Deoxyuridine accumulation in urine in thymidine phosphorylase deficiency (MNGIE)

We report the presence of the unusual nucleoside deoxyuridine in the urine of a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (MIM 603041) due to thymidine phosphorylase (TP:EC 2.4.2.4) deficiency. Thymidine, uracil and thymine were also elevated. We propose that inhibition of thymidylate synthetase by TMP leads to the accumulation of dUMP which may be degraded to deoxyuridine or metabolised to dUTP. Incorporation of dUTP into mtDNA may explain the multiple deletions characteristic of TP deficiency.     

The role of parenteral nutrition

Patients with acute leukemia who undergo hematopoietic stem cell transplantation (HSCT) are susceptible to malnutrition caused by several factors including intensive cytotoxic therapy. This paper discusses the significance of malnutrition in these patients and provides an overview of nutrition therapy by the oral, enteral, and parenteral routes. The goal is to investigate whether the use of parenteral nutrition (PN) produces improved clinical outcomes in patients with acute leukemia and to identify criteria for the selection of patients most likely to benefit from this therapy. Although PN may be appropriate for patients suffering from complications such as graft-versus-host disease (GVHD) and mucositis, the data available at this time do not support PN as first-line therapy for all recipients of HSCT.     

Posttraumatic stress and depressive reactions among Nicaraguan adolescents after hurricane Mitch

OBJECTIVE: This study determined the severity of posttraumatic stress and depressive reactions among Nicaraguan adolescents after Hurricane Mitch and the relationship of these reactions to objective and subjective features of hurricane exposure, death of a family member, forced relocation, and thoughts of revenge. METHOD: Six months after the hurricane, 158 adolescents from three differentially exposed cities were evaluated by using a hurricane exposure questionnaire, the Child Posttraumatic Stress Disorder Reaction Index, and the Depression Self-Rating SCALE: RESULTS: Severe levels of posttraumatic stress and depressive reactions were found among adolescents in the two most heavily affected cities. Severity of posttraumatic stress and depressive reactions and features of objective hurricane-related experiences followed a "dose-of-exposure" pattern that was congruent with the rates of death and destruction across cities. Level of impact (city), objective and subjective features, and thoughts of revenge accounted for 68% of the variance in severity of posttraumatic stress reaction. Severity of posttraumatic stress reaction, death of a family member, and sex accounted for 59% of the variance in severity of depression. CONCLUSIONS: After a category 5 hurricane, adolescents in heavily affected areas with extreme objective and subjective hurricane-related traumatic features of exposure experience severe and chronic posttraumatic stress and comorbid depressive reactions. The recovery of the severely affected Nicaraguan adolescents is vital to the social and economic recovery of a country ravaged by years of political violence and poverty. These findings strongly indicate the need to incorporate public mental health approaches, including systematic screening and trauma/grief-focused interventions, within a comprehensive disaster recovery program.     

Operative techniques of uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty is, for the most part, both safe and effective as a surgical treatment for obstructive sleep apnea and severe snoring. Most complications can be avoided with proper surgical technique. Palatal dysfunction can be avoided if the shortening of the soft palate in the midline (uvula) area is minimized. Nasopharyngeal stenosis can be avoided with minimization of the posterior pillar resection and by avoidance of pharyngeal undermining. The effectiveness of surgery can be improved by placing emphasis 1) on opening the nasopharynx widely in the lateral port areas and 2) on tissue removal deep in the inferior tonsillar poles (and hypopharynx) with mucosal advancement and suturing.     

Aprt/Opn double knockout mice: osteopontin is a modifier of kidney stone disease severity

BACKGROUND: Osteopontin (OPN) is reported to have two distinct functions in kidney disease: Promotion of inflammation at sites of tissue injury, and inhibition of calcium oxalate monohydrate stone formation. However, many of the studies supporting these functions were carried out in animal models of acute renal injury or in cultured cells; thus, the role of OPN in chronic renal disease is not well defined. We examined the role of OPN in adenine phosphoribosyltransferase (Aprt) knockout mice, in which inflammation and formation of 2,8-dihydroxyadenine (DHA) kidney stones are prominent features, by generating Aprt/Opn double knockout mice. METHODS: We characterized the phenotypes of six- and 12-week-old Aprt-/- Opn-/-, Aprt-/- Opn+/+, Aprt+/+ Opn-/-, and Aprt+/+ Opn+/+ male and female mice using biochemical, histologic, immunohistochemical, and in situ hybridization techniques. RESULTS: At 6 weeks of age, there was no difference in phenotype between double knockout and Aprt knockout mice. At 12 weeks, there was increased adenine and DHA excretion, renal crystal deposition, and inflammation in double knockout versus Aprt knockout male mice. Double knockout and Aprt knockout female mice at 12 weeks had less pathology than their male counterparts, but kidneys from double knockout females showed more inflammation compared with Aprt knockout females; both genotypes had similar levels of DHA crystal deposition. CONCLUSION: We conclude that (1) OPN is a major inhibitor of DHA crystal deposition and inflammation in male mice; and (2) OPN is a major modifier of the inflammatory response but not of crystal deposition in female mice. Thus, separate mechanisms appear responsible for the tissue changes seen in DKO males versus females.     

