Robust longitudinal multi-cohort results: The development of self-control during adolescence.

Longitudinal data from multiple cohorts may be analyzed by Bayesian research synthesis. Here, we illustrate this approach by investigating the development of self-control between age 13 and 19 and the role of sex therein in a multi-cohort, longitudinal design. Three Dutch cohorts supplied data: the Netherlands Twin Register (NTR; N = 21,079), Research on Adolescent Development and Relationships-Young (RADAR-Y; N = 497), and Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2229). Self-control was assessed by one measure in NTR and RADAR-Y, and three measures in TRAILS. In each cohort, we evaluated evidence for competing informative hypotheses regarding the development of self-control. Subsequently, we aggregated this evidence over cohorts and measures to arrive at a robust conclusion that was supported by all cohorts and measures. We found robust evidence for the hypothesis that on average self-control increases during adolescence (i.e., maturation) and that individuals with lower initial self-control often experience a steeper increase in self-control (i.e., a pattern of recovery). From self-report, boys have higher initial self-control levels at age 13 than girls, whereas parents report higher self-control for girls.

Beyond not bad or just okay: social predictors of young adults' wellbeing and functioning (a TRAILS study).

BACKGROUND: Various childhood social experiences have been reported to predict adult outcomes. However, it is unclear how different social contexts may influence each other's effects in the long run. This study examined the joint contribution of adolescent family and peer experiences to young adult wellbeing and functioning. METHODS: Participants came from the TRacking Adolescents' Individual Lives Survey (TRAILS) study (n = 2230). We measured family and peer relations at ages 11 and 16 (i.e. family functioning, perceived parenting, peer status, peer relationship quality), and functioning as the combination of subjective wellbeing, physical and mental health, and socio-academic functioning at age 22. Using structural equation modelling, overall functioning was indicated by two latent variables for positive and negative functioning. Positive, negative and overall functioning at young adulthood were regressed on adolescent family experiences, peer experiences and interactions between the two. RESULTS: Family experiences during early and mid-adolescence were most predictive for later functioning; peer experiences did not independently predict functioning. Interactions between family and peer experiences showed that both protective and risk factors can have context-dependent effects, being exacerbated or overshadowed by negative experiences or buffered by positive experiences in other contexts. Overall the effect sizes were modest at best. CONCLUSIONS: Adolescent family relations as well as the interplay with peer experiences predict young adult functioning. This emphasizes the importance of considering the relative effects of one context in relation to the other.

The International Spinal Cord Injury Pain Extended Data Set (Version 1.0).

OBJECTIVES: The objective of this study was to develop the International Spinal Cord Injury Pain Extended Data Set (ISCIPEDS) with the purpose of guiding the assessment and treatment of pain after spinal cord injury (SCI). SETTING: International. METHODS: The ISCIPEDS was reviewed by members of the International SCI Data Sets Committee, the International Spinal Cord Society Executive and Scientific Committees, American Spinal Injury Association and American Pain Society Boards, and the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain, individual reviewers and societies. RESULTS: The working group recommended four assessment domains for the ISCIPEDS: (i) Pain symptoms including variables related to pain type, temporal course, severity, unpleasantness, tolerability of pain and questionnaires assessing pain type and symptom severity; (ii) Sensory signs to detect and quantify sensory abnormalities commonly associated with neuropathic pain, including dynamic mechanical and thermal allodynia, and hyperalgesia; (iii) Treatments (ongoing and past 12 months); and (iv) Psychosocial factors and comorbid conditions. CONCLUSION: The ISCIPEDS was designed to be used together with the International SCI Pain Basic Data Set and provide a brief yet thorough assessment of domains related to chronic pain in individuals with SCI. The data set includes pain-relevant self-reported assessments, questionnaires and sensory examinations. The recommendations were based on (i) their relevance to individuals with SCI and chronic pain, (ii) the existence of published findings supporting the utility of the selected measures for use in individuals with SCI, and to the greatest extent possible (iii) their availability in the public domain free of charge.

Adolescent behavioral and neural reward sensitivity: a test of the differential susceptibility theory.

Little is known about the causes of individual differences in reward sensitivity. We investigated gene-environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Reward responses were assessed during a monetary incentive delay task in 178 participants with and 265 without attention-deficit/hyperactivity disorder (ADHD), from N=261 families. We examined interactions between variants in candidate plasticity genes (DAT1, 5-HTT and DRD4) and social environments (maternal expressed emotion and peer affiliation). HTTLPR short allele carriers showed the least reward speeding when exposed to high positive peer affiliation, but the most when faced with low positive peer affiliation or low maternal warmth. DAT1 10-repeat homozygotes displayed similar GxE patterns toward maternal warmth on general task performance. At the neural level, DRD4 7-repeat carriers showed the least striatal activation during reward anticipation when exposed to high maternal warmth, but the most when exposed to low warmth. Findings were independent of ADHD severity. Our results partially confirm the differential susceptibility theory and indicate the importance of positive social environments in reward sensitivity and general task performance for persons with specific genotypes.

