Central tegmental tract lesion in a girl with holoprosencephaly presenting with West syndrome

We described a 16-month-old female patient who developed West syndrome at 3 months of age. MRI revealed a holoprosencephaly with incomplete fusion of the cerebrum, associated with central tegmental tract (CTT) lesions. At 1 year of age, the CTT lesion was still present on T2-weighted MRI. The CTT represents an important projection pathway of the extrapyramidal tract and the CTT lesions have rarely been reported using MRI in patients with neonatal hypoxic–ischemic encephalopathy and several inborn errors of metabolism. Although the exact mechanism remains obscure, we suggest that disturbances in midbrain fibers that connect to the basal ganglia, may have contributed to the etiology of West syndrome in this patient.     

Complexation of Bisphenol A with Calix[6]arene‐Polymer Conjugates

Sodium calix[6]arenehexasulfonic acid (SCX₆) was introduced into polymer molecules by the cross‐linking of SCX₆ with epichlorohydrin (PolySCX₆) or by the covalent binding of carboxymethylated SCX₆ to an amino group‐carrying vinyl polymer (Poly(SCX₆HMA‐co‐AAm)). The complexation of bisphenol A (BPA) with the SCX₆ group in the polymers was examined fluorimetrically using acridine red (AR) as a probe. From the inhibitory effect of BPA on the complexation of AR with the SCX₆ group in the polymers, the association constant (K_assoc) of BPA with the SCX₆ group was evaluated and the value for BPA with the SCX₆ group in Poly(SCX₆HMA‐co‐AAm) was much larger than that with the non‐conjugated SCX₆, probably because of the support of hydrophobic interactions between the guest and the hydrocarbon moieties in the polymer (polymer main chain and hexamethylene groups introduced for the conjugation of SCX₆). The K_assoc value for bisphenol B (BPB) with a non‐conjugated SCX₆ was larger than those for bisphenol A and bisphenol F, because of the higher hydrophobicity of BPB among the bisphenols examined. Thermodynamic parameters indicated that the inclusion of BPA into the cavity of sodium propyloxycalix[6]arenehexasulfonic acid (SPCX₆) was enthalpy driven, and the entropy change was largely negative (?92 J · mol^?1 · K^?1). This is probably because of a tight fit of guest molecules in the SPCX₆ cavity, resulting in the loss of freedom of both the SPCX₆ and the guest molecules. The entropy change for the complexation of BPA with the SCX₆ group in the polymer was less negative, probably because of a partial release of water molecules around the SCX₆ group upon the complexation. The effect of the structure of guest and host molecules on the complexation was also examined.

Chemical structure of various calix[6]arenes: R = H, sodium calix[6]arenehexasulfonic acid; R = C₃H₇, sodium propyloxycalix[6]arenehexasulfonic acid; R = C₄H₉, sodium butyloxycalix[6]arenehexasulfonic acid; R = C₆H₁₃, sodium hexyloxycalix[6]arenehexasulfonic acid.     

Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis

Anaphylaxis is an acute, severe, and potentially fatal systemic allergic reaction. Immunoglobulin E (IgE), mast cells, and histamine have long been associated with anaphylaxis, but an alternative pathway mediated by IgG has been suggested to be more important in the elicitation of anaphylaxis. Here, we showed that basophils, the least common blood cells, were dispensable for IgE-mediated anaphylaxis but played a critical role in IgG-mediated, passive and active systemic anaphylaxis in mice. In vivo depletion of basophils but not macrophages, neutrophils, or NK cells ameliorated IgG-mediated passive anaphylaxis and rescued mice from death in active anaphylaxis. Upon capture of IgG-allergen complexes, basophils released platelet-activating factor (PAF), leading to increased vascular permeability. These results highlight a pivotal role for basophils in vivo and contrast two major, distinct pathways leading to allergen-induced systemic anaphylaxis: one mediated by basophils, IgG, and PAF and the other "classical" pathway mediated by mast cells, IgE, and histamine.     

