Effects of melengestrol acetate on onset of puberty, follicular growth, and patterns of luteinizing hormone secretion in beef heifers

Our objective was to test the hypothesis that short-term (8 days) treatment of prepubertal heifers with melengestrol acetate (MGA) and subsequent steroid withdrawal would stimulate LH secretion and follicular growth. Angus heifers were divided randomly into two groups; MGA-treated (n = 8) or control (CON; n = 9). Puberty was determined by monitoring circulating concentrations of progesterone and ovarian morphology during a 14-day period following MGA withdrawal. LH secretory patterns were assessed upon initiation of MGA (Day 0), during MGA (Day 7), and 1 day after withdrawal of MGA (Day 9). All MGA-treated heifers, versus four CON heifers, exhibited corpora lutea and luteal phase concentrations of progesterone within 10 days after treatment (p = 0.01). Mean LH and LH pulse frequency increased (p = 0.005 and 0.0001, respectively) between Days 0 and 9 in MGA-treated heifers. In CON heifers, mean LH concentrations and pulse frequencies did not change. During the same period, diameter of the largest follicle increased in MGA-treated animals (p = 0.003) but did not change in the CON heifers. On the basis of these results, we suggest that MGA withdrawal enhances onset of puberty by stimulating pulsatile LH secretion that accelerates follicle growth to the preovulatory stage.     

Implant reconstruction following removal of tumors of the head and neck

Functional maxillofacial rehabilitation following tumor ablation depends on many variables. These include the magnitude of hard or soft tissue defects, the use of adjunctive chemotherapy or radiation therapy, and the presence of underlying systemic disease. The physiologic effects of tumor ablation and radiation therapy on local tissues and grafted bone are discussed in this article in relation to the ultimate use of implant supported prostheses. Cases are presented to illustrate a variety of clinical situations.     

Ras effector-homologue region on Rac regulates protein associations in the neutrophil respiratory burst oxidase complex

Rac, a small molecular weight GTPase in the Ras superfamily, participates in the activation of the multicomponent superoxide-generating NADPH oxidase of human neutrophils. Rac is 30% identical to Ras overall, but is 75% identical within the sequence corresponding to the effector region of Ras, which regulates mitogenesis through interactions with the protein kinase Raf1. We investigated the role of this region in Rac1 using site-directed mutagenesis. In a cell-free semirecombinant NADPH oxidase system, mutants in the 26, 33, 38, and 45 amino acids showed 20-110-fold reduced binding to the oxidase complex as judged by EC50 values and reduced (44-80%) maximal activities in superoxide generation. Only the GTP gamma S-bound form associated, since the GDP-bound form of Rac neither activated alone nor competed with GTP gamma S-Rac. EC50 values for neither p47-phox nor p67-phox were affected when mutant Racs were used in place of Rac. Data indicate direct binding of the Rac effector region to one or more components of the respiratory burst oxidase. Results indicate a general role for conserved effector-equivalent regions in small GTPases in the regulation of protein-protein interactions.     

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent

3-?4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl?-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-?4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl?propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-?4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl? ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.     

UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins

When nasoseptal dislocation or deviation contributes to nasal obstruction or external deformity, successful nasal surgery should include septal restructuring, maintenance or restoration of adequate nasal support, and stabilization of the reconstructed elements.     

Primary chondrosarcoma of long bones and limb girdles

BACKGROUND: Chondrosarcomas are common solid malignant tumors of bone, second in incidence only to osteosarcomas. The biologic evolution of chondrosarcomas is slow, requiring long follow-up intervals for meaningful survival analysis. METHODS: This study describes the clinicopathologic profiles of 344 patients, 194 male and 150 female (M:F, 1.3:1.0), with primary chondrosarcoma of long bones and limb girdles seen at 1 institution over a period of 80 years. RESULTS: The average age at presentation was 46 years (range, 5-82 years). The pelvis was the most common location (1.7% of all patients). Local pain was the most frequently reported initial symptom (81.4%). Survival analysis was limited to 233 patients whose primary treatment was given at the Mayo Clinic. All 233 patients had potential follow-up of at least 5 years. The overall 5-year survival rate was 77% (the expected rate was 96%). Local recurrence developed in 19.7% of patients and metastatic lesions in 13.7%. The recurrence rate was higher for tumors of the shoulder and pelvis than for tumors of long bones. Radiographically, chondrosarcomas had a characteristic appearance, including a combination of bone expansion and cortical thickening. Entering the tumor at surgery increased the risk of local recurrence. Histologic tumor grade was an important predictor of local recurrence and metastasis. CONCLUSIONS: With adequate initial surgical intervention, chondrosarcoma is primarily a local disease with a low metastatic rate.     

Repair of a complex retinal detachment with proliferative vitreoretinopathy in an eye with extreme scleral thinning

Two new withanolides (steroidal lactones) named coagulin F [27-hydroxy-14,20-epoxy-1-oxo-(22R)-witha-3,5,24-trienolide] (1) and coagulin G [17beta,27-dihydroxy-14,20-epoxy-1-oxo-(22R)-witha-2,5, 24-trienolide] (2) were isolated from the whole plant of Withania coagulans, and their structures were deduced by spectral analysis.     

Altered functional responsiveness of thymocyte subsets from CD3delta-deficient mice to TCR-CD3 engagement

CD3delta-deficient (delta degrees) mice are defective in alphabeta T cell development. Here we explore the capacity of TCR-CD3 signaling complexes expressed on delta degrees thymocytes to mediate the following functional outcomes in response to antibody cross-linking: (i) the transition from the CD4-CD8- to CD4+CD8+ stage, (ii) the transition from the CD4+CD8+ to CD4+CD8- or CD4-CD8+ stages and (iii) the induction of apoptosis. We provide evidence that CD3deltaepsilon complexes are dispensable for mediating the anti-CD3-mediated CD4-CD8- to CD4+CD8+ transition. On the other hand, CD3delta is critical at the CD4+CD8+ stage. We demonstrate that CD4+CD8+ thymocytes from delta degrees mice, unlike delta degrees CD4-CD8- thymocytes and wild-type CD4+CD8+ thymocytes, require prolonged or consecutive stimuli to elicit functional responses. Depending on the nature of the secondary stimulus, delta degrees thymocytes can be induced to undergo apoptosis or preferential maturation to the CD4-CD8+ stage. Taken together these results indicate that the signaling capacity of the TCR-CD3 complex is noticeably altered in the absence of CD3delta. The essential role of CD3delta at the CD4+CD8+ stage of development correlates with the onset of TCRalpha rearrangement, consistent with a critical structural and/or functional relationship between CD3delta and TCRalpha.