Alu-mediated large deletion of the CDSN gene as a cause of peeling skin disease.

Peeling skin disease (PSD) is an autosomal recessive skin disorder caused by mutations in CDSN and is characterized by superficial peeling of the upper epidermis. Corneodesmosin (CDSN) is a major component of corneodesmosomes that plays an important role in maintaining epidermis integrity. Herein, we report a patient with PSD caused by a novel homozygous large deletion in the 6p21.3 region encompassing the CDSN gene, which abrogates CDSN expression. Several genes including C6orf15, PSORS1C1, PSORS1C2, CCHCR1, and TCF19 were also deleted, however, the patient showed only clinical features typical of PSD. The deletion size was 59.1 kb. Analysis of the sequence surrounding the breakpoint showed that both telomeric and centromeric breakpoints existed within Alu-S sequences that were oriented in opposite directions. These results suggest an Alu-mediated recombination event as the mechanism underlying the deletion in our patient.

Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131).

Engaging inhibitory FcγRIIb by Fc region has been recently reported to be an attractive approach for improving the efficacy of antibody therapeutics. However, the previously reported S267E/L328F variant with enhanced binding affinity to FcγRIIb, also enhances binding affinity to FcγRIIa(R131) allotype to a similar degree because FcγRIIb and FcγRIIa(R131) are structurally similar. In this study, we applied comprehensive mutagenesis and structure-guided design based on the crystal structure of the Fc/FcγRIIb complex to identify a novel Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131). This novel variant has more than 200-fold stronger binding affinity to FcγRIIb than wild-type IgG1, while binding affinity to FcγRIIa(R131) and FcγRIIa(H131) is comparable with or lower than wild-type IgG1. This selectivity was achieved by conformational change of the C(H)2 domain by mutating Pro to Asp at position 238. Fc variant with increased binding to both FcγRIIb and FcγRIIa induced platelet aggregation and activation in an immune complex form in vitro while our novel variant did not. When applied to agonistic anti-CD137 IgG1 antibody, our variant greatly enhanced the agonistic activity. Thus, the selective enhancement of FcγRIIb binding achieved by our Fc variant provides a novel tool for improving the efficacy of antibody therapeutics.

A mathematical model for predicting outcome in preterm labour.

OBJECTIVE: This study aimed to develop a model for predicting the outcome and evaluating the treatment of patients with threatened of preterm labour. METHODS: Clinical data from 236 patients at <32 weeks gestation who were in preterm labour were analysed to develop a discriminant function using multiple logistic regression to identify significant risk factors. The function was validated retrospectively in a further 501 patients and prospectively in 63 patients with premature labour. RESULTS: Factors that increased the risk of preterm birth were premature rupture of the membranes, intrauterine infection, dilatation of the cervix and uterine bleeding. Factors that decreased the risk of preterm birth were hospital admission after 28 weeks of gestation and intravenous administration of ritodrine. The predictive accuracy of the function was 75.4% in the 236 patients analysed, 84.8% in the further 501 retrospectively studied patients and 85.7% in the prospective group. CONCLUSIONS: The discriminant function described was clinically useful for predicting the outcome of threatened preterm labour before initiating treatment and for determining the medical care of patients, including maternal transfer to a high-level perinatal care centre.

Rectangular mucosal flap with artificial dermis grafting for vermilion deformity in cleft lips.

UNLABELLED: The treatment of whistling deformity in patients with cleft lip remains controversial. Previous reconstruction methods of whistling deformity have been limited in volume due to the necessity for primary closure of the donor site. This article presents a new method for secondary reconstruction of the vermilion deformity in patients with cleft lip. Our method is very simple and advantageous, in that primary closure after correction is not required. A rectangular mucosal flap is designed at the wet mucosal aspect of the upper lip. Inferiorly, this flap is based at the junction of the vermilion and mucosa, while the upper incision line should be at the buccal sulcus. This rectangular flap is advanced sagittally, and a labial thickness is reconstructed. Artificial dermis is grafted to the mucosal defect after flap advancement and mucosa regenerates secondarily. We applied this technique to secondary reconstruction in 32 patients with cleft lip between January 2001 and January 2005. Major complications (necrosis of mucosal flap and recurrence of whistling deformity) did not occur in any of the patients. Four patients required minor operations to reduce the volume. CONCLUSIONS: This rectangular mucosal flap with artificial dermis offers many advantages, including easy technique and minimal sacrifices. The combination of mucosal flap and artificial dermis prevents postoperative scar contracture and reduces the limitations of using the available volume of flap. We believe that this procedure is versatile and reliable not only for whistling deformity in cleft lip patients, but also for tissue defects of the lip resulting from other causes.

