Citations

Mucins are the major glycoprotein component of respiratory tract secretions. Little is known about their expression in the upper respiratory tract. In order to define this expression, in situ hybridization was performed on 19 normal and 4 vasomotor rhinitis (VMR) inferior turbinates to identify mucin mRNA. MUC1, MUC2, MUC4, MUC5AC, MUC5B, and MUC7 were expressed in both the normal and VMR turbinates. MUC 4 and MUC5AC were the most highly expressed mucins. MUC1, MUC2, MUC4, and MUC5AC were expressed mainly by the epithelial border, whereas MUC5B and MUC7 were expressed by the submucosal glands. MUC1 and MUC4 exhibited a diffuse expression by multiple cell types along the mucosal border, whereas MUC2 and MUC5AC expression appeared to be limited to a subpopulation of epithelial cells, most likely goblet cells. Although MUC1, MUC4, and MUC5AC showed sporadic submucosal glandular expression, MUC5B and MUC7 appeared to be the predominant submucosal gland mucins in the inferior turbinates. MUC3 and MUC6 expression, which have been found primarily in the gastric mucosa, were not seen in any of the inferior turbinate samples examined. The only difference seen between normal and VMR turbinates was a slight decrease in MUC1 expression in the VMR group. The variety of mucins expressed and the diversity of their expression patterns may have significance in terms of the rheologic and particle clearance properties of nasal secretions. Understanding the expression patterns in normal turbinates will serve as the foundation for further study of these mucins in disease states.

Abstract To determine if replacement of GH improves BMD in adult-onset GHD, we administered GH in physiologic amounts to men and women with GHD. GH replacement significantly increased spine BMD in the men by 3.8%. Introduction: Growth hormone (GH) deficiency (GHD) acquired in adulthood results in diminished BMD; the evidence that replacement of GH improves BMD is not conclusive. We therefore performed a randomized, placebo-controlled trial to determine whether GH replacement would increase lumbar spine BMD in a combined group of men and women with adult-onset GHD. Materials and Methods: We randomized 67 men and women to receive GH (n = 33) or placebo (n = 34) for 2 yr. The GH dose was initially 2 μg/kg body weight/d, increased gradually to a maximum of 12 μg/kg/d and adjusted to maintain a normal IGF-I concentration for age and sex. BMD was assessed before treatment and at 6, 12, 18, and 24 mo of treatment. Fifty-four subjects completed the protocol. Results: BMD of the lumbar spine in the entire group increased by 2.9 ± 3.9% above baseline in the GH-treated subjects, which was significantly (p = 0.037) greater than the 1.4 ± 4.5% increase in the placebo-treated subjects. In a secondary analysis, spine BMD in GH-treated men increased 3.8 ± 4.3% above baseline, which was significantly (p = 0.001) greater than that in placebo-treated men (0.4 ± 4.7%), but the change in GH-treated women was not significantly different from that in placebo-treated women. Treatment with GH did not increase total hip BMD more than placebo treatment after 2 yr. Conclusions: We conclude that GH replacement in men who have adult-onset GHD improves their spine BMD, but we cannot draw any conclusions about the effect of GH replacement on spine BMD in women with adult-onset GHD.

Abstract Purpose: YKL-40 is a secreted protein that has been reported to be overexpressed in epithelial cancers and gliomas, although its function is unknown. Previous data in a smaller sample set suggested that YKL-40 was a marker associated with a poorer clinical outcome and a genetically defined subgroup of glioblastoma. Here we test these findings in a larger series of patients with glioblastoma, and in particular, determine if tumor YKL-40 expression is associated with radiation response. Experimental Design: Patients (n = 147) with subtotal resections were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. An additional set (n = 140) of glioblastoma patients who underwent a gross-total resection was tested to validate the survival association and extend them to patients with minimal residual disease. Results: In the subtotal resection group, higher YKL-40 expression was significantly associated with poorer radiation response, shorter time to progression and shorter overall survival. The association of higher YKL-40 expression with poorer survival was validated in the gross-total resection group. In multivariate analysis with both groups combined (n = 287), YKL-40 was an independent predictor of survival after adjusting for patient age, performance status, and extent of resection. YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization. YKL-40 was significantly associated with 10q loss. Conclusions: The findings implicate YKL-40 as an important marker of therapeutic response and genetic subtype in glioblastomas and suggest that it may play an oncogenic role in these tumors.

