spine. Purpose: The purpose of this study was to investigate whether the vertebral lateral notch of the cervical spine is an effective landmark to determine the entry point for lateral mass screwing. A modified Roy-Camille technique was used to determine the entry point associated with the lateral notch of the cervical spine. Overview of Literature: The Roy-Camille technique has been a popular technique for the posterior fixation of the cervical spine. A problem with this technique is determining the entry point on the lateral mass via visual inspection, such as in cases with degenerative or destructive cervical facet joints. Methods: Thirty-three female patients with cervical spondylotic myelopathy underwent reconstructed CT scanning of the cervical spine. Overall, 132 vertebrae from C3 to C6 were reviewed using reconstructed CT. The probable trajectory using a modified Roy-Camille technique was determined using reconstructed CT scans, and the optimal entry point was identified. Horizontal and vertical distances from the vertebral lateral notch were measured. Results: The entry point determined using the modified Roy-Camille technique was significantly superior and medial compared with that determined using the conventional Roy-Camille technique. At C3 and C4 levels, the entry point using the modified technique was 1.4 mm below and 4.4 mm medial to the lateral notch, and at C5 and C6 levels, it was 2.3 mm below and 4.9 mm medial to the lateral notch. Conclusions: The vertebral lateral notch of the cervical spine was an effective landmark to determine the entry point for lateral mass screwing. The modified Roy-Camille technique proposed here may prevent surgical complications and poor outcomes

The Combination of Prognostic Nutritional Indicator and Serum Carcinoembryonic Antigen is Useful in Predicting Postoperative Recurrence in Stage II Colorectal Cancer

[Background] The efficacy of adjuvant chemotherapy in stage II colorectal cancer (CRC) patients has not been clearly demonstrated. Therefore, identification of robust prognostic factors is crucial for the assessment of recurrence risk in stage II CRC and appropriate adjuvant treatment, in clinical practice. [Methods] We enrolled 135 colorectal adenocarcinoma patients who underwent proctocolectomies and had histologically diagnosed stage II CRC. [Results] Receiver operating characteristic (ROC) analysis, to evaluate the predictive ability of certain serum factors for CRC recurrence, indicated that the prognostic nutritional indicator (PNI), followed by serum carcinoembryonic antigen (CEA) level, were the strongest predictive metrics. Based on cutoff values from ROC analyses, patients were divided as follows; CEAHigh (≥ 4.55 ng/mL), CEALow (< 4.55 ng/mL), PNIHigh (≥ 47.72), and PNILow (< 47.72). The recurrence rates of patients with CEAHigh and PNILow, CEAHigh and PNIHigh, CEALow and PNILow, and CEALow and PNIHigh were 34.3%, 0%, 6.8%, and 2.6%, respectively (a significant difference at P < 0.0001). Logistic regression analysis revealed that the combination of serum CEA level and PNI was an independent predictive indicator of tumor recurrence after operation in stage II CRC patients. The 5-year disease specific survival rates of patients with CEALowPNIHigh, CEAHighPNIHigh, CEALowPNILow, CEAHighPNILow were 100%, 100%, 97.4%, and 77.5%, respectively (P < 0.0001). [Conclusion] The combination of CEA and PNI was useful in predicting postoperative recurrence in stage II CRC patients

Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity