General Homologation Strategy for Synthesis of L-glycero- and D-glycero-Heptopyranoses.

A general and stereospecific homologation strategy for the synthesis of heptopyranosides is reported. The strategy employs the Wittig olefination and proline-catalyzed α-aminoxylation to achieve one carbon elongation and stereoselective hydroxylation at the C6 position, respectively. The L-glycero- and D-glycero-heptopyranosides can be obtained with nearly perfect stereoselectivity. Further study reveals the difference in the chemical shift of the C6 proton of L/D-glycero-heptopyranosyl diastereomers, which is found to be useful for assignment of the configuration of heptopyranosides.

A general synthetic strategy and the anti-proliferation properties on prostate cancer cell lines for natural phenylethanoid glycosides.

A general strategy for the synthesis of phenylethanoid glycosides (PhG) including echinacoside 1, acteoside 2, calceolarioside-A 3 and calceolarioside-B 4 is reported. The strategy features the application of low substrate concentration glycosylation and N-formyl morpholine modulated glycosylation methods for the construction of 1,2-trans ß- and α-glycosidic bonds. The reported strategy does not invoke the use of the participatory acyl protecting function, which is incompatible with the ester function present in target PhG compounds. A preliminary study of the anti-proliferation properties of the PhG compounds 1­4 was performed; the acteoside 2 exhibited the best inhibition on the prostatic cancer cell proliferation.

Modulating glycosylation with exogenous nucleophiles: an overview.

The major challenge in carbohydrate synthesis is stereochemical control of glycosidic bond formation. Different glycosylation methods have been developed that are based on the modulation effect of external nucleophiles. This review highlights the development, synthetic application, challenges and outlook of the modulated glycosylation methods.

Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: elevated levels correlate with severity scoring.

BACKGROUND: Interleukin-31 (IL-31) is a novel T-helper-lymphocyte-derived cytokine that plays an important role in human T-cell-mediated skin diseases. When overexpressed in transgenic mice, IL-31 induces severe pruritus resembling eczema in humans. Serum IL-31 was previously found overexpressed in adults with atopic dermatitis (AD). The novelty of this study is the use of a pediatric patient group as well as comparison of IL-31 levels during flare and quiescence. OBJECTIVE: This case-controlled longitudinal study was designed to determine the levels of IL-31 in serum of AD children and its associations in relation to disease activity and severity. METHODS: Sera were obtained from 50 AD children and 40 healthy volunteers. IL-31 levels were measured using a sandwich ELISA. All AD patients were followed up and re-sampled for serum IL-31 after clinical remission. Serum IL-31 levels were correlated with AD disease activity and severity variables. RESULTS: Serum IL-31 levels were significantly higher whether during AD flare [median, 1600; mean (SD)=1457.8±770.4 pg/mL] or quiescence (1040; 958.7±419.5 pg/mL), than those in controls (220; 197.3±91.9 pg/mL). Serum IL-31 levels were significantly higher in the high disease severity group compared with the moderate or low severity group. Moreover, serum IL-31 levels correlated positively with the calculated severity scores (LSS, SSS and SCORAD index). CONCLUSION: The results of this study confirm the importance of IL-31 in AD pathophysiology. Serum IL-31 level is an objective reliable marker of AD severity in children. It may represent a novel target for antipruritic drug development.

Serum mucosa-associated epithelial chemokine in atopic dermatitis: a specific marker for severity.