[The efficacy of perioperative administration of steroid and erythromycin in the surgery for lung cancer complicated with interstitial pneumonia].

OBJECTIVES: We evaluated the efficacy of perioperative administration of steroid and erythromycin in surgery for lung cancer complicated with interstitial pneumonia (IP) to prevent postoperative acute exacerbation. PATIENTS AND METHODS: We operated on 21 lung cancer patients with IP for 10 years. The patients were given 400 mg of erythromycin over 1 week before surgery and re-administered on the 1st operative day. The patients were also given 125 mg of methylprednisolone intravenously just before operation and continued until the 2nd operative day. RESULTS: Lobectomy was performed in 16, segmentectomy or partial resection in 2 each, and completion pneumonectomy in 1. Three patients developed acute exacerbation of IP, but it occurred after the re-operation due to postoperative complications in 2. We experienced no operative death within 30 days, however, 2 died during the hospital stay due to multiple organ failure and sepsis. Seven of 21 patients had postoperative complications; air leakage over 1 week in 4, arrhythmia in 3, and atelectasis, postoperative bleeding, and pneumonia in 1 each, the morbidity rate was 33%. CONCLUSIONS: We conclude that the administration of steroid and erythromycin in surgery for lung cancer with IP was suspected the usefulness to prevent a postoperative acute exacerbation of IP.

A case of solitary pulmonary lymphangioma.

Solitary pulmonary lymphangiomas are rare benign lesions thought to result from the development of abnormally proliferating lymphatic vessels. This report describes a case of solitary pulmonary lymphangioma resected under video assisted thoracoscopic surgery and diagnosed using histological and immunohistochemical investigations.

Effect of SMP-500, a novel acyl-coA:cholesterol acyltransferase inhibitor, on the cholesterol esterification and its hypocholesterolemic properties.

We investigated the effects of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activities in the liver and intestine, and in macrophages. We measured its effects on the serum cholesterol levels and hepatic cholesterol content in mice, rabbits and hamsters. SMP-500 inhibited ACAT activities in rabbit liver and small intestine microsomes with IC(50) values of 72 and 84 nmol/l, respectively, and acted as a competitive inhibitor of rabbit liver ACAT. SMP-500 potently inhibited cholesterol esterification in rat peritoneal macrophages (IC(50) = 15 nmol/l). In high-fat and high-cholesterol diet-fed mice and in high-cholesterol diet-fed rabbits, SMP-500 reduced the serum cholesterol levels and the hepatic cholesterol content. SMP-500 also reduced the serum and hepatic cholesterol in normal chow-fed hamsters in a dose-dependent manner. In all the animal models, SMP-500 reduced the hepatic free cholesterol content as well as the total and esterified cholesterol. Administered orally, SMP-500 had a direct inhibitory effect on hepatic ACAT activity. These results indicate that SMP-500 is a potent and competitive ACAT inhibitor and may have a therapeutic potential for treating hypercholesterolemia and atherosclerosis.

Skeletal muscle regeneration associated with the stroma reaction during tumor invasion in the rat tongue.

This study was aimed to demonstrate the regeneration of skeletal muscle fibers in the stroma reaction during tumor invasion, using the rat model of tongue carcinoma. By oral administration of 4-nitroquinoline N-oxide, squamous cell carcinoma (SCC) appeared in the epithelium, and deeply invaded the muscular layer, inducing the stroma reaction around the tumor. Regenerating muscle fibers, characterized by the immature profiles of sparse myofibrils, centrally disposed multi-nuclei, and abundant mitochondria, were extended from the surrounding normal muscles into the stroma. By immunohistochemistry, some of them expressed BF-45, a marker for an early stage of myodifferentiation, similar to the regenerating muscle fibers in the bupivacaine hydrochloride-induced injury. They were closely associated with the stromal components such as ED-1-positive macrophages, alpha-smooth muscle actin-positive myofibroblasts, and factor VIII-related antigen-positive vascular endothelial cells, suggesting the roles of their interactions in muscle regeneration. Immature muscle fibers were usually devoid of acetylcholinesterase-positive endplates on them, but some were reinnervated by the terminal axons. The present results indicate that skeletal muscle regeneration is induced in association with the stroma reaction during SCC invasion in the tongue.