AbstractBecause fruits and vegetables are rich in bioactive compounds with potential cancer-preventive actions, increased consumption may reduce the risk of ovarian cancer. Evidence on the association between fruit and vegetable intake and ovarian cancer risk has not been consistent. We analyzed and pooled the primary data from 12 prospective studies in North America and Europe. Fruit and vegetable intake was measured at baseline in each study using a validated food-frequency questionnaire. To summarize the association between fruit and vegetable intake and ovarian cancer, study-specific relative risks (RR) were estimated using the Cox proportional hazards model, and then combined using a random-effects model. Among 560,441 women, 2,130 cases of invasive epithelial ovarian cancer occurred during a maximum follow-up of 7 to 22 years across studies. Total fruit intake was not associated with ovarian cancer risk—the pooled multivariate RR for the highest versus the lowest quartile of intake was 1.06 [95% confidence interval (95% CI), 0.92-1.21; P value, test for trend = 0.73; P value, test for between-studies heterogeneity = 0.74]. Similarly, results for total vegetable intake indicated no significant association (pooled multivariate RR, 0.90; 95% CI, 0.78-1.04, for the highest versus the lowest quartile; P value, test for trend = 0.06; P value, test for between-studies heterogeneity = 0.31). Intakes of botanically defined fruit and vegetable groups and individual fruits and vegetables were also not associated with ovarian cancer risk. Associations for total fruits and vegetables were similar for different histologic types. These results suggest that fruit and vegetable consumption in adulthood has no important association with the risk of ovarian cancer.

Patent ductus arteriosus (PDA) is a common congenital heart disease that results when the ductus arteriosus, a muscular artery, fails to remodel and close after birth. A syndromic form of this disorder, Char syndrome, is caused by mutation in TFAP2B , the gene encoding a neural crest-derived transcription factor. Established features of the syndrome are PDA, facial dysmorphology, and fifth-finger clinodactyly. Disease-causing mutations are missense and are proposed to be dominant negative. Because only a small number of families have been reported, there is limited information on the spectrum of mutations and resulting phenotypes. We report the characterization of two kindreds (K144 and K145) with Char syndrome containing 22 and 5 affected members, respectively. Genotyping revealed linkage to TFAP2B in both families. Sequencing of TFAP2B demonstrated mutations in both kindreds that were not found among control chromosomes. Both mutations altered highly conserved bases in introns required for normal splicing as demonstrated by biochemical studies in mammalian cells. The abnormal splicing results in mRNAs containing frameshift mutations that are expected to be degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency; even if produced, the protein in K144 would lack DNA binding and dimerization motifs and would likely result in haploinsufficiency. Examination of these two kindreds for phenotypes that segregate with TFAP2B mutations identified several phenotypes not previously linked to Char syndrome. These include parasomnia and dental and occipital-bone abnormalities. The striking sleep disorder in these kindreds implicates TFAP2B-dependent functions in the normal regulation of sleep.

ABSTRACT Introduction The optimal approach for identification and evaluation of the sexual problems in men and women in primary care or general medicine practice has not been consensed. Aim To provide recommendations/guidelines concerning state-of-the-art knowledge for clinical evaluation and management strategies in the evaluation and treatment of sexual dysfunction in men and women, emphasizing evidence-based medicine and a patient-centered framework. Methods An International Consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a 2-year period. Concerning the Clinical Evaluation and Management Strategies Committee, there were 12 experts from five countries. Main Outcome Measure Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. Results Three concepts underlie sexual medicine management: (i) adoption of a patient-centered framework for evaluation and treatment; (ii) application of the principles of evidence-based medicine in diagnostic and treatment planning; and (iii) use of a unified management approach in men and women. When taken together, these three principles provide a balanced and integrated approach to sexual dysfunction management. Common algorithms for diagnosis and management of men and women with sexual dysfunction, brief sexual symptom checklists, basics in history and physical examination, indications for specialized referral and development of a follow-up strategy are presented. Conclusions More research is needed in understanding the role of evidence-based and patient-centered medicine in the clinical evaluation and management strategies of men and women with sexual dysfunction.