BACKGROUND: Mucosa-associated epithelial chemokine (MEC; CCL28) is considered pivotal in mediating migration of CCR3 and CCR10-expressing skin-homing memory CLA(+) T cells. CCL28 is selectively and continuously expressed by epidermal keratinocytes, but highly upregulated in inflammatory skin diseases such as atopic dermatitis (AD). AIMS: This controlled longitudinal study was designed to evaluate the expression of CCL28 serum levels in childhood AD and bronchial asthma (BA) and its possible relations to disease severity and activity. METHODS: Serum CCL28 levels were measured in 36 children with AD, 23 children with BA, and 14 children who had both conditions as well as in 21 healthy age and gender-matched subjects serving as controls. Sixteen patients in the AD group were followed-up and re-sampled for serum CCL28 after clinical remission. Serum CCL28 levels were correlated with some AD disease activity and severity variables. RESULTS: Serum CCL28 levels in patients with AD whether during flare (median = 1530; mean +/- SD = 1590.4 +/- 724.3 pg/ml) or quiescence (median = 1477; mean +/- SD = 1575.2 +/- 522.1 pg/ml) were significantly higher than the values in healthy children (median = 301; mean +/- SD = 189.6 +/- 92.8 pg/ml). However, the levels during flare and quiescence were statistically comparable. The serum levels in BA (median = 340; mean +/- SD = 201.6 +/- 109.5 pg/ml) were significantly lower than the AD group and comparable with the healthy control values. Serum CCL28 levels in severe AD were significantly higher as compared with mild and moderate cases and correlated positively to the calculated severity scores (LSS and SCORAD). CCL28 levels during exacerbation of AD could be positively correlated to the corresponding values during remission, the peripheral absolute eosinophil counts, and the serum lactate dehydrogenase levels. Serum CCL28 did not vary with the serum total IgE values in AD. CONCLUSION: Our data reinforce the concept that CCL28 might share in the pathogenesis of AD probably through selective migration and infiltration of effector/memory Th2 cells into the skin. It may also represent an objective prognostic marker for disease severity. Further studies may pave the way for CCL28 antagonism among the adjuvant therapeutic strategies.

Prospective analysis of psychosocial outcomes in breast reconstruction: one-year postoperative results from the Michigan Breast Reconstruction Outcome Study.

In the past decade, changing attitudes toward breast reconstruction among both patients and providers have led a growing number of women to seek breast reconstruction after mastectomy. Although investigators have documented the psychological, social, emotional, and functional benefits of breast reconstruction, little research has evaluated the effects of procedure choice on these outcomes. The current study prospectively evaluated and compared psychosocial outcomes for three common options for mastectomy reconstruction: tissue expander/implant, pedicle TRAM, and free TRAM techniques. In a prospective cohort design, patients undergoing postmastectomy reconstruction for the first time with expander/implant, pedicle TRAM, or free TRAM procedures were recruited from 12 centers and 23 plastic surgeons in the United States and Canada. Before reconstruction and at 1 year after reconstruction, patients were evaluated by a battery of questionnaires consisting of both generic and condition-specific surveys. Outcomes assessed included emotional well-being, vitality, general mental health, social functioning, functional well-being, social well-being, and body image. Baseline (preoperative) scores and the change in scores (the difference between postoperative and preoperative scores) were compared across procedure types using t tests and analysis of covariance. Preoperative and 1-year postoperative surveys were obtained from 273 patients. Procedure type was reported in 250 patients, of whom 56 received implant reconstructions, 128 pedicle TRAM flaps, and 66 free TRAM flaps. A total of 161 immediate and 89 delayed reconstructions were performed. Among women receiving immediate reconstruction, significant improvements were observed in all psychosocial variables except body image. However, no significant effects of procedure type on these changes over time existed. Similarly, delayed reconstruction patients had significant increases in emotional well-being, vitality, general mental health, functional well-being, and body image. Although the choice of reconstructive technique did not significantly impact most of these outcomes, significant differences existed among procedure types for three psychosocial subscales. Patients undergoing delayed expander/implant reconstructions reported greater improvements in vitality and social well-being relative to women receiving delayed TRAM procedures. By contrast, delayed TRAM patients noted significantly greater gains in body image compared with women choosing delayed expander-implant reconstruction. The authors conclude that both immediate and delayed breast reconstructions provide substantial psychosocial benefits for mastectomy patients. Although the choice of reconstructive procedure does not seem to significantly affect improvements in psychosocial status with immediate reconstruction, our data suggest that procedure type does have a significant effect on gains in vitality and body image for women undergoing delayed reconstruction.

Fetal cleft lip and palate detection by three-dimensional ultrasonography.