Fingertip replantation using a single volar arteriovenous anastomosis and drainage with a transverse tip incision.

Four cases of fingertip replantation using a single volar arteriovenous anastomosis and drainage with a transverse tip incision are reported. Because of lack of suitable arteries for anastomosis in the amputated finger, in each case a volar radial vein was anastomosed to the proximal digital artery and external drainage was performed through a transverse tip incision. In 3 cases the replanted fingertip survived completely; partial necrosis occurred in 1 case. Because veins are more superficial and larger than arteries, they are more available for anastomosis. The results indicate that this method is a useful alternative in fingertip replantation.

Insertion of intradermal needles into painful points provides analgesia for intractable abdominal scar pain.

BACKGROUND AND OBJECTIVES: Conventional treatments are often ineffective for patients having painful abdominal scars. There are painful points in and around scar tissue. We tested the hypothesis that insertion of intradermal needles into these painful points reduces scar pain. METHODS: Patients with abdominal scar pain with painful points that is not relieved by conventional treatments were allocated to a treatment group (n = 23), a sham-treatment group (n = 23), or a control group (n = 24). In the treatment group, intradermal needles were inserted into painful points detected by a pressure threshold meter (pain < or = 2.5 kg/cm(2)). In the sham-treatment group, the same needles were inserted into nonpainful points. The needles were kept in place for 24 hours. This process was repeated 20 times over a 4-week period. Responses were evaluated before and at the end of treatment, and 4 and 26 weeks after the treatment. Continuous and lancinating pain was evaluated on a 10-cm visual analog scale. We measured the area of pain and the pressure required to initiate painful-point pain. All patients took diclofenac as needed and completed a diary of daily diclofenac consumption. RESULTS: Patients in the treatment group showed a marked reduction in all pain parameters (>70%). In contrast, analgesia was minimal in the other groups. The decreases in the pain threshold pressure correlated with the decreases in continuous and lancinating pain (r =.57 and r =.63, respectively). CONCLUSION: Our data suggest that insertion of intradermal needles into painful points is a remarkably effective treatment for intractable abdominal scar pain. Analgesia presumably results from inactivation of painful points, through a yet to be elucidated mechanism.

Intraoperative prostaglandin E1 improves antimicrobial and inflammatory responses in alveolar immune cells.

OBJECTIVE: Anesthesia and surgery decrease antimicrobial and increase proinflammatory functions of alveolar immune cells. Thus, anti-inflammatory agents that do not further suppress antimicrobial functions are required. We tested the hypothesis that intraoperative prostaglandin E1 (PGE1) suppresses proinflammatory responses and prevents the reduction in antimicrobial responses of alveolar immune cells. DESIGN: Prospective, randomized, controlled, double-blind study. SETTING: University hospital. PATIENTS: A total of 40 patients undergoing elective orthopedic surgery under propofol/fentanyl anesthesia. INTERVENTION: In double-blind fashion, the patients received PGE1 from the beginning to the end of surgery (PGE1 group, n = 20) or nothing (control group, n = 20). METHODS AND MAIN RESULTS: Alveolar immune cells were harvested by bronchoalveolar lavage immediately after induction of anesthesia; 2, 4, and 6 hrs after induction of anesthesia; and at the end of surgery. We measured opsonized and nonopsonized phagocytosis. Microbicidal activity was evaluated to directly kill Listeria monocytogenes in alveolar macrophages. Finally, we determined the expression of proinflammatory cytokines including interleukin (IL)-1beta, IL-8, interferon-gamma, and tumor necrosis factor-alpha, and that of anti-inflammatory cytokines (IL-4 and IL-10) by semiquantitative polymerase chain reaction. Nonopsonized and opsonized phagocytosis and microbicidal activity of alveolar macrophages decreased and the expression of genes for all pro- and anti-inflammatory cytokines increased significantly over time in both groups. Starting 2-4 hrs after induction of anesthesia, the increases in gene expression of proinflammatory cytokines were 1.5-3 times smaller in the PGE1 than in the control group. Starting 6 hrs after anesthesia, the increase in gene expression of IL-10 was 1.5-3 times greater in the PGE1 than in the control group. Intraoperative decreases in phagocytic and microbial activities were the same in the two groups. CONCLUSION: Intraoperative PGE1 not only suppressed proinflammatory responses, but also protected antimicrobial functions of alveolar macrophages, possibly because PGE1 is mostly inactivated in the pulmonary intravascular space. Our results suggest that intraoperative PGE1 protects the pulmonary immune defense in alveolar immune cells.

