Nicotinamide mononucleotide inhibits oxidative stress-induced damage in a SIRT1/NQO-1-dependent manner.

Oxidative stress causes endothelial dysfunction, which is associated with vascular cellular aging and is causally related to cardiovascular disease pathogenesis. Preclinical studies indicate that a nicotinamide adenine dinucleotide (NAD+) precursor, nicotinamide mononucleotide (NMN), alleviates oxidative stress in aged vessels, granting vasoprotective effects. However, the associated cellular mechanism remains largely unclear. In this study, we used human umbilical vein endothelial cells (HUVECs) to demonstrate that NMN inhibits oxidative stress-induced damage by activating the sirtuin 1 (SIRT1)/NAD(P)H: quinone oxidoreductase 1 (NQO-1) axis. We found that NMN inhibited H2O2-induced cytotoxicity and senescence-associated protein expression, such as p16 and p21. Furthermore, NMN prevented H2O2-induced actin cytoskeletal disorganization via inhibiting reactive oxygen species (ROS) production. NMN increased NQO-1 mRNA and protein expression that in turn was abrogated by SIRT1 inhibition, suggesting that NMN-inducible NQO-1 was associated with SIRT1 activity. SIRT1 and NQO-1 inhibition attenuated the inhibitory effect of NMN on H2O2-inducible cytotoxicity, senescence-related protein upregulation, and actin cytoskeletal disorganization. Our findings provide new insights into the mechanism by which NMN exerts protective effects against vascular oxidative stress.

Reliability and validity of DESIGN, a tool that classifies pressure ulcer severity and monitors healing.

OBJECTIVE: This study reviews the validity and reliability of DESIGN, a tool for classifying pressure ulcer severity and monitoring progression towards healing. Only the tool's healing progression component was evaluated. METHOD: Inter-rater reliability was evaluated by calculating the agreement rate of scores, based on eight photos of pressure ulcers and six actual ulcers, made by a panel of seven nurses. Validity was assessed, using the same eight photos, by comparing DESIGN scores with those made using the validated Pressure Sore Status Tool (PSST). RESULTS: The DESIGN inter-rater reliability results showed a high correlation of r = 0.98 for the photos and r = 0.91 for the real-life patients with pressure ulcers, respectively, for all seven raters based on total scores. For validity, a correlation greater than 0.91 was found between the DESIGN and PSST scores. CONCLUSION: Based on our results, DESIGN was found to have both high inter-rater reliability and high validity among the seven nurses who quantitatively evaluated the wound-healing progress of the pressure ulcers in this study.

Significant gene expression of insulin-like growth factor II and proliferating cell nuclear antigen in a rapidly growing recurrent pituitary acth-secreting adenoma.

BACKGROUND: We quantified the expression of various growth-related factors in an adrenocorticotropic hormone (ACTH)-secreting adenoma that had recurred very rapidly as invasive macroadenoma. METHODS/RESULTS: A 43-year-old woman underwent successful transsphenoidal surgery for Cushing's disease. Seven years later, she was admitted to our ward for further endocrine examinations. In spite of a very high plasma ACTH level, the serum cortisol level was normal. Discrepancies between ACTH and cortisol levels were detected on the basis of diurnal rhythms, dexamethasone suppression tests, and corticotropin-releasing hormone test. The patient showed no clinical features of Cushing's disease. Magnetic resonance imaging of the pituitary showed an almost empty sella, and no microadenoma was found. These results, along with those of Sephadex column gel filtration and high-performance liquid chromatography of plasma-immunoreactive ACTH, suggested that the patient's residual corticotrophs secreted biologically inactive ACTH. Two years later, the patient suddenly developed diplopia and right abducens nerve palsy. She was slightly moonfaced and centrally obese. Her plasma ACTH and serum and urinary free cortisol levels were elevated, although discrepancies between ACTH and cortisol still existed. Magnetic resonance imaging revealed a large pituitary mass with suprasellar and cavernous sinus extensions. The tumor was excised, and the proopiomelanocortin gene and the expression of growth-related factors were analyzed. No mutations were found in the ACTH-coding region of the proopiomelanocortin gene. A significant expression of insulin-like growth factor II and proliferating cell nuclear antigen mRNAs was demonstrated. A high MIB-1 antibody labeling index was also detected in the adenoma tissue, suggesting high Ki-67 expression. CONCLUSION: These growth- and proliferation-related factors might be involved in the rapid growth and aggressiveness of this patient's pituitary adenoma.

[Immunohistochemical study on the expression of copper and zinc-superoxide dismutase (Cu, Zn-SOD) in human adenohypophysis and pituitary adenomas].

A location of copper and zinc- superoxide dismutase (Cu, Zn-SOD) in adenohypophysis and pituitary adenomas was examined with immunohistochemical technique. Pituitary adenomas include thirteen functioning, five nonfunctioning; functioning adenomas consist seven prolactinomas, four growth hormone (GH) secreting, two adrenocorticotropic hormone (ACTH) secreting adenomas. Three specimens of normal adenohypophysis were used for control study. The Cu, Zn-SOD was localized diffusely in the cytoplasm of normal adenohypophyseal cells and the tumor cells. Sometimes immunoreactive products of Cu, Zn-SOD revealed in the cytoplasm of endothelial cell, neutrophil, macrophage and the cell membrane of erythrocyte in the vessels. The content of Cu, Zn-SOD in normal adenohypophyseal cells and pituitary adenomas was markedly higher in normal cells than adenoma cells. No significant difference of the SOD content was observed not only in non-functioning adenoma but also in functioning adenoma cells including PRL, GH and ACTH cells.

Comprehensive planning of operative strategy for separation of ischiopagus tripus twins with particular reference to quality of life.

A 27-year-old mother was diagnosed by prenatal ultrasonography as having triplets at gestational age 32 weeks. Following cesarean section at 37 weeks, a pair of female babies were noted for the first time to be joined by a common pelvis with three lower limbs. They had separate upper gastrointestinal tracts, which joined in the distal ileum, leading to a common colon, rectum, and a single anus. Each twin had a functioning kidney, with a single ureter leading to a common bladder. A common urethra originating from the bladder neck ran into the urogenital sinus of one baby. Prior to the surgical separation, placement of four tissue expanders and 20 pneumoperitoneums were performed, in order to stretch the parietes for easier approximation of the wound edges. At 13 months of age, separation was performed, requiring 17 hours. The skin and musculature from the conjoined third leg was used as a fillet for abdominal wall closure in each patient. One infant was given the distal half of the colon and an entire anus with a temporary jejunostomy, and the right half of the bladder with the urethra. The other infant was given the proximal half of the colon with a permanent colostomy, and the left half of the bladder with permanent cystostomy using appendiceal pedicle graft (Mitrofanoff's procedure). This is the 10th case of surgical separation in ischiopagus tripus twins reported in the literature, and the seventh successful separation with both patients alive.

Advantages and pitfalls of amnion inversion repair for the treatment of large unruptured omphalocele: results of 22 cases.

This is a report of our experience with 22 cases of large unruptured omphaloceles treated by amnion inversion during the period 1973 through 1990. The method is characterized by three stages: (1) a silastic sheet is sutured directly to the skin around the amniotic membrane, under local anaesthesia, without dissection between the skin and the amnion; (2) the reduction of herniated viscera into the abdominal cavity is achieved by squeezing the sheeting using a specially modified stapler; and (3) the amniotic membrane is preserved intact, and inverted into the abdominal cavity at the time of abdominal wall closure. Of the 22 infants, 19 survived with satisfactory results. Two patients died of multiple associated anomalies, and the remaining patient died of sepsis arising at the time of the final abdominal closure. This procedure has proved to be effective and safe for high-risk patients with congenital heart diseases, anal atresia, tracheoesophageal fistula, or bronchial stenosis and prematurity. The practical aspects of the procedure, as well as its advantages and pitfalls, are illustrated.

Prader-Willi syndrome with del(15)(q11,q13) associated with hepatoblastoma.

A case of Prader-Willi syndrome who later developed hepatoblastoma is reported. Prader-Willi syndrome was suspected because of hypotonia, hypopigmentation, and undescended testes when he was a newborn infant. The diagnosis was confirmed by chromosome analysis, which showed 46XY del(15)(q11, q13). When he was 1 year 4 months old, a liver tumor and high serum AFP were found. At operation a large tumor arising from the caudate lobe was found and the tumor was totally resected. After completion of the hepatectomy, he developed circulatory collapse of unknown cause and died shortly after the operation. Histopathologic examination revealed that the tumor was composed of two components, well differentiated cells and poorly differentiated cells. The well differentiated part did not dominate the poorly differentiated part, so it was diagnosed as poorly differentiated hepatoblastoma. This is the first reported case of Prader-Willi syndrome with a pediatric malignant tumor.

Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children.

Analysis of data from the Kanto-Ko-Shin-Etsu Branch of the Japan Children's Cancer Registry revealed that mass screening for neuroblastoma increased the detection of cases in infants younger than 1 year from about 25% before screening to about 50%, and the percentage of neuroblastomas among all pediatric cancers almost doubled, from approximately 10% to 19.3%. However, when the cases found on screening were subtracted, the numbers after the onset of mass screening were similar to those before screening. It is likely that neuroblastoma mass screening has identified a unique type of tumor, which may not be recognized without mass screening, rather than that it has contributed to the earlier diagnosis of tumors in older children.

Proposal and assessment of Japanese tumor node metastasis postsurgical histopathological staging system for neuroblastoma based on an analysis of 495 cases.

In 1971, the Japanese Society of Pediatric Surgeons' Committee on Malignancies proposed new criteria for neuroblastoma staging. It was fundamentally, based on the system of Evans et al. described in 1971. The main difference was the separation of stage IV disease into stages IV-A, with metastases to bone, orbita, distant lymph nodes and viscera other than liver, IV-B, the primary tumor extending over the midline and with metastases to bone marrow, liver and skin, and IV-S, which was the same as that of Evans et al. The new criteria did not include the resectability of the primary tumor, assessment of regional lymph node involvement or any other disease assessment resulting from therapeutic intervention. For the purpose of international usage, the Japanese system has been newly formulated and proposed as the Japanese Tumor Node Metastasis (TNM) Postsurgical Histopathological Classification for Neuroblastoma. In the present report, 495 neuroblastomas, registered between 1970 and 1985, were analyzed retrospectively according to the International Union Against Cancer (UICC) TNM classification and the proposed Japanese TNM system. The analyses suggested that the Japanese system reflected both the extent of tumor invasion and its biological neuroblastoma characteristics better than the UICC TNM classification based on statistical analysis.

Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the Study Group of Japan.

One hundred nine newly treated patients with advanced neuroblastoma were entered in this study between January 1985 and May 1989. The eligible patients included infants younger than 12 months of age with Stage IVA disease (bone cortex, distant lymph node, and/or remote organ metastases) and patients aged 12 months or older with Stage III or IV disease (IVA plus IVB with tumor crossing the mid-line and with metastases confined to bone marrow, liver, and skin). The patients first received six cyclic course of intensive chemotherapy (regimen A1), consisting of cyclophosphamide (1200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (pyrarubicin; 40 mg/m2), and cisplatin (90 mg/m2). Original tumors and the regional lymph node metastases were removed some time during these first six cycles of chemotherapy. The patients were further divided into three groups. Patients in course 1 received alternating treatment by regimen B (cyclophosphamide and ACNU) and intensified regimen A1, and those in course 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in course 3 were treated with bone marrow transplantation (BMT) preceded by high-dose preconditioning chemotherapy. Survival rates were 77% in Stage III and 54% in Stage IV at 2 years, and 70% in Stage III and 45% in Stage IV at 3 years. The major toxicities encountered were bone marrow suppression with leukocyte counts down to 100/mm3, mild cystitis, and hearing impairment. The 2-year survival rate was 78% in 21 patients who underwent BMT when complete remission was achieved. We concluded that our intensive induction chemotherapy is of significant value in increasing the rate of complete response, and in widening the indications for and achieving improved results of treatment with BMT.

