Septation of the respiratory and digestive tracts in human embryos: Crucial role of the tracheoesophageal sulcus

Esophageal atresia and tracheoesophageal fistula, common malformations of the respiratory and digestive tracts, are of unsettled pathogenesis. Part of the difficulty in understanding these abnormalities arises from the uncertainties about the normal developmental processes in the region. This study examined the development and fate of the tracheoesophageal septum. Normal human embryos from the Carnegie Embryological Collection and fetuses from the Hopkins Pathology Collection were examined, and reconstructions of selected specimens were made from photomicrographs of serial histologic sections. The results show that the lung bud appears in Carnegie stage 12, rapidly enlarges, and bend caudally, thereby producing a sulcus between the foregut and the respiratory system on its caudal aspect. The cranial aspect of this tracheoesophageal sulcus remains fixed at the levels of the first cervical vertebra throughout subsequent embryonic and fetal development. At the same time the trachea and esophagus elongate to bring those parts of the respiratory and digestive systems into their definitive anatomic positions. Examination of the tracheoesophageal sulcus shows that its growth-limiting properties may be explained by its catenoidal configuration. Catenoidal, or saddle-shape, sulci have been shown to have similar regional growth-limiting properties in the embryonic heart. These regions contrast with outwardly convex regions in both the developing heart and lung where growth of the tissues occurs. The observations made here suggest that the origin of the tracheoesophageal malformations must be sought in a configurational abnormality in the area of the developing lung bud in Carnegie stage 12. © 1994 Wiley-Liss, Inc.     

Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat

1. The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine.
2. Sibutramine (3 and 10 mg kg⁻¹, p.o.) and (+)-fenfluramine (1 and 3 mg kg⁻¹, p.o.) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration.
3. Fluoxetine (3, 10 and 30 mg kg⁻¹, p.o.), and nisoxetine (3, 10 and 30 mg kg⁻¹, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg⁻¹, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration.
4. Venlafaxine (100 and 300 mg kg⁻¹, p.o.) and duloxetine (30 mg kg⁻¹, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration.
5. The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity.

     

Lymph Node Tumor Volumes in Patients Undergoing Sentinel Lymph Node Biopsy for Cutaneous Melanoma

Background: Regional lymph node tumor volumes in patients undergoing sentinel lymph node (SN) biopsy (SNB) for treatment of cutaneous melanoma have not been described. The objectives of this study were to describe the lymph node tumor volumes typically seen in this population and to correlate tumor volumes with tumor thickness and positive SN characteristics.Methods: Review of a consecutive series of patients with clinically localized cutaneous melanoma who underwent SNB of nonpalpable regional lymph node basins followed by complete lymphadenectomy (LND) was performed. Multiple lymph node sections from positive SNs and nonsentinel nodes (NSNs) in LND specimens were examined microscopically. Individual tumor deposit diameters were measured using an ocular micrometer. Aggregate tumor volumes were calculated for SN and LND specimens. Tumor volumes and SN and LND positivity rates were correlated with tumor thickness, the number of positive SNs, and the presence of multiple SN tumor deposits.Results: SNB procedures were performed for 149 melanomas in 189 regional nodal basins. The mean tumor depth was 2.48 mm. The mean number of SNs/basin was 2.1. Thirty-two of 149 SNB procedures (21.5%) revealed a total of 34 nodal basins with at least one positive SN. The median tumor volume in positive SNs was 4.7 mm³ (range, 0.1-3618 mm³; mean, 209 mm³). The median aggregate tumor volume in positive LND specimens was 4.9 mm³ (range, 0.1-3618 mm³; mean, 224 mm³). Six basins (17.6%) contained at least one positive NSN. The regional node aggregate tumor volume correlated weakly with tumor thickness (Pearsons correlation coefficient = .302, P = .0934). NSN positivity was not predicted by tumor thickness, American Joint Committee on Cancer tumor stage, number of positive SNs, or number of metastatic deposits within SNs.Conclusions: Most melanoma-positive SNs contain minute tumor volumes. Tumor thickness and patterns of SN metastases may not be predictive of tumor burden or the presence of positive NSNs.     

Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women.

