Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats.

BACKGROUND: Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl- Cl- exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats. METHODS: Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations. RESULTS: Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups. CONCLUSIONS: Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.

Skeletal integrity and visceral transplantation.

Despite continuous improvement in long-term survival, there is no knowledge about risk of bone health impairment and management strategies before and after intestinal transplantation. Therefore, 147 adults were retrospectively studied via chart review; 70 long-term survivors, 53 candidates and 24 recipients with longitudinal follow-up. Evaluation process included measurement of bone mineral density (BMD) and allied biochemical markers. Both long-term survivors and candidates showed low bone mass with lower (p < 0.05) z-scores at hip, femoral neck and spine. Vitamin D deficiency and secondary hyperparathyroidism were observed in both groups. Prevalence of osteoporosis was 44% among long-term survivors and 36% in candidates with age, BMD, duration of parenteral nutrition, type of immunosuppression and rejection being significant risk factors. Fragility fractures occurred at a higher (p = 0.02) rate among long-term survivors (20%) compared to candidates (6%). The longitudinal study documented acceleration (p = 0.025) of bone loss after transplantation with a decline of 13.4% (femoral neck), 12.7% (hip) and 2.1% (spine). Alendronate reduced (p < 0.05) but did not prevent bone loss. In conclusion, intestinal transplant recipients are at risk of osteoporosis secondary to bone loss before and after transplantation. Accordingly, current management includes comprehensive preventive measures with prompt therapeutic intervention utilizing intravenous bisphosphonates or subcutaneous human PTH.

The "good enough" body size as judged by people of varying age and weight.

OBJECTIVE: To examine the concept of the "good enough" body size acceptability across a wide range of ages and weight status. RESEARCH METHODS AND PROCEDURES: Subjects were 303 children, 427 adolescents, 261 young adults, and 326 middle-age adults who selected acceptable body sizes from an array of drawings representing their own age and gender. They also selected body sizes representing their own actual and ideal size. RESULTS: A large majority (87%) of subjects considered their own body size socially acceptable. This finding applied to both genders in all age groups and to underweight, normal weight, and overweight subjects. Even among obese subjects, 48% considered their own body size socially acceptable. For the large percentage of subjects who reported a discrepancy between their actual and ideal body sizes, most considered their own body size acceptable. This finding also applied to both genders in all age groups and to underweight, normal weight, and overweight subjects. DISCUSSION: Most male and female subjects across a wide range of ages and status considered their own body size to be within the range of socially acceptable body sizes even though, for many, it did not match their ideal. The implications of expanding body size research to include the conceptual framework of body size acceptability is discussed in terms of contributing to a paradigm of positive psychology.

Differentiation of murine premigratory primordial germ cells in culture.

In the mouse embryo, primordial germ cells first appear in the extraembryonic mesoderm and divide rapidly while migrating to the fetal gonad. Shortly after their arrival in the gonad, germ cells sexually differentiate as proliferation ceases. Previous studies have established that primordial germ cells proliferate and migrate in feeder layer culture. To explore cellular regulation of fetal germ cell development, we have used germ cell nuclear antigen 1 (GCNA1), a marker normally expressed only in postmigratory germ cells, to investigate the developmental potency of both pre- and postmigratory cells in this culture system. We found that explanted premigratory germ cells will initiate expression of this marker and are, therefore, capable of undertaking some aspects of gonocyte differentiation without intimate exposure to the fetal gonad. We have also tested whether postmigratory gonocytes are stable in culture. As detected by either alkaline phosphatase or GCNA1, we did not detect long-term survival of either prospermatogonia or oogonia under conditions that support the survival, proliferation, and differentiation of earlier premigratory cells. These observations are consistent with an autonomous cellular mechanism governing the initial stages of gonocyte differentiation, and suggest that differentiation towards gonocytes is accompanied by a change in requirements for cell survival.

Characteristics and quality of Papanicolaou smears obtained by primary care clinicians using a single commercial laboratory.

