The population distribution of the sagittal abdominal diameter (SAD) and SAD/height ratio among Finnish adults.

Sagittal abdominal diameter (SAD; 'abdominal height' measured in supine position) may improve upon conventional anthropometry for predicting incident cardiometabolic diseases. However, the SAD is used infrequently by practitioners and epidemiologists. A representative survey of Finnish adults in 2000-2001 collected body measurements including SAD (by sliding-beam calliper) using standardized protocols. Sampled non-pregnant adults (ages 30+ years; 79% participation) provided 6123 SAD measurements from 80 health centre districts. Through stratified, complex survey design, these data represented 2.86 million adults at ages 30+ years. SAD ranged from 13.5 to 38.0 cm, with a population mean (standard error) of 21.7 (0.05) cm and median (interquartile range) of 21.0 (19.1-23.4). Median SAD was higher at ages 50+ years compared with ages 30-49 both for men (22.4 [20.5-24.6] vs. 20.8 [19.3-22.7]) and women (21.7 [19.6-23.9] vs. 19.4 [17.8-21.4]). The SAD/height ratio was similar (0.118) for both sexes at 30-39 years, rising more steeply with age for women than men. Attaining only a basic education, compared with a high level, was associated with increased mean (95% confidence interval) SADs for men (22.6 [22.3-22.8] vs. 22.0 [21.7-22.2]) and women (21.8 [21.5-22.0] vs. 20.6 [20.4-20.8]). Finland's early experience with nationally representative SAD measurements provides normative reference values and physiological insights useful for investigations of cardiometabolic risk.

Salvage abdominoperineal resection after failed Nigro protocol: modest success, major morbidity.

OBJECTIVE: Chemotherapy and radiation (C-XRT) is the first-line therapy for epidermoid carcinomas of the anal canal (ECAC). Treatment failure occurs in up to 33% of patients. Salvage-abdominoperineal resection (APR) is the treatment of choice for locoregional failure but pre-operative radiation may increase wound complications. The purpose of this study was to evaluate patient survival and wound complications after salvage-APR for C-XRT failure. METHODS: We reviewed the clinical records of all patients who failed initial C-XRT for ECAC diagnosed between 1992 and 2002. We evaluated patient demographics, treatment, tumour characteristics, survival and postoperative complications. RESULTS: Nineteen patients were identified. The mean age at diagnosis was 55 years. Eight (42%) patients had persistent disease; 11 (58%) had tumour recurrence. APR was performed in 15 patients. Perineal wound complications occurred in 12 (80%) patients; half were major complications. Primary flap reconstruction at time of APR was performed in 5 (33%) patients; 2 experienced major wound complications. Overall-survival after salvage APR was 40% (6/15) and disease-free survival was 47% (7/15) at a median follow-up of 14 months (range 2-95 months). Recurrence after salvage-APR occurred in 7 (47%) patients at a median follow-up of 5 months (range 3-19 months). Kaplan-Meier survival analysis showed an advantage for recurrent over persistent disease with 2-year and 5-year survival rates of 75%vs 34% and 28%vs 0%, respectively. CONCLUSIONS: Failure of C-XRT for ECAC is associated with a poor prognosis. Although salvage APR may be curative in some patients, perineal wound complications are frequent and primary flap reconstruction is not reliable.

Adjuvant radiation for rectal cancer: do we measure up to the standard of care? An epidemiologic analysis of trends over 25 years in the United States.

PURPOSE: In the United States, adjuvant radiation therapy is currently recommended for most patients with rectal cancer. We conducted this population-based study to evaluate the rate of radiation therapy and the factors affecting its delivery. METHODS: We used the Surveillance Epidemiology and End Results database to assess treatment of patients with nonmetastatic rectal cancer diagnosed over a 25-year period (1976 through 2000). We evaluated the rate of radiation therapy use and its timing (preoperative vs. postoperative) and the influence of factors such as tumor stage and grade; patient gender and race; and geographic location. RESULTS: In this 25-year period, 45,627 patients met our selection criteria. The rate of radiation therapy use increased dramatically over time: from 17 percent of advanced-stage patients in 1976 to 65 percent in 2000 (P < 0.0001). Until 1996, the increase was due almost entirely to postoperative radiation therapy. Since 1996, the rate of preoperative radiation therapy use has increased (P < 0.0001) and the rate of postoperative radiation therapy use has begun to decline. We found, after controlling for the year of diagnosis, that female patients, African Americans, older patients, and patients with low-grade lesions were less likely to undergo radiation therapy (P < 0.0001). Geographic location was also an important predictor of radiation therapy use. CONCLUSIONS: The use of radiation therapy for patients with rectal cancer has dramatically increased over the 25-year period studied, with a recent shift to the use of preoperative radiation therapy; however, in 2000, over 30 percent of patients with advanced-stage nonmetastatic rectal cancer did not undergo radiation therapy. Given the variation in radiation therapy use that we found to be due to demographic factors, access to adjuvant radiation therapy can be improved.