Loss of tumor necrosis factor alpha potentiates transforming growth factor beta-mediated pathogenic tissue response during wound healing

Animal cornea is an avascular transparent tissue that is suitable for research on wound healing-related scarring and neovascularization. Here we show that loss of tumor necrosis factor alpha (TNFalpha) potentiates the undesirable, pathogenic response of wound healing in an alkali-burned cornea in mice. Excessive invasion of macrophages and subsequent formation of a vascularized scar tissue were much more marked in TNFalpha-null knockout (KO) mice than in wild-type mice. Such an unfavorable outcome in KO mice was abolished by Smad7 gene introduction, indicating the involvement of transforming growth factor beta or activin/Smad signaling. Bone marrow transplantation from wild-type mice normalized healing of the KO mice, suggesting the involvement of bone marrow-derived inflammatory cells in this phenomenon. Co-culture experiments showed that loss of TNFalpha in macrophages, but not in fibroblasts, augmented the fibroblast activation as determined by detection of alpha-smooth muscle actin, the hallmark of myofibroblast generation, mRNA expression of collagen Ialpha2 and connective tissue growth factor, and detection of collagen protein. TNFalpha in macrophages may be required to suppress undesirable excessive inflammation and scarring, both of which are promoted by transforming growth factor beta, and for restoration of tissue architecture in a healing alkali-burned cornea in mice.     

Nerve fiber analysis for the lingual nerve of the human adult subjects

The neuro-motor control of the human tongue musculature had not been investigated in detail. This study identified first that the lingual nerve should play the neuro-motor control of some lingual muscles. Six en bloc samples (12 sides), including the tissues from the skull base to the hyoid bone, and three whole tongues were obtained from adult human cadavers. The former samples were used for the study of nerve fiber analysis of the lingual nerve with the aid of binocular stereomicroscope, and the latter samples were used for histological study by serial section method. On nerve fiber analysis of the lingual nerve from the trigeminal ganglion to the tongue musculature, we found that the motor- root of the trigeminal nerve gave off its supply to the lingual nerve and traveled into the lingual nerve, and branched to the superior and the inferior longitudinal muscles. On histological study, it was revealed that in the anterior part of the tongue the superior and the inferior longitudinal muscles surrounded the other lingual musculature and combined with the sub-mucosal connective tissues closely like the cutaneous muscle, for example, the facial muscles. The lingual nerve entered the inner side of the space between the genioglossus and the inferior longitudinal muscles with the lingual artery. These findings suggested that the superior and the inferior longitudinal muscles should be innervated by the motor fibers traveled into the lingual nerve from the motor root of the trigeminal nerve, and do not originate from the myotome originating in occipital somites but branchial muscles.     

Increase of nuclear ceramide through caspase-3-dependent regulation of the "sphingomyelin cycle" in Fas-induced apoptosis

Regardless of the existence of ceramide-related molecules, such as sphingomyelin (SM), neutral sphingomyelinase (nSMase), and SM synthase, in the nucleus, the regulation of ceramide in the nucleus is poorly understood in stress-induced apoptosis. In Fas-induced Jurkat T-cell apoptosis, we found a time- and dose-dependent increase of ceramide content in the nuclear and microsomal fractions. Fas-induced increase of ceramide content in the nucleus also was detected by confocal microscopy using anticeramide antibody. Activation of nSMase and inhibition of SM synthase were evident in the nuclear fraction after Fas cross-linking, whereas nSMase was activated, but SM synthase was not affected, in the microsomal fraction. Pretreatment with D-609, a putative SM synthase inhibitor, enhanced Fas-induced increase of ceramide in the nucleus and induction of apoptosis along with increase of Fas-induced inhibition of nuclear SM synthase. Fas-induced activation of caspase-3 was detected in the nuclear fraction and in whole cell lysate. A caspase-3 inhibitor, acetyl-Asp-Glu-Val-Asp-chloromethyl ketone, blocked not only Fas-induced increases of apoptosis and ceramide content but also Fas-induced activation of nSMase and inhibition of SM synthase in the nuclear fraction. Taken together, it is suggested that the nucleus is a site for ceramide increase and caspase-3 activation in Fas-induced Jurkat T-cell apoptosis and that caspase-3-dependent regulation of the "SM cycle" consisting of nSMase and SM synthase plays a role in Fas-induced ceramide increase in the nucleus.     