BACKGROUND: Few data are available on factors associated with the quality of Papanicolaou smears performed in primary care. OBJECTIVE: To identify the patterns and proficiency of cervical cancer screening among different primary care specialties. MATERIALS AND METHODS: Clinical and cytologic data from 21,833 Papanicolaou smears, submitted to a single large commercial laboratory by 176 clinicians during a 7-month period, were correlated with individual clinician and specialty characteristics according to indexes of specimen quality. RESULTS: Obstetrician-gynecologists, nurse practitioners, and physician assistants provided screening to a younger population of women compared with family physicians, internists, and general practitioners. Factors positively associated with a greater probability of a "satisfactory" smear or the presence of endocervical cells (as a marker of adequate sampling) were increasing patient age, use of the cytobrush, and the specialty of the obstetrician-gynecologist. Satisfactory smears were not associated with any increased identification of cytologic abnormalities compared with "limited" smears. In contrast, smears with endocervical cells showed a higher proportion of abnormalities compared with specimens without such cells. CONCLUSIONS: Differences in the performance of obtaining Papanicolaou smears exist between primary care specialties, but need further clarification. The use of the cytobrush and the presence of endocervical cells are criteria that reflect clinician proficiency more realistically than the laboratory criterion of satisfactory smear.

Bursal cyst: an unusual axillary mass.

We discuss an unusual case of a bursal cyst presenting as an axillary mass in a previously healthy individual. Although both bursal and ganglion cysts not uncommonly arise from other joints, they also rarely occur in the axilla as well. Clinicians should include cysts in their differential of diagnoses when examining axillary masses and deciding on their appropriate treatment.

The effect of the quality of Papanicolaou smears on the detection of cytologic abnormalities.

BACKGROUND: Controversy continues regarding the relation between the quality of Papanicolaou (Pap) smears, especially the presence of endocervical cells (ECC), with the finding of cytologic abnormalities. METHODS: As part of a study regarding performance feedback on the quality of Pap smears, data from 56,475 Pap smears obtained by 176 participating clinicians over a 20-month period were analyzed to assess the relation between the presence of ECC, the categorization of global specimen adequacy as "satisfactory" or "satisfactory with limitations," and the prevalence of atypia and squamous intraepithelial lesions (SILs). RESULTS: Atypia was less likely to be found in "satisfactory" Pap smears than in "satisfactory with limitations" quality Pap smears (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.5-0.6; P < 0.001), even though the latter could contain ECC. No association was found between satisfactory Pap smears and cytologic abnormalities. Compared with specimens with no ECC, an ECC count of > or = 50 on a slide was associated positively with the detection of atypia (OR, 2.1; 95% CI, 1.8-2.4; P < 0.001) or SILs (OR, 1.7; 95% CI, 1.3-2.2; P < 0.001). A similar relation existed between ECC counts of 25-50 (OR, 1.9; 95% CI, 1.1-2.2; P = 0.01) and the detection of SILs. No relation was found between specimens with < 25 ECC and the presence of atypia or abnormalities. CONCLUSIONS: The global adequacy criterion of "satisfactory" assigned to a Pap smear does not indicate that there is a greater likelihood of detecting cytologic abnormalities compared with lower quality Pap smears. To the authors' knowledge, previous studies regarding the link between ECC in the Pap smear and cytologic abnormalities have not addressed the relevance of how many ECC are needed to maximize the identification of abnormalities. The data from the current study support the value of obtaining at least 25 ECC as a quality indicator of sampling.

A comparison of body size evaluations of obesity surgery patients and general population adults.

OBJECTIVE: To compare post-operative obesity surgery patients and general population adults in their assessments of a wide range of body sizes. RESEARCH METHODS AND PROCEDURES: Obesity surgery patients (n = 274) and general population adults (n = 326) rated ideal and socially acceptable body sizes in separate arrays of babies, children, young adults, and middle-aged and older adults. Nine line figure drawings ranging from very thin to very obese were rated for each array. RESULTS: Both groups selected the same ideal body size for all arrays except for babies. Both groups rejected obese and very thin body sizes as socially acceptable. However, the obesity surgery patients were more restrictive than general population adults in their ratings of socially acceptable body sizes. Current obesity status did not impact ratings for the patient or general population subjects. In the patient sample, time since surgery did not influence body size evaluations. DISCUSSION: The study of body size ratings limited only to the "ideal" size may be misleading because it may mask subtle but meaningful differences between groups. The consistent difference in more restrictive ratings of obesity surgery patients compared to general population adults may be due to patients' greater psychological investment in endorsing the societal ideal body size. It may also be due to patients' status as peripheral group members of the normal weight community. The inability of some patients to maintain their post-operative weight loss may be particularly problematic for those who have defined "socially acceptable" body size most narrowly.

Activin and TGFbeta limit murine primordial germ cell proliferation.