UDP-sugar transporter implicated in glycosylation and processing of Notch.

Glycosylation modifies protein activities in various biological processes. Here, we report the functions of a novel UDP-sugar transporter (UST74C, an alternative name for Fringe connection (Frc)) localized to the Golgi apparatus in cellular signalling of Drosophila. Mutants in the frc gene exhibit phenotypes resembling wingless and Notch mutants. Both Fringe-dependent and Fringe-independent Notch pathways are affected, and both glycosylation and proteolytic maturation of Notch are defective in mutant larvae. The results suggest that changes in nucleotide-sugar levels can differently affect Wingless and two distinct aspects of Notch signalling.

Completion pneumonectomy for recurrent or second primary lung cancer.

OBJECTIVE: We studied 8 patients undergoing completion pneumonectomy for recurrent or second primary lung cancer. METHODS: Subjects were men who averaged 62 years of age. Of these 6 had p-stage I, and 2 p-stage II disease at initial operation. At the second operation, we diagnosed 3 with second primary lung cancer and 5 with recurrent lung cancer. We predicted postoperative pulmonary function by calculating the predicted forced expiratory volume in 1.0 second (FEV1.0) from residual numbers of subsegments after completion pneumonectomy. All predicted FEV1.0 in our 8 cases ranged from 544 to 926 (773 +/- 144) ml/m2. RESULTS: Six patients experienced postoperative complications and morbidity was 75%. One patient undergoing completion sleeve pneumonectomy after radiation therapy for local carina recurrence died on 7th postoperative day due to anastomotic dehiscence and pneumonia. Overall operative mortality was 12.5% (1/8). Four remain alive and actuarial 5-year survival was 37.5%. CONCLUSIONS: Careful consideration is needed in determining operative indications for completion pneumonectomy for patients after radiation therapy. Patients with recurrent squamous cell carcinoma who have p-stage I disease at initial operation and those with second primary lung cancer and p-stage I or II disease can expect relatively a long-term survival, and we concluded that completion pneumonectomy could be conducted in these cases with a satisfactory prognosis.

Rebound perioperative hyperkalemia in six patients after cessation of ritodrine for premature labor.

IMPLICATIONS: This report describes six patients who had marked hyperkalemia 60-150 min after cessation of intravenous ritodrine, which had been administered for management of preterm labor. Abnormal electrocardiographic findings are very important clues for a prompt diagnosis of hyperkalemia.

Recovery of intraoperative microbicidal and inflammatory functions of alveolar immune cells after a tobacco smoke-free period.