OBJECTIVES: To demonstrate a standardized approach for the evaluation of cleft lip and palate by three-dimensional (3D) ultrasonography. DESIGN: This was a retrospective study of seven fetuses with confirmed facial cleft anomalies. Post-natal findings were compared to a blinded review of 3D volume data from abnormal fetuses with seven other normal fetuses that were matched for gestational age. Upper lip integrity was examined by 3D multiplanar imaging. Sequential axial views were used to evaluate the maxillary tooth-bearing alveolar ridge contour and anterior tooth socket alignment. Alveolar ridge disruption suggested cleft palate. Premaxillary protrusion, either by multiplanar imaging or surface rendering, indicated bilateral cleft lip and palate. RESULTS: Post-natal findings confirmed bilateral cleft lip and palate (four cases), unilateral cleft lip and palate (one case), and unilateral cleft lip (two cases). Multiplanar review identified all three fetuses with unilateral cleft lip, three of four fetuses with bilateral cleft lip, one fetus with unilateral cleft palate, and three of four fetuses with bilateral cleft palate. Surface rendering correctly identified all cleft lips, with the exception of one fetus, who was thought to have a unilateral cleft lip and palate, despite the actual presence of a bilateral lesion. One cleft palate defect was directly visualized by 3D surface rendering. No false-positives occurred. CONCLUSION: Interactive review of standardized 3D multiplanar images allows one to evaluate labial defects, abnormalities of the maxillary tooth-bearing alveolar ridge, and presence of premaxillary protrusion for detecting cleft lip and palate anomalies. Surface rendering may increase diagnostic confidence for normal or abnormal studies. This technology provides an array of visualization tools that may improve the prenatal characterization of facial clefts, particularly of the palate.

Treatment outcome with radiation therapy after breast augmentation or reconstruction in patients with primary breast carcinoma.

BACKGROUND: Analyses were performed to determine local control and cosmetic outcome of breast carcinoma patients with prosthetically augmented or reconstructed breasts who had received radiation therapy (RT). METHODS: Twenty-one newly diagnosed breast carcinoma patients with prosthetically augmented or reconstructed breasts were treated with external beam RT. All patients received whole breast RT (median dose, 50.4 gray [Gy]) and 19 were boosted to a median dose of 60.4 Gy. A median dose of 50.4 Gy was delivered to the regional lymph nodes in 12 patients. Tissue equivalent bolus material was used in six patients. Seventeen patients received adjuvant systemic therapy. Cosmetic results were evaluated at 3-6-month intervals. RESULTS: With a median follow-up of 32 months, good/excellent cosmetic results were observed in 71% of patients (100% in those with augmented breasts and 54% in those with reconstructed breasts). Four patients (19%) with fair/poor cosmetic outcomes required implant removal and/or revision. Multiple clinical and treatment-related factors were analyzed for their impact on cosmetic outcome. A worsened cosmetic result was observed with increasing stage (P = 0.076), breast reconstruction (vs. augmentation) (P = 0.030), and bolus application (P = 0.016). All patients with fair/poor cosmetic outcomes had time intervals from implant insertion to RT ranging from 53-213 days. Two patients developed an isolated local recurrence within the augmented breast. CONCLUSIONS: Patients with prosthetically augmented breasts can undergo RT and expect good/excellent cosmetic results. Patients with reconstructed breasts are at a significantly greater risk for cosmetic failure. This risk may be related to the higher percentage of patients with advanced disease, those who received bolus application, and those who received earlier delivery of RT (after the cosmetic procedure) in reconstructed breasts.

Wound complications and treatment of the infected implantable cardioverter defibrillator generator.

Since 1980, the automatic implantable cardioverter defibrillator (ICD) has evolved as effective therapy for prevention of sudden cardiac death following documented sustained ventricular tachycardia or fibrillation. During a 5-year period, 412 ICD devices were implanted at the University of Michigan Hospitals with a wound complication rate of 4.1%. In this group, there were 13 infections, 3 erosions of the generator pocket, and 1 wound hematoma. Of the 16 patients with infection or erosion, 12 patients were treated with a rectus abdominis muscle flap closure and 4 with ICD generator removal. In 83% (n = 12) of the muscle flap patients, the wound healed uneventfully. Preoperative chest CT scanning was found to be helpful in identifying probable infection of the epicardial leads. In these cases, all hardware had to be removed to achieve resolution of the infection. We concluded that rectus abdominis muscle flaps were helpful in salvaging infected or exposed ICD generators in the absence of infected epicardial leads.