Mammalian primordial germ cells (PGCs) proliferate as they migrate from their initial location in the extraembryonic mesoderm to the genital ridge, the gonadal anlage. Once in the genital ridge, PGCs cease dividing and differentiate according to their gender. To identify ligands that might limit PGC proliferation, we analyzed growth factor receptors encoded in RNA obtained from purified germ cells shortly after their arrival in the genital ridge. Receptors for two members of the TGFbeta superfamily were found, TGFbeta1 and activin. As the signal-transducing domains of both receptor systems are highly conserved, the effects of both TGFbeta1 and activin on PGCs would be expected to be similar. We found that both ligands limited the accumulation of germ cells in primary PGC cultures. BrdU incorporation assays demonstrated that either ligand inhibits PGC proliferation. These results suggest that these signal transduction pathways are important elements of the mechanism that determines germ cell endowment.

A comparison of breast stimulation and intravenous oxytocin for the augmentation of labor.

BACKGROUND: Breast stimulation to augment labor has been used for centuries in tribal societies and by midwives. In recent years it has been shown to be effective in ripening the cervix, inducing labor, and as an alternative to oxytocin for the contraction stress test. This study compared the effectiveness of breast stimulation with oxytocin infusion in augmenting labor. METHODS: Women admitted to the labor ward were eligible for the study if they had inadequate labor with premature rupture of the membranes and met inclusion criteria. They were assigned to oxytocin augmentation or breast stimulation (manual or pump), and were switched to oxytocin in the event of method failure. Outcomes included time to delivery, intervention to delivery, proportion of spontaneous deliveries, and Apgar scores. One hundred participants were needed in each arm of the study to demonstrate a 2- to 3-hour difference in delivery time, with a power of 80 percent. RESULTS: Analysis was performed on 79 women, of whom 49 were in the breast stimulation group and 30 in the oxytocin group. Sixty-five percent of the participants failed breast stimulation and were switched to oxytocin infusion. Although augmentation start to delivery was shorter for the oxytocin group (p < 0.001), no differences in total labor time occurred between the groups. Nulliparas receiving breast stimulation had more spontaneous (relative risk 1.7, p = 0.04), and fewer instrumental deliveries than those receiving oxytocin (relative risk 0.2, p = 0.02). No significant differences in adverse fetal outcomes occurred between the study groups. CONCLUSIONS: The small number of participants and a variety of problems with the conduct of the study prevented the formulation of reliable conclusions from the results. However, the study provided important insights into the feasibility and problems of developing a high-quality randomized trial of augmentation by breast stimulation.

Role of fibroblast growth factors and their receptors in mouse primordial germ cell growth.

Primordial germ cells (PGCs) are the embryonic progenitors of mature germ cells. During their proliferative stage, murine PGCs may be transiently cultured on mitotically inactive feeder layers. This culture system has permitted identification of several growth factors active toward PGCs. We and others have previously identified basic fibroblast growth factor (bFGF) as a powerful mitogen in this system. Here we characterize some of the functions of bFGF in PGC culture. Our data demonstrate that fibroblast growth factor (FGF) receptors I and II are present in the developing gonad and are consistent with expression of these receptors by PGCs. Moreover, PGCs can bind radiolabeled bFGF in vitro, demonstrating that the factor can act directly on these cells. While mitotic PGCs of either sex are shown to bind radiolabeled bFGF, oogonia that are undergoing meiotic arrest exhibit reduced bFGF binding, indicating potential developmental regulation of an FGF receptor.

A mouse model for Prader-Willi syndrome imprinting-centre mutations.

Imprinting in the 15q11-q13 region involves an 'imprinting centre' (IC), mapping in part to the promoter and first exon of SNRPN. Deletion of this IC abolishes local paternally derived gene expression and results in Prader-Willi syndrome (PWS). We have created two deletion mutations in mice to understand PWS and the mechanism of this IC. Mice harbouring an intragenic deletion in Snrpn are phenotypically normal, suggesting that mutations of SNRPN are not sufficient to induce PWS. Mice with a larger deletion involving both Snrpn and the putative PWS-IC lack expression of the imprinted genes Zfp127 (mouse homologue of ZNF127), Ndn and Ipw, and manifest several phenotypes common to PWS infants. These data demonstrate that both the position of the IC and its role in the coordinate expression of genes is conserved between mouse and human, and indicate that the mouse is a suitable model system in which to investigate the molecular mechanisms of imprinting in this region of the genome.

Primordial germ cells, stem cells and testicular cancer.