Impaired wound contraction in stromelysin-1-deficient mice.

OBJECTIVE: To determine whether the deletion of stromelysin-1, a single metalloproteinase gene product, will alter the time course and quality of dermal wound repair in mice. SUMMARY BACKGROUND DATA: After dermal injury, a highly coordinated program of events is initiated by formation of a fibrin clot, followed by migration of keratinocytes, contraction of the dermis, recruitment of inflammatory macrophages, formation of granulation tissue with angiogenesis, and finally tissue remodeling. Matrix metalloproteinases are rapidly induced in the dermis and granulation tissue and at the leading edge of the epidermis in the healing wounds. METHODS: Incisional and circular full-thickness wounds 2 to 10 mm were made in the dermis of stromelysin-1-deficient and wild-type mice. The wounds were analyzed for rate of cellular migration and epithelialization. The wound contraction was examined by immunohistochemical staining for alpha-smooth muscle actin and fluorescent staining for fibrillar actin. RESULTS: Independent of the age of the animal, excisional wounds in stromelysin-1-deficient mice failed to contract and healed more slowly than those in wild-type mice. Cellular migration and epithelialization were unaffected in the stromelysin-1-deficient animals. The functional defect in these mice is failure of contraction during the first phase of healing because of inadequate organization of actin-rich stromal fibroblasts. CONCLUSIONS: Excisional dermal wound healing is impaired in mice with a targeted deletion in the stromelysin-1 gene. Incisional wound healing is not affected. These data implicate stromelysin-1 proteolysis during early wound contraction and indicate that stromelysin-1 is crucial for the organization of a multicellular actin network.

Stromelysin-1-deficient fibroblasts display impaired contraction in vitro.

Targeted disruption of the stromelysin-1 gene in mice causes a delay in excisional wound healing due to a failure in wound contraction. Therefore, we postulated that stromelysin-1 activity is responsible for initiating contraction. To test this hypothesis, we compared the contractile capacity of fibroblasts from stromelysin-1 knockout mice (strom-1 KO) with that of normal fibroblasts using a collagen gel contraction model. Fibroblast cultures were established from explants of skin and lung parenchyma from strom-1 KO and wild-type mice, then transferred to the surface of collagen gels. The extent of contraction was determined by measuring greatest gel diameter. Results demonstrated that (1) all fibroblasts contracted collagen gels in a uniform concentric fashion, (2) skin fibroblasts from both sets of mice exhibited greater gel contraction than did lung fibroblasts, and (3) strom-1 KO fibroblasts demonstrated significantly less contraction (21-23%) than wild-type fibroblasts. These data support the hypothesis that absence of stromelysin-1 results in defective fibroblast contraction that may contribute to delayed wound healing.

Epidermal integrin expression is upregulated rapidly in human fetal wound repair.

BACKGROUND/PURPOSE: The fetus heals skin wounds rapidly and scarlessly. The mechanisms that mediate the rapid reepithelialization that is seen in this process are unknown. Integrins are a family of cell surface receptors that bind fibronectin, tenascin, collagen, and other extracellular matrix proteins that are deposited rapidly in fetal wounds. The authors hypothesized that epidermal integrin receptors specific for fibronectin and other wound matrix proteins are upregulated rapidly during human fetal repair. METHODS: To investigate the spatial and temporal expression of integrins in scarless fetal repair, fetal skin from six human abortuses (16 to 23 weeks' gestation) was transplanted subcutaneously into severe combined immunodeficient mice. After graft take, full-thickness incisional wounds were made in the grafts, and grafts were harvested at various time-points from 4 hours to 28 days after wounding. Integrin receptor protein expression was analyzed at each time-point using immunohistochemistry with monoclonal antibodies specific for the receptors that bind fibronectin, tenascin, collagen, and laminin (alpha5, alpha(v), beta6, alpha2, alpha3, alpha6, and beta4). RESULTS: In this model, wounded human fetal skin grafts reepithelialized rapidly (within 24 to 36 hours) and healed scarlessly. Within 4 hours of wounding, the grafts showed increased, suprabasal expression (alpha2, alpha3, alpha6, beta4) or neoexpression (alpha5, alpha(b), beta6) of integrins at the epidermal wound edge. This increased expression persisted until reepithelialization was complete. CONCLUSIONS: Early upregulation of integrins in fetal wounds may permit rapid keratinocyte migration and reepithelialization, and may be important in limiting the induction of inflammatory mediators and scar.