The stress response in skin: the role of neutrophil products in preconditioning.

In this study we tested the hypothesis that neutrophil products are present in ischemic skin flaps and that they are abolished with preconditioning of the skin. Random back flaps were created on rats, and the sequential appearance of neutrophil products and tissue oxidants was measured in the skin flaps. These flaps had predictable skin necrosis (4.7 +/- 0.8 cm) in the distal ends, while preconditioned flaps had no skin necrosis. Neutrophil products were assayed by both histomorphometrics and myeloperoxidase assays. Lipid peroxidation products were measured to assess tissue oxidant production. These data demonstrate that there is an increase in myeloperoxidase activity in skin flaps that is statistically significantly greater in the distal ends of the flaps at 24 hours (p < 0.05). The lipid peroxidation products were statistically significantly elevated at 48 hours in the distal ends (p < 0.05). Preconditioning the skin as a bipedicled skin flap for 7 days and then dividing the distal attachment abolished neutrophil products and tissue oxidant activity in the skin flaps (p < 0.05). These data suggest that neutrophil products and oxidant production are increased in ischemic skin and that preconditioning of the flap markedly attenuates this response.

Extracorporeal membrane oxygenation for the circulatory support of children after repair of congenital heart disease.

We have treated 39 infants and children with congenital heart disease with extracorporeal membrane oxygenation during the past 5 years. Thirty-six were treated for low cardiac output or pulmonary vasoreactive crisis after repair of congenital heart defects. Twenty-two (61%) survived. Most patients were cannulated from the neck via the right internal jugular vein and the right common carotid artery. Six patients were cannulated from the chest, including three who had separate drainage of the left side of the heart with a left atrial cannula. Two of these patients survived and were the only survivors of the nine patients cannulated in the operating room because they could not be weaned from cardiopulmonary bypass after open cardiac operations. We also reviewed 312 patients (the predictor study series) having open cardiac operations before the availability of extracorporeal membrane oxygenation; 27 of these patients died. Data were collected at 1 and 8 hours postoperatively to determine if any parameters might predict early mortality. With these parameters used as criteria, patients who went on extracorporeal membrane oxygenation were as sick as those who died before extracorporeal membrane oxygenation was available. The most common complication was bleeding related to heparinization. The mean transfusion requirement in survivors was 1.50 +/- 1.13 ml/kg/hr, 5.63 +/- 7.0 ml/kg/hr in the nonsurvivors, and 7.46 +/- 8.29 ml/kg/hr in those cannulated in the operating room because they could not be weaned from bypass. Four children had intracranial hemorrhage, and two of them died. There was one late death. Nine of the 22 survivors are entirely normal. All survivors who do not have Down's syndrome are considered to have normal central nervous system function. We conclude that extracorporeal membrane oxygenation can improve survival in patients with both pulmonary artery hypertension and low cardiac output after operations for congenital heart disease.

Regional cholesterol screening: problems and potentials.

Mass cholesterol level screening was carried out in 3,288 individuals. Over a wide range of ages, moderate or high risk values were found in 16%. Follow-up of those with abnormal cholesterol levels revealed that a low percentage visited their family physicians. Moreover, successful responses to treatment were identified in a very small number. The cost of lowering an elevated serum cholesterol level identified in this manner was approximately $800. Problems and potentials of this approach are discussed. Interest in serum cholesterol level control and understanding of its importance have greatly increased. Patients and physicians have become more well informed as a result of the Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) and recent guidelines proposed by the National Heart Lung and Blood Institute (NHLBI). As a result of these reports, it is now recognized that lowering an elevated cholesterol by 1% causes a 2% reduction in mortality from coronary artery occlusive disease. Moreover, it is now conceded that normal levels are much less than had been thought previously and it is recommended that all adults receive treatment to maintain a serum cholesterol less than 200 mg/dl. We were recently invited to present an exhibit in the high technology area of the Kentucky State Fair. This provided an opportunity to develop and test the mass screening process, collect data, and to evaluate the cost-effectiveness of such screening processes.