BACKGROUND: Tobacco smoking inhibits alveolar macrophage function, but cessation of smoking markedly reduces the risk of postoperative pulmonary complications. The authors therefore evaluated the effect of nonsmoking duration on both antimicrobial and inflammatory functions of alveolar macrophages during anesthesia and surgery. METHODS: The authors studied 15 patients who had never smoked, 15 current smokers, and 41 former smokers, all of whom underwent general anesthesia. Former smokers were further allocated to one of three groups depending on their smoke-free periods: 2 months (n = 13), 3-5 months (n = 13), and 6-12 months (n = 15). Alveolar immune cells were collected by bronchoalveolar lavage immediately after induction of anesthesia, at 2 and 4 h after induction of anesthesia, and at the end of surgery. Opsonized and nonopsonized phagocytosis were measured. Microbicidal activity was determined as the ability of the macrophages to kill Listeria monocytogenes directly. Finally, we determined the expression of proinflammatory cytokines, including interleukin 1beta, interleukin 8, interferon gamma, and tumor necrosis factor alpha, and of antiinflammatory cytokines (interleukin 4 and 10) by semiquantitative polymerase chain reaction. RESULTS: Nonopsonized and opsonized phagocytosis and microbicidal activity of alveolar macrophages (antimicrobial functions) decreased 20-50%, and the expression of genes for all proinflammatory and antiinflammatory cytokines increased 3-30-fold over time in all groups. Starting 4 h after induction of anesthesia, the decreases in antimicrobial functions were 1.5-3 times greater in current and former smokers (2 months' abstinence) than in patients who had never smoked. Starting 4 h after anesthesia, the increase in expression of all cytokines, except interleukin 8, was twofold to fivefold less in current and former smokers (2-6 months' abstinence) than in patients who had never smoked. CONCLUSION: Our data suggest that former smokers may have a limited ability to mount effective pulmonary immune defenses for long as 6 months after stopping cigarette use.

[A surgical treatment for ischemic heart disease associated with systemic lupus erythematodes: report of a case].

We reported a case of coronary artery bypass grafting (CABG) associated with systemic lupus erythematodes (SLE). A 45-year-old male who had been treated for SLE with prednisolone for 9 years was transferred to our department for a surgical treatment due to ischemic heart disease (IHD). We successfully performed CABG resolving various perioperative complications. The intensive care is indispensable in the case of IHD with SLE.

Organochlorine pesticides, polychlorinated biphenyls, and butyltin compounds in blubber and livers of stranded California sea lions, elephant seals, and harbor seals from coastal California, USA.

Concentrations of polychlorinated biphenyls (PCBs), DDTs (p,p'-DDE, p,p'-DDD, p,p'-DDT), chlordanes (CHLs; cis-chlordane, cis-nonachlor, trans-nonachlor, and oxychlordane), hexachlorocyclohexane isomers (HCHs), hexachlorobenzene (HCB), tris(4-chlorophenyl)methane (TCPMe), tris(4-chlorophenyl)methanol (TCPMOH), and mono- (MBT), di-(DBT), and tri-butyltin (TBT) were determined in blubber and livers of 15 California sea lions (Zalophus californianus), 6 northern elephant seals (Mirounga augustirostris), and 10 harbor seals (Phoca vitulina) found stranded along the coasts of California, USA, during 1991-1997. Among the organochlorines analyzed, DDTs were predominant, followed in decreasing order by PCBs, CHLs, TCPMe, TCPMOH, HCHs, and HCB. The greatest concentrations of organochlorines were found in California sea lions. The highest DDT and PCB concentrations found in the blubber of California sea lions were 2,900 and 1,300 microg/g, lipid weight, respectively. Concentrations of TCPMe and TCPMOH in California sea lions were correlated significantly with DDT concentrations. Concentration ratios of various organochlorines in harbor seal livers were different from those in California sea lions and elephant seals, which suggested that the sources of exposure of harbor seals to organochlorines were different from those in the other two species. Concentrations of butyltin compounds in livers of pinniped species ranged from 2 to 99 ng/g, wet weight, which were less than those observed in cetaceans and in California sea otters.

Molecular characterization of human UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter, a novel nucleotide sugar transporter with dual substrate specificity.

A novel human nucleotide sugar transporter (NST) which transports both UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetylgalactosamine (UDP-GalNAc) has been identified, cloned and characterized. The strategy for the identification of the novel NST involved a search of the expressed sequence tags database for genes related to the human UDP-galactose transporter-related isozyme 1, followed by heterologous expression of a candidate gene (hUGTrel7) in Saccharomyces cerevisiae and biochemical analyses. Significantly more UDP-GlcA and UDP-GalNAc were translocated from the reaction medium into the lumen of microsomes prepared from the hUGTrel7-expressing yeast cells than into the control microsomes from cells not expressing hUGTrel7. The possibility that this transporter participates in glucuronidation and/or chondroitin sulfate biosynthesis is discussed.