Capillary sample introduction of polymerase chain reaction (PCR) products separated in ultrathin slab gels.

Polymerase chain reaction (PCR) amplified short tandem repeat (STR) samples from the HUMVWF locus have been analyzed using a unique sample introduction and separation technique. A single capillary is used to transfer samples onto an ultrathin slab gel (57 microm thin). This ultrathin nondenaturing polyacrylamide gel is used to separate the amplified fragments, and laser-induced fluorescence with ethidium bromide is used for detection. The feasibility of performing STR analysis using this system has been investigated by examining the reproducibility for repeated samples. Reproducibility is examined by comparing the migration of the 14 and 17 HUMVWF alleles on three consecutive separations on the ultrathin slab gel. Using one locus, separations match in migration time with the two alleles 42 s apart for each of the three consecutive separations. This technique shows potential to increase sample throughput in STR analysis techniques although separation resolution still needs to be improved.

Correction of congenital diaphragmatic hernia in utero VII: a prospective trial.

BACKGROUND: Congenital diaphragmatic hernia (CDH) remains an unsolved problem. Despite optimal postnatal care, up to 60% of CDH babies die. Experimental evidence and clinical experience have shown that in utero repair of CDH is feasible and can reverse pulmonary hypoplasia, but only in fetuses without liver herniation. For this subgroup, the safety and efficacy of repair before birth has not been compared with standard care after birth. METHODS: Four fetuses in whom CDH without liver herniation was diagnosed underwent open fetal surgery for repair of the CDH. Seven comparison fetuses were treated conventionally. Neonatal mortality was the principle outcome variable. Secondary outcome variables included death of all causes until 2 years of age, number of days of ventilatory support, length of hospital stay, requirement for extracorporeal membrane oxygenation (ECMO), and total hospital charges. RESULTS: There was no difference in survival between the fetal surgery group and the postnatally treated comparison group (75% v 86%). Fetal surgery patients were born more prematurely than the comparison group (32 weeks v 38 weeks' gestation). Length of ventilatory support and requirement for ECMO were equivalent in the fetal surgery group and the postnatally treated comparison group. Length of hospital stay and hospital charges did not differ between the groups. CONCLUSIONS: Open fetal surgery is physiologically sound and technically feasible, but does not improve survival over standard postnatal treatment in the subgroup of CDH fetuses without liver herniation, primarily because overall survival in this subgroup is favorable with or without prenatal intervention. These data suggest that fetuses who have prenatally diagnosed CDH and without evidence of liver herniation should be treated postnatally.

A new in vivo model for the study of fetal wound healing.

We have developed a new in vivo model for the study of fetal wound healing. Fetal ICR mice (total gestation, 21 days) received a full-thickness incisional wound in the hind limb at gestational day 14 (N = 100). The wound was made with a 28.5-gauge needle that was passed transplacentally into the amniotic cavity. The wounds were analyzed histologically on postoperative days 0, 1, 3, and 5 by hematoxylin-eosin and Mallory's trichrome stains. Once the wounding technique was mastered, the overall mortality rate for this model was 20% by postwounding day 5. Each fetus healed their wound without scar by postwounding day 3. In 3 animals, 5 microliters of human transforming growth factor beta 1 (25 micrograms per microliter) was injected into the wound site, resulting in scar and an inflammatory cell infiltrate, indicating that the 14-day-gestation fetal mouse can be manipulated if necessary. This model offers the advantages of an in vivo system that can be studied at an early gestational age. Furthermore, it is inexpensive, easy to manipulate, and can be studied with commercially available murine probes.

Ultrathin slab gel separations of DNA using a single capillary sample introduction system.

We demonstrate here a novel method for DNA separations which combines the parallel processing capabilities of slab gels with the advantages of sample introduction obtained with a single capillary. This sample introduction format allows rapid sequential separations or continuous analysis to be carried out on ultrathin slab gels with efficient heat dissipation. Ultrathin slab gels have been fabricated by using 57-micron spacers between quartz plates, and a single capillary has been used to introduce plugs of dsDNA fragments into the ultrathin gel. These fragment plugs were deposited along the entrance to the ultrathin gel at spatially discrete locations by micromanipulation of the capillary. Spatially resolved detection has been accomplished with an argon ion laser focused to a line for excitation and a CCD for collection of fluorescence. Double-stranded DNA separations are demonstrated in a plug injection format. This approach allows multiple unique samples to be rapidly deposited on the ultrathin slab gels for separation.