Family caregivers of individuals with spinal cord injury: exploring the stresses and benefits.

STUDY DESIGN: Cross-sectional, focus group. OBJECTIVES: To explore positive and negative issues reported by family caregivers of people with spinal cord injury (SCI) to develop a relevant and valid tool to assess caregiver distress and benefit for this unique population. METHODS: Seventy-three family caregivers of people with SCI participated in 16 focus groups. We audio-recorded all focus group discussions and transcribed the recordings verbatim. Qualitative analysis of the transcripts was performed to identify major themes and subthemes relating to family caregiving activities. RESULTS: Positive themes were disproportionately limited in comparison with negative themes. Positives included changes in self-awareness, enhanced family cohesiveness and feeling appreciated. Negative themes included physical and emotional strain, dissatisfaction with hired carers and strain on family relationships. Health-related themes included fatigue and lack of sleep. Caregivers identified sources of strength that helped them manage stresses including faith and support from friends and co-workers. CONCLUSION: The numerous themes help lay the groundwork to develop a valid and reliable assessment tool to assist health-care providers in treatment planning and the provision of long-term assistance to people with SCI by enhancing areas of strengths and addressing factors that contribute to burden and distress for family caregivers.

Screening for neuropathic pain after spinal cord injury with the spinal cord injury pain instrument (SCIPI): a preliminary validation study.

STUDY DESIGN: Cross-sectional. OBJECTIVE: To preliminarily evaluate the validity of an interview-based spinal cord injury (SCI) neuropathic pain screening instrument. SETTING: Six university-based SCI centers in the United States. METHODS: Clinician diagnoses of neuropathic pain (NP) and non-neuropathic pain subtypes were collected independently of descriptions of the pain characteristics provided by the persons with SCI by using the Spinal Cord Injury Pain Instrument (SCIPI); SCIPI information and physician diagnoses for 82 pain sites of which they were most confident were subsequently compared. RESULTS: Four of the SCIPI items correlated significantly with the NP subtype as determined by the clinician. The best cutoff score for identifying NP was an endorsement of two or more of these four items. Using this cutoff, sensitivity of the SCIPI was 78%, specificity was 73% and overall diagnostic accuracy was 76%. CONCLUSION: In this preliminary study, the SCIPI, which can be administered by a nonclinician, appears to have good sensitivity, specificity and diagnostic accuracy in a SCI population; it may have a role as a screening tool for NP after SCI. Further study is needed.

The International Spinal Cord Injury Pain Basic Data Set (version 2.0).

OBJECTIVES: To revise the International Spinal Cord Injury Pain Basic Data Set (ISCIPBDS) based on new developments in the field and on suggestions from the spinal cord injury (SCI) and pain clinical and research community. SETTING: International. METHODS: The ISCIPBDS working group evaluated suggestions regarding the utility of the ISCIPBDS and made modifications in response to these and to significant developments in the field. The revised ISCIPBDS (version 2.0) was reviewed by members of the Executive Committee of the International SCI Standards and Data Sets, the International Spinal Cord Society (ISCoS) Executive and Scientific Committees, the American Spinal Injury Association and American Pain Society Boards and the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain, individual reviewers and societies and the ISCoS Council. RESULTS: The ISCIPBDS (version 2.0) is significantly shortened but still contains clinically relevant core questions concerning SCI-related pain. The revisions include an updated SCI pain classification, omission of three questions regarding temporal pain pattern and three pain interference questions. The remaining three pain interference questions concern perceived interference with activities, mood and sleep for overall pain rather than for individual pain problems and are scored on a 0 to 10 scale.

International Spinal Cord Injury Pain (ISCIP) Classification: Part 2. Initial validation using vignettes.