Flaxseed, the richest known source of plant lignans, has been shown to have chemoprotective effects in animal and cell studies. Some of its effects may be mediated through its influence on endogenous hormone production and metabolism. Two competing pathways in estrogen metabolism involve production of the 2-hydroxylated and 16 alpha-hydroxylated metabolites. Because of the proposed differences in biological activities of these metabolites, the balance of the two pathways has been used as a biomarker for breast cancer risk. We examined the effects of flaxseed consumption on urinary estrogen metabolite excretion in postmenopausal women. Twenty-eight postmenopausal women were studied for three seven-week feeding periods in a randomized crossover design. During the feeding periods, subjects consumed their usual diets plus ground flaxseed (0, 5, or 10 g/day). Urinary excretion of the estrogen metabolites 2-hydroxyestrogen (2-OHEstrogen) and 16 alpha-hydroxyestrone (16 alpha-OHE1) as well as their ratio, 2/16 alpha-OHE1, was measured by enzyme immunoassay. Flaxseed supplementation significantly increased urinary 2-OHEstrogen excretion (p < 0.0005) and the urinary 2/16 alpha-OHE1 ratio (p < 0.05) in a linear, dose-response fashion. There were no significant differences in urinary 16 alpha-OHE1 excretion. These results suggest that flaxseed may have chemoprotective effects in postmenopausal women.     

186Re-labeled antibodies to p185HER2 as HER2-targeted radioimmunopharmaceutical agents: comparison of physical and biological characteristics with 125I and 131I-labeled counterparts

Overexpression of the HER2/neu protooncogene has been shown to correlate with poor clinical prognosis. A murine monoclonal antibody (4D5) directed against the extracellular domain (ECD) of p185HER2 has been shown to inhibit in vitro and in vivo growth of carcinomas overexpressing HER2 and has been humanized (rhuMAb HER2). The objective of the study was the identification of an agent which might be useful for in vitro studies, tumor imaging and/or radioimmunotherapy by linking beta-emitting radionuclides to these HER2-targeted antibodies. Murine 4D5 and humanized rhuMAb HER2 were radiolabeled with 125I, 131I or 186Re. Physical characteristics (TCA precipitability, SDS-PAGE, size exclusion chromatography), binding affinities to the HER2 ECD (in an ELISA and on SK-BR-3 cells) and antiproliferative activities of the radiolabeled antibodies were determined. Although 131I-4D5 and 131I-rhuMAb HER2 usually retained > 85% ECD binding, they exhibited increased aggregation and fragment content, drastically reduced antiproliferative activities and poor stability upon storage at 4 degrees C. For these antibody preparations, conservation of binding did not necessarily correlate with preservation of bioactivity indicating the importance of bioactivity determinations in radiolabeled antibody studies. Conversely, 4D5 and rhuMAb HER2 labeled with 125I or 186Re maintained physical properties, ECD binding, antiproliferative activities and were stable upon storage at 4 degrees C for at least 8 days. The superior retention of physical and biological characteristics of 186Re-labeled 4D5 and rhuMAb HER2 compared with their 131I-labeled counterparts suggests the potential for their use as radioimaging and radioimmunotherapeutic agents in the treatment of HER2 overexpressing tumors.     

Binding of psychotropic drugs to isolated alpha-acid glycoprotein

Alpha1-acid glycoprotein (alpha1-AG) was purified from human sera, and its binding properties with respect to psychotropic drugs were examined by equilibrium dialysis methods in order to clarify the specificity of binding. Radioactive imipramine, a tricyclic antidepressant, was used as the primary ligand. Other drugs, representative of different classes, were tested as potential inhibitors of the alpha1-AG-imipramine binding. The K(a) for imipramine was 2.8 x 10(5) (+/- 0.8) M(-10 (mean +/- S.D.). Chlorpromazine, fluphenazine, thioridazine, loxapine and thiothixene, which are antipsychotic drugs, were competitive inhibitors of imipramine binding, and their K(a) values were in the same range. Propranolol, haloperidol and diazepam were also competitive inhibitors but their affinities were lower. Molindone, an indolic antipsychotic, when tested at the same concentrations as the other drugs, did not affect imipramine binding. Trihexyphenidyl, an anti-Parkinson drug, was a potent but noncompetitive inhibitor. These data identify the antidepressant and major tranquilizer drugs that exhibit high affinity for alpha1-AG and indicate that alpha1-AG may account for 40 per cent of total imipramine bound in serum. Since in psychiatric clinical practice two drugs are frequently administered together, possible competitive effects are discussed as well as the potential role of alpha1-AG in psychiatric illness.     