Transforming growth factor beta-1 decreases interstitial collagenase in healing human fetal skin.

Fetal dermal wounds heal without scarring. Because wound repair requires extracellular matrix turnover, the authors hypothesized that fetal skin would have increased levels of proteinases responsible for matrix degradation compared with adult skin. It was further hypothesized that transforming growth factor beta-1 (TGF-beta1) induces scarring in fetal skin by altering proteinase synthesis. A model of human fetal skin transplanted subcutaneously onto immunodeficient mice was used to study the role of matrix metalloproteinases in healing human fetal skin. In this model, transplanted second trimester fetal skin heals without scarring; addition of TGF-beta1 induces scarring. Proteinases were detected by immunohistochemistry in untransplanted fetal skin, untransplanted adult skin, TGF-beta1-treated fetal skin grafts, and sucrose-treated control grafts. In untransplanted fetal skin, interstitial collagenase, stromelysin-1, and gelatinase A were found in dermal cells and keratinocytes, and around vascular structures. Proteinases were detected in adult skin at similar locations but stained less intensely. Addition of TGF-beta1 decreased interstitial collagenase in fetal skin, but detection of gelatinase A and stromelysin-1 was unchanged. The authors conclude that matrix metalloproteinases are present in midgestation human fetal skin and that more proteinase-containing cells are found in fetal skin than in adult skin. Manipulation of fetal skin with TGF-beta1 is accompanied by a decrease in interstitial collagenase. These data suggest that the increased matrix metalloproteinases found in fetal skin contribute to scarless healing and that the fibrotic effects of TGF-beta1 on fetal skin may be mediated in part by decreasing the synthesis of interstitial collagenase.

A mediastinal window approach to aortopexy.

Between 1989 and 1994 six infants underwent aortopexy for symptomatic tracheomalacia via an anterior mediastinal window. This approach avoids a thoracotomy by using a small transverse incision over the second and third intercostal spaces followed by subchondral excision of these costal cartilages to expose the mediastinum. All patients had stridor and significant respiratory difficulty preoperatively; all experienced significant improvement in symptoms after aortopexy. There were no significant complications attributable to the procedure. The authors recommend this approach for aortopexy.

Wound size and gestational age modulate scar formation in fetal wound repair.

The early-gestation fetus heals incisional skin wounds rapidly and scarlessly. The morphology with which the fetus heals excisional skin wounds remains unclear. To characterize excisional fetal wound repair, and to determine whether there is a developmentally regulated wound-size threshold beyond which fetal skin heals with scar, the authors created excisional wounds in fetal lambs of varying gestational age. Time-mated pregnant ewes carrying 22 fetuses at 60 to 90 days' gestation (term, 145 days) underwent laparotomy and hysterotomy. An incisional wound and four circular, punch biopsy wounds of 2, 4, 6, and 10 mm in diameter were placed on the back of each fetal lamb and marked with India ink. The wounds were harvested at 14 days' postwounding and examined grossly and microscopically after serial sectioning and histological staining. Morphological features of all wounds were graded. By 14 days' postwounding all fetal wounds had healed completely. for lambs at each gestational age, increasing wound size was strongly associated with an increase in the frequency of scar. Also, as gestational age increased from 60 to 90 days' gestation the frequency of scarless repair decreased. By understanding the cellular and molecular processes that mediate scar formation with increasing wound size and advancing gestational age, the authors hope to gain further insight into the mechanisms of scarless fetal wound repair.

Tracheal ligation increases cell proliferation but decreases surfactant protein in fetal murine lungs in vitro.

Tracheal occlusion affects both fetal lung growth and maturation. The authors used a murine in vitro whole organ culture model to investigate these effects. The authors hypothesized that tracheal ligation would increase lung growth by increasing cell proliferation and would change surfactant protein synthesis in this system. Lungs were removed from day 14 gestation murine fetuses (term, 21 days). Tracheas were ligated and explants cultured in chemically defined, serum-free media for 1, 3, 4, 5, 7, or 14 days. DNA synthesis and cell division were assessed using a 5-bromo-2'-deoxy-uridine (BrdU) incorporation assay. Surfactant proteins A and B, markers of lung maturity, were detected using immunohistochemistry. Ligated lungs showed more BrdU-labeled cells per 1,000 x field (cells/hpf) at every time point. Ligated lungs on day 1 showed 27% more cells/hpf than unligated, on day 3, 21% more, on day 5, 54% more, on day 7, 60% more, and on day 14, 123% more (P < .05). In contrast, ligated lungs showed significantly less staining for surfactant proteins A and B than did unligated lungs. The authors conclude that tracheal ligation increases cell division but decreases surfactant protein in fetal murine lungs in vitro. These data suggest that although tracheal occlusion increases lung growth, it may decrease or delay lung maturation. This model provides a powerful tool for investigating the mechanisms underlying fetal lung development and tracheal occlusion-induced pulmonary hyperplasia.