Mid-cervical malignant pleomorphic adenoma presenting with upper airway obstruction.

The case of a 1 year and 6 months old girl with pleomorphic adenoma arising from the upper middle part of the neck is reported. Although the tumor invaded the hyoid bone, it was removed completely and symptoms of upper airway obstruction disappeared. We suspect it may have originated from thyroglossal duct structures.

Intussusception-type antireflux valve in the Roux-en-Y loop to prevent ascending cholangitis after hepatic portojejunostomy.

An intussusception-type antireflux valve was created in the Roux-en-Y loop in 23 infants with biliary atresia (17 new cases, and six others after episodes of ascending cholangitis) and 10 patients with congenital bile duct dilatation, in order to prevent ascending cholangitis after hepatic portojejunostomy. Mesenteric blood vessels were divided in a 4 cm length of the Roux-en-Y loop, and the distal 1.5 cm of this portion was further denuded of the seromuscular layer; an antireflux valve was thus established by invaginating the proximal portion into the denuded jejunum. No case, in which this technique was used, was associated with any surgical complications, and ascending cholangitis never developed in any of the 17 new cases with biliary atresia, during an average follow-up of 32 months.

[A preliminary treatment report of the Study Group of Japan for Advanced Neuroblastoma].

We present preliminary treatment results of a nation-wide cooperative clinical study for advanced neuroblastoma supported by a grant-in-aid for cancer research from the Japanese Ministry of Health and Welfare. This study involves 28 major pediatric oncology institutions in Japan and started in May, 1985. Until 1987 we treated 84 patients with stage III and IV neuroblastoma whose prognosis was considered to be extremely poor. Every patient who entered this study received 6 cycles of A1 protocol consisted of high dose cyclophosphamide, vincristine, cis-platinum and THP-adriamycin, a newly introduced low-cardiotoxic anthracycline derivative. Having received 6 cycles of A1 protocol, patients were divided into 3 groups, i.e., ACNU course, DTIC course and bone marrow transplantation course preconditioned by high dose melphalan. Of 77 patients who received more than 3 cycles of A1 protocol, tumor extirpation was performed in 69 patients. Total or subtotal resection of the original tumor and the regional lymph-nodes was possible in 57 cases. The high resectability of the tumor indicates marked effectiveness of this protocol. Of the 57 patients who followed this treatment protocol from the beginning (virgin case), 31 (54.4%) showed complete response and 26 still remains in complete remission. 93.0% of response rate (CR + PR) was obtained by the treatment protocols, which was considerably high as compared with the results of other treatment protocol reported. This protocol also worked well in the patients who had failed with other treatment protocol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cyclophosphamide, cis-platinum, nitrosourea (ACNU), melphalan, and dacarbazine on a cytogenetically highly malignant neuroblastoma xenograft.

The effects of eight different chemotherapeutic agents were studied on a human neuroblastoma xenograft, designated TNB9, according to the standard Battelle Columbus Laboratories protocol. Cytogenetically and molecular-cytogenetically, this xenograft is known to have a homogeneously staining region (HSR) on chromosome 20 and to exhibit 60- to 80-fold amplification of clone #8 (1.75 kb) and N-myc (2.1 kb) in the HSR. Our previous analyses of cytogenetic and phenotypic characteristics on nine human neuroblastoma xenografts demonstrated that TNB9 is one of the most malignant strains of neuroblastoma. The in vivo chemotherapeutic sensitivity assessment disclosed that cyclophosphamide, cis-platinum, nitrosourea (ACNU), melphalan, and dacarbazine (DTIC) are effective, while aclarubicin, vincristine, and cytosine arabinoside are quite ineffective against this neuroblastoma xenograft.