Reducing the demand for admission to intensive care after major abdominal surgery by a change in anaesthetic practice and the use of remifentanil

We have used a remifentanil-based anaesthetic for patients undergoing major abdominal surgery who would normally have gone to the intensive care unit in this hospital. Avoiding intensive care unit admission was considered an advantage as a shortage of intensive care unit beds was leading to the cancellation of operations. We first used remifentanil as part of a safety and efficacy study. The aim was to see if the rapid and complete awakening obtained when using this drug would allow us to avoid the need for admission to an intensive care unit and use a high dependency unit instead. This was shown to be practicable. In comparison with a group of patients matched retrospectively for the type of operation before remifentanil was used there was a reduction in the length of time (mean+/- SD) patients' lungs were ventilated (612+/-417 vs. 9.9+/-28.9 min P< 0.0001). There was no saving in cost ( pound808.71+/- pound187.06 vs. pound795.27+/- pound253.49). When remifentanil was used routinely (after the safety and efficacy study), there were significant reductions in the time to tracheal extubation (612+/-417 vs. 4+/-10 min P < 0.0001) and costs (808.71I vs. 392.10 I P < 0.0001) compared with other patients in whom it was not used. Patients waiting for a liver transplant were also being cancelled when a donor organ became available because of the shortage of intensive care unit beds. Based on our other experience with remifentanil, we used a similar anaesthetic technique for these patients. It proved possible to extubate the trachea in 12 of 15 patients at the end of the operation. No patient needed re-intubation. The need for intensive care and therefore cancellation of surgery was reduced. In contrast, only one patient's trachea was extubated immediately after surgery in the group of patients anaesthetized before the introduction of remifentanil. A remifentanil-based technique in combination with a change in organization has therefore enabled us to avoid admission to the intensive care unit for these patients.     

Open femur fractures in children: treatment, complications, and results

We evaluated retrospectively the treatment of 44 open femur fractures occurring between the lesser trochanter and the distal femoral physis in 43 children aged 16 years and younger. Fractures that involved the physis or that were a consequence of gunshot wounds were excluded. There were 25 grade I, 9 grade II, and 9 grade III fractures. The mean age at injury was 9.5 years. Ninety percent of the fractures were automobile related. More than 70% of the children had associated injuries. The average time to healing for all fractures in this study was 17 weeks. Our data indicate that there is a statistically significant increased time to heal with increasing age of the child (p = 0.04). Additionally, grade III fractures healed more slowly than grade I or II fractures (p = 0.0006). Fractures treated with external fixation took longer to unite than those treated with other methods (p = 0.05). The presence of complications increased the time to fracture union (p = 0.00001). Grade III injuries were the most difficult to manage; 50% of the fractures in this group developed osteomyelitis and 20% malunited. In contrast, none of the fractures in either the grade I or II groups developed deep infection. After aggressive debridement, grade I and grade II fractures may be stabilized with age-appropriate fixation methods. Grade III injuries should be managed with vigorous debridement and vigilance, as these injuries are prone to deep infection and malunion. The optimal method of skeletal stabilization in grade III fractures remains unresolved.     

Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer.

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.     

Structural mass spectrometry: rapid methods for separation and analysis of peptide natural products

A significant challenge in natural product discovery is the initial discrimination of discrete secondary metabolites alongside functionally similar primary metabolic cellular components within complex biological samples. A property that has yet to be fully exploited for natural product identification and characterization is the gas-phase collision cross section, or, more generally, the mobility-mass correlation. Peptide natural products possess many of the properties that distinguish natural products, as they are frequently characterized by a high degree of intramolecular bonding and possess extended and compact conformations among other structural modifications. This report describes a rapid structural mass spectrometry technique based on ion mobility-mass spectrometry for the comparison of peptide natural products to their primary metabolic congeners using mobility-mass correlation. This property is empirically determined using ion mobility-mass spectrometry, applied to the analysis of linear versus modified peptides, and used to discriminate peptide natural products in a crude microbial extract. Complementary computational approaches are utilized to understand the structural basis for the separation of primary metabolism derived linear peptides from secondary metabolite cyclic and modified cyclic species. These findings provide a platform for enhancing the identification of secondary metabolic peptides with distinct mobility-mass ratios within complex biological samples.