Human acellular dermal matrix as a novel model of malignant epithelial cell invasion.

Cancer invasion and metastasis are associated with matrix degradation. We describe a novel in vivo model of invasion by squamous epithelial neoplastic cells derived from transgenic mice grown on acellular human dermis. Human dermis was subjected to multiple freeze-thaw cycles to render it acellular, maintaining the basement membrane of the former dermal-epidermal junction. Cells representing discrete stages of a multistep transgenic mouse model of epidermal carcinogenesis (neonatal transgenic keratinocytes, moderately/poorly differentiated squamous cell carcinoma, and lymph node metastasis) were seeded onto the basement membrane surface, grown in culture for 4 days, grafted in a subpannicular pocket of athymic mice, and harvested after 3 weeks. Histological analysis demonstrated that neonatal transgenic keratinocytes did not degrade the basement membrane or invade the underlying dermis. In contrast, malignant cells derived from both a moderately differentiated squamous carcinoma and a lymph node metastasis were highly invasive. Immunohistochemical analysis revealed collagenase only in nests of invading malignant cells in contact with the dermal matrix, but not in the tumor mass remaining above the basement membrane, suggesting that this proteinase may be required for stromal invasion. This novel model recapitulates the events seen in malignant invasion: transgenic keratinocytes are unable to penetrate the dermis while cells from a moderately differentiated carcinoma and from lymph node metastasis consistently invade.

In utero management of congenital diaphragmatic hernia.

Fetal surgery offers the possibility of prenatal treatment of congenital diaphragmatic hernia (CDH). The in utero management of CDH has evolved with continued experimental and clinical experience. Topics covered include the experimental rationale and techniques of in utero repair of CDH, methods of accurate diagnosis, criteria for patient selection, approaches to ethical concerns, operative techniques, and a review of the clinical experience.

Diagnosis and treatment of bacteremia and intravascular catheter infections.

The past decade has witnessed an explosive rise in the rate of bacteremia and intravascular catheter infection. Although gram-negative organisms continue to account for up to one third of these infections, gram-positive organisms have become increasingly prevalent pathogens. Virulent antibiotic-resistant bacterial strains have emerged and present a formidable treatment challenge. Simultaneously, management of catheter infection has evolved. Although patients who develop fungemia, gram-negative bacteremia, or sepsis syndrome are best treated by catheter removal in addition to antimicrobial therapy, an increasing body of evidence suggests that many gram-positive bacterial catheter infections can be treated by use of antimicrobial agents without catheter removal. Advances in catheter design and immunotherapy for sepsis syndrome also hold promise. Despite these innovations, determining the initial need for catheter placement, adherence to meticulous sterile surgical technique during insertion, and subsequent fastidious catheter maintenance remain the mainstays of preventing these potentially disastrous infections.

Before the horse is out of the barn: fetal surgery for hydrops.

Hydrops fetalis, a condition characterized by abnormal accumulation of fluid and edema in the fetus, is the final common pathway in a number of pathological conditions. The diagnosis of hydrops is based on ultrasonographic findings of generalized edema along with a serous effusion (ascites, pleural effusion, or pericardial effusion). Polyhydramnios and placentomegaly may also be present. Historically, hydrops fetalis has been described in cases of Rh alloimmunization and severe erythroblastosis (immune hydrops). Hydrops is considered "nonimmune" if there is no evidence of fetal-maternal blood group incompatibility. Over the past few decades, nonimmune hydrops has been recognized more frequently. In a number of series, 80% to 90% of hydropic fetuses were considered nonimmune. Incidence ranges from 1 in 1,500 to 1 in 3,800 births. Etiology is diverse and associated conditions include cardiovascular malformations, chromosomal abnormalities, thoracic lesions, infections, metabolic disorders, fetal anemia and twinning. Overall prognosis is poor, with mortality between 50% and 98%. Advances in obstetric ultrasound and prenatal diagnosis have made it possible to diagnose a number of congenital anomalies early in gestation. In some cases, anatomic anomalies diagnosed in utero progress to nonimmune hydrops and almost certain fetal demise. It is these conditions that can be considered for fetal surgical intervention. This article reviews the pathophysiology and rationale behind surgical correction of two conditions that lead to hydrops: fetal thoracic lesions (congenital cystic adenomatoid malformation, pulmonary sequestration, and fetal pleural effusions) and sacrococcygeal teratoma (SCT).