High-resolution studies in patients with aniridia-Wilms tumor association, Wilms tumor or related congenital abnormalities.

We attempted to determine whether all cases of AWTA (anirida-Wilms tumor association) or any of the following groups of patients show 11p deletion: cases of Wilms tumor with congenital abnormalities other than aniridia, those without any congenital abnormalities, tumor itself in cases of Wilms tumor without constitutional 11p deletion and cases of aniridia or hemihypertrophy without Wilms tumor. We studied a total of 29 index patients including five cases of AWTA, four cases of Wilms tumor with various congenital abnormalities, 16 cases of Wilms tumor without other abnormalities, three cases of aniridia in one of which Wilms tumor developed later and a case of hemihypertrophy. In all five cases of AWTA and in a case of aniridia who later developed Wilms tumor, 11p deletion involving the p13 band was detected. The mother of the latter also showed an identical 11p deletion. The common segment of deletion was the middle part of the p13. Two possible hypotheses on the mechanism through which Wilms tumor might develop were evaluated, based on the distribution of break points. All other cases, including five with tumor culture, showed a normal karyotype.

Wilms' tumor, nephron disorder and ambiguous genitalia.

Two male cases with Wilms' tumor in association with ambiguous genitalia and nephrotic syndrome are described. Seventeen similar cases reported in the literature are also analyzed. In these patients, nephrotic syndrome was noticed at younger ages, and progressed more rapidly than usual. Renal damage was so serious that at least 11 out of 9 patients died of renal failure, though not of Wilms' tumor itself. It should be stressed that the clinical course and associated anomalies were quite similar among these patients. We suggest that Wilms' tumor, ambiguous genitalia and this type of nephrotic syndrome may have some etiologic connection.

The proposed Japanese TNM classification of primary liver carcinoma in infants and children.

The TNM classifications of neuroblastoma, nephroblastoma and soft tissue sarcoma were adopted at the International Conference for TNM Classification (UICC) held in May 1980. There is no TNM system under contemplation, however, for primary liver carcinoma in childhood. Accordingly, we have formulated the proposed Japanese TNM system for this carcinoma in children and examined its validity in 136 cases of hepatoblastoma seen in the listed 14 institutions. The basic policy of the Committee on the Japanese TNM Classification is not to include the resectability of the tumor and regional lymph nodes or any other status of the disease resulting from therapeutic intervention as a component of the pTNM system. This is a feature which makes our proposed system widely divergent from the accepted classification scheme for the three types of tumor cited above.

Idiopathic gastric volvulus in infancy and childhood.

Idiopathic gastric volvulus is not rare, especially in the neonate and in infancy. Between 1966 and 1980 we managed 44 cases of gastric volvulus. In 22 of the cases, initial examination was performed under 1 year of age. The main symptoms in this group were vomiting and abdominal distention, while those in the group over 2 years of age were abdominal distention, weight loss, nausea, appetite loss etc. The upper G.I. series were the most important in diagnosis. There was only one case of acute volvulus, which was treated operatively on an emergency basis. Chronic volvulus could be treated conservatively, except in 2 cases. This consisted in the positioning of the patient in the upright right recumbent position after feeding, for at least 1 hour. In the supine position, the gastric fundus is filled and dilated when the milk is poured into the stomach, the fundus is pulled postero-caudally and the antrum is pulled upwards, resulting in the combined type of organo-axial and mesenterico-axial volvulus. Over 2 years of age, 77% required operation. The fixation of the gastric fornix with the diaphragm was performed, using 5 or 6 stitches. The result was quite satisfactory. We recommend this procedure in this operation.