Patterns and implications of lower extremity injuries in a community level I trauma center

This study examined specific types of lower extremity injuries, their treatment, and trends in length of stay (LOS) as seen in an academic community hospital. The authors' trauma registry was queried for lower extremity injuries requiring surgical intervention from 1992 to 2000. A total of 5567 patients were identified. A total of 574 patients with 857 injuries met the criteria. The only significant difference in injury severity score among various injury types was found between traumatic amputations and open fractures (P = 0.006). However, there was no statistical difference between these 2 groups with regard to LOS. Patients requiring 1 or 2 procedures had a significantly shorter LOS than those requiring 3 procedures (P = 0.002 and P = 0.021 respectively). In this population of patients, it was not the manner of initial reconstruction, but the number of reconstructive procedures required that had an impact on LOS. LOS reduction might be possible when patients with lower injury severity scores can be treated in a more efficient manner.     

Fibroblast growth factor 10 (Fgf10) invalidation results in anorectal malformation in mice

Background/purpose

Anorectal malformations occur in 1 per 4,000 live births and represent a surgical challenge. Although critically important, the basic mechanisms of normal anorectal union are incompletely understood. Fgf10 signaling is known to serve a key role in mesenchymal/epithelial interactions in many organ systems including the gastrointestinal tract (GIT). The authors therefore hypothesized that Fgf10 signaling has a central role in normal anorectal development.

Methods

Fgf10 expression in wild-type (Wt) embryos was evaluated using whole-mount in situ hybridization. Wt and Fgf10^−/− embryos were harvested from timed pregnant mothers at E12.5 through E17.5 and were analyzed for anorectal phenotype.

Results

Wt development of union between anorectal structures is completed between E12.5 and E13.5 with luminal communication between distal rectal epithelium and anus. Fgf10 is discreetly expressed at E12.5 in the distal rectum. Fgf10^−/− mutants show failure of union of the rectum and anus at an early stage (E13.5) and near term (E17.5).

Conclusions

Fgf10 is expressed in the rectum at the time when anorectal continuity is established, indicating a role in normal anorectal development. Fgf10 invalidation (Fgf10^−/− mutant) results in a genetically reproducible anorectal malformation phenotype. Fgf10 function is critical for normal anorectal development.     

A genetic mechanism for cecal atresia: the role of the Fgf10 signaling pathway

BACKGROUND: Intestinal atresia represents a significant surgically correctable cause of intestinal obstruction in neonates. Intestinal development proceeds as a tube-like structure with differentiation along its axis. As the intestine differentiates, the cecum develops at the transition from small to large intestine. Fgf10 is known to serve a key role in budding morphogenesis; however, little is known about its role in the development of this transitional structure. Here we evaluate the effect of Fgf10/Fgfr2b invalidation on the developing cecum. MATERIALS AND METHODS: Wild-type C57Bl/6, Fgf10(-/-), and Fgfr2b(-/-) embryos harvested from timed pregnant mothers were analyzed for cecal phenotype, Fgf10 expression, and differentiation of smooth muscle actin. RESULTS: Wt cecal development is first evident at E11.5. FGF10 is discreetly expressed in the area of the developing cecum at early stages of development. One hundred percent of Fgf10(-/-) and Fgfr2b(-/-) mutant embryos demonstrate cecal atresia with absence of epithelial and muscular layers. The development of neighboring anatomical structures such as the ileocecal valve is not affected by Fgf10/Fgfr2b invalidation. CONCLUSIONS: FGF10 expression is localized to the cecum early in the normal development of the cecum. Fgf10(-/-) and Fgfr2b(-/-) mutant embryos demonstrate cecal atresia with complete penetrance. Epithelial and muscular layers of the cecum are not present in the atretic cecum. The Fgf10(-/-) and Fgfr2b(-/-) mutants represent a genetically reproducible animal model of autosomal recessive intestinal atresia.