A case of 5-FU-resistant recurrent colon cancer treated with low-dose CPT-11/CDDP on an outpatient basis

We report a case of recurrent colon cancer resistant to 5-FU, whose QOL and PS has been well maintained with low-dose CPT-11/CDDP administered on an outpatient basis for more than 28 months. A 42-year-old male had lymph node recurrence 27 months after curative resection of colon cancer. He had been administered pharmacokinetic modulating chemotherapy (PMC, oral tegafur/uracil plus fluorouracil infusion) after surgery. Combined treatment with CPT-11 (50 mg/m2)/CDDP (6 mg/m2) was performed on an outpatient basis. Nine months of NC was obtained without any severe side effect. Modified administration of this treatment with 5'-DFUR and TS-1 lead to further maintenance of quality of life and performance status. This case suggests the efficacy of low-dose CPT-11/CDDP for cases of 5-FU-resistant colon cancer in terms of QOL and PS.     

N-cadherin is regulated by activin A and associated with tumor aggressiveness in esophageal carcinoma.

PURPOSE: Activin A is a member of the transforming growth factor beta superfamily and plays an important role in the differentiation of embryonic stem cells. We have reported previously that the expression of activin A is associated with lymph node metastasis in esophageal cancer, and our purpose in the current work is to clarify the molecular mechanism of the aggressive behavior of tumors that have high activin A expression. EXPERIMENTAL DESIGN: We have compared the gene expression profiles of human esophageal carcinoma cell lines that were stably transfected with activin beta A, which is a subunit of activin A, with those of control human esophageal carcinoma cell lines, using a cDNA microarray. RESULTS: We found that the expression level of neuronal cadherin (N-cadherin) was higher in the transfectants than in the control cells. N-cadherin was located on the cell surface of the transfectants, irrespective of the expression of epithelial cadherin (E-cadherin), and the expression of N-cadherin mRNA was significantly associated with that of activin beta A mRNA in clinical samples of esophageal carcinoma (n = 51; r = 0.855). A clinicopathologic analysis suggested that expression of N-cadherin mRNA was associated with the depth of tumor wall invasion, and a group of patients with high expression of N-cadherin mRNA showed a significantly poorer prognosis than a group of patients with low N-cadherin expression (P = 0.046). CONCLUSIONS: These results indicate that activin A might mediate the expression of N-cadherin and that this may be associated with depth of invasion and poor prognosis.     

Pregnancy-associated plasma protein-A polymorphism and the risk of recurrent pregnancy loss

Pregnancy-associated plasma protein-A (PAPP-A)/insulin-like growth factor-binding protein-4 (IGFBP4) protease is a member of the metzincin family of metalloproteases, known as a sensitive biomarker of adverse pregnancy outcomes. Recently, a missense A/C (Tyr/Ser) polymorphism (dbSNP: rs7020782) in the PAPPA gene has been reported. To examine the association between recurrent pregnancy loss (RPL) and this polymorphism, a case-control study of 215 cases with two or more pregnancy losses (PLs) and 420 fertile controls was performed. Genotyping of the PAPPA polymorphism was determined by allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Sixty-nine cases (32.1%) were heterozygous and 11 cases (5.1%) were homozygous for the C allele of PAPPA; the respective figures were 127 (30.2%) and 11 (2.6%) in the controls. Women carrying the C allele had a tendency to increased risk of RPL (AA genotype [reference]; AC genotype: odds ratio [OR], 1.17; 95% confidence interval [CI], 0.82–1.68; CC genotype: OR, 2.06; 95% CI, 0.87–4.90), but it was not significant. Women with three or more PLs had a similar tendency (AA genotype [reference]; AC genotype: OR, 1.04; 95% CI, 0.66–1.64; CC genotype: OR, 2.20; 95% CI, 0.82–5.91). The risk of RPL with at least one PL after 9 weeks’ gestation significantly increased in women carrying the C allele (AA genotype [reference]; AC genotype: OR, 1.54; 95% CI, 0.95–2.49; CC genotype: OR, 2.83; 95% CI, 1.00–8.05; AC + CC genotypes: OR, 1.65; CI, 1.04–2.62). This is the first report on the PAPPA gene polymorphism in women with RPL, demonstrating some association between the investigated polymorphism and the risk of RPL.