Primordial Germ Cells (PGCs) arise in the mouse embryo as a small population of cells some way from the gonad anlagen. In order for the embryo to develop into a fully fertile adult animal the PGCs must increase in number and reach the gonad. Mutations causing sterility in the mouse have identified some of the genes involved in regulating PGC development and some of these genes have been molecularly cloned. Similarly, mutations affecting the development and differentiation of PGC-derived tumors (teratomas and teratocarcinomas) have been identified in certain strains of mice and these identify genes involved in the normal growth and differentiation of PGCs. These studies should help to define the role of growth factors in PGC development and in the development of germ-cell-derived tumors.

Assessment of socially acceptable body sizes by university students.

The objective of this study was to determine if more than one body size (the ideal) is considered socially acceptable. Two hundred undergraduates rated ideal male and female sizes, all socially acceptable male and female sizes, and their own current and desired sizes. Stimuli were arrays of nine outline drawings illustrating extremely thin to very fat male and female sizes. Most students considered three of nine sizes socially acceptable. There was high consensus on the sizes considered ideal. Although nearly three-quarters of women and half of men desired to be a different size, most considered their current size socially acceptable for other people. The results clearly demonstrate the existence of a range of socially acceptable male and female body sizes. The current size of most students was within this range. Exclusive focus on ideal body size distorts understanding of both other-size and own-size evaluations.

Browpexy: lateral orbicularis muscle fixation as an adjunct to upper blepharoplasty.

Lateral ptosis of the eyebrow is a major part of the complex changes that patients are seeking to improve with an upper blepharoplasty. Two hundred and eight patients have undergone a browpexy procedure at the time of blepharoplasty. This operative maneuver, which is performed through the blepharoplasty incision, prevents the brow from dropping below the superior orbital rim and creates a defined tarsal sulcus to produce a sculptured upper eyelid.

Percutaneous needle biopsy diagnosis of benign neurogenic neoplasms.

Preoperative diagnosis of benign neurogenic neoplasms (BNNs) provides useful information in guiding management. To assess the effectiveness of fine-needle aspiration (FNA) and needle core biopsy (NCB) in diagnosing schwannomas and neurofibromas, 40 percutaneous biopsies interpreted as BNNs or obtained from lesions subsequently shown by excision to be BNNs were reviewed. The 13 aspirates diagnostic of BNN revealed spindle cells arranged haphazardly in irregular tissue fragments and in parallel as elongated ropy fascicles, with a myxoid to fibrillary background. The nuclei were buckled, often with intranuclear cytoplasmic inclusions. Four lesions showed nuclear pleomorphism without mitoses. Of 19 schwannomas evaluated by FNA, four (21%) were diagnosed as schwannomas and seven (37%) as BNNs. Ten neurofibromas were aspirated, revealing two (20%) BNNs. Of seven nondiagnostic FNAs accompanied by NCB, three (43%) indicated a BNN. The sensitivities of FNA, NCB, and both modalities in diagnosing BNNs were 43,60, and 71%, respectively. For the 16 FNAs showing features of BNNs, subsequent excisions revealed 11 schwannomas, two neurofibromas, one neurogenic sarcoma, one fibromyxoid neoplasm of uncertain malignant potential, and one unclassified low-grade myxoid sarcoma. FNA can be effective in diagnosing BNNs. If collagenous or myxoid lesions yield paucicellular nondiagnostic aspirates, NCB is helpful. Lowgrade sarcoma and neurofibromatous areas of neurogenic sarcoma may be misinterpreted as BNNs by percutaneous biopsy. BNNs may show nuclear pleomorphism without mitotic activity, and should not be mistaken for sarcoma.

Recall and treatment decisions of primary care providers in response to Pap smear reports.

INTRODUCTION: Although the frequency of cervical cancer screening has been extensively studied, little is known about how clinicians decide to screen or recall patients for Pap smears. This study reports the management decisions made by office-based clinicians for 10 different Pap smear reports describing adequacy limitations and cytological diagnoses. METHODS: We surveyed 186 clinicians using a commercial laboratory in the southeastern United States and analyzed results by frequency and comparison statistics. RESULTS: Our respondents were 148 clinicians (79.6% response rate) from different specialties. There was variation in reported management of inflammation, atypia, and low-grade abnormalities (LGSIL), in regard to recall for repeat or routine testing as well as arranging colposcopy. In only 3 of 10 Pap smear results did more than 50% of respondents agree on a specific test recall interval. CONCLUSIONS: The variation in responses from office-based clinicians suggests either uncertainty or different opinions in making recall and treatment decisions for smears of limited quality even when associated with cytologic abnormalities. These differences may have relevance to outcomes, clinician workload, and costs of care in cervical cancer screening.