STUDY DESIGN: International validation study using self-administered surveys. OBJECTIVES: To investigate the utility and reliability of the International Spinal Cord Injury Pain (ISCIP) Classification as used by clinicians. METHODS: Seventy-five clinical vignettes (case histories) were prepared by the members of the ISCIP Classification group and assigned to a category by consensus. Vignettes were incorporated into an Internet survey distributed to clinicians. Clinicians were asked, for each vignette, to decide on the number of pain components present and to classify each using the ISCIP Classification. RESULTS: The average respondent had 86% of the questions on the number of pain components correct. The overall correctness in determining whether pain was nociceptive was 79%, whereas the correctness in determining whether pain was neuropathic was 77%. Correctness in determining if pain was musculoskeletal was 84%, whereas for visceral pain, neuropathic at-level spinal cord injury (SCI) and below-level SCI pain it was 85%, 57% and 73%, respectively. Using strict criteria, the overall correctness in determining pain type was 68% (versus an expected 95%), but with maximally relaxed criteria, it increased to 85%. CONCLUSIONS: The reliability of use of the ISCIP Classification by clinicians (who received minimal training in its use) using a clinical vignette approach is moderate. Some subtypes of pain proved challenging to classify. The ISCIP should be tested for reliability by applying it to real persons with pain after SCI. Based on the results of this validation process, the instructions accompanying the ISCIP Classification for classifying subtypes of pain have been clarified.

International spinal cord injury pain classification: part I. Background and description. March 6-7, 2009.

STUDY DESIGN: Discussion of issues and development of consensus. OBJECTIVE: Present the background, purpose, development process, format and definitions of the International Spinal Cord Injury Pain (ISCIP) Classification. METHODS: An international group of spinal cord injury (SCI) and pain experts deliberated over 2 days, and then via e-mail communication developed a consensus classification of pain after SCI. The classification was reviewed by members of several professional organizations and their feedback was incorporated. The classification then underwent validation by an international group of clinicians with minimal exposure to the classification, using case study vignettes. Based upon the results of this study, further revisions were made to the ISCIP Classification. RESULTS: An overall structure and terminology has been developed and partially validated as a merger of and improvement on previously published SCI pain classifications, combined with basic definitions proposed by the International Association for the Study of Pain and pain characteristics described in published empiric studies of pain. The classification is designed to be comprehensive and to include pains that are directly related to the SCI pathology as well as pains that are common after SCI but are not necessarily mechanistically related to the SCI itself. CONCLUSIONS: The format and definitions presented should help experienced and non-experienced clinicians as well as clinical researchers classify pain after SCI.

Either Kras activation or Pten loss similarly enhance the dominant-stable CTNNB1-induced genetic program to promote granulosa cell tumor development in the ovary and testis.

WNT, RAS or phosphoinositide 3-kinase signaling pathways control specific stages of ovarian follicular development. To analyze the functional interactions of these pathways in granulosa cells during follicular development in vivo, we generated specific mutant mouse models. Stable activation of the WNT signaling effector ß-catenin (CTNNB1) in granulosa cells results in the formation of premalignant lesions that develop into granulosa cell tumors (GCTs) spontaneously later in life or following targeted deletion of the tumor suppressor gene Pten. Conversely, expression of oncogenic KRAS(G12D) dramatically arrests proliferation, differentiation and apoptosis in granulosa cells, and consequently, small abnormal follicle-like structures devoid of oocytes accumulate in the ovary. Because of the potent anti-proliferative effects of KRAS(G12D) in granulosa cells, we sought to determine whether KRAS(G12D) would block precancerous lesion and tumor formation in follicles of the CTNNB1-mutant mice. Unexpectedly, transgenic Ctnnb1;Kras-mutant mice exhibited increased GC proliferation, decreased apoptosis and impaired differentiation and developed early-onset GCTs leading to premature death in a manner similar to the Ctnnb1;Pten-mutant mice. Microarray and reverse transcription-PCR analyses revealed that gene regulatory processes induced by CTNNB1 were mostly enhanced by either KRAS activation or Pten loss in remarkably similar patterns and degree. The concomitant activation of CTNNB1 and KRAS in Sertoli cells also caused testicular granulosa cell tumors that showed gene expression patterns that partially overlapped those observed in GCTs of the ovary. Although the mutations analyzed herein have not yet been linked to adult GCTs in humans, they may be related to juvenile GCTs or to tumors in other tissues where CTNNB1 is mutated. Importantly, the results provide strong evidence that CTNNB1 is the driver in these contexts and that KRAS(G12D) and Pten loss promote the program set in motion by the CTNNB1.

Molecular and functional characteristics of ovarian surface epithelial cells transformed by KrasG12D and loss of Pten in a mouse model in vivo.

Ovarian cancer is a complex and deadly disease that remains difficult to detect at an early curable stage. Furthermore, although some oncogenic (Kras, Pten/PI3K and Trp53) pathways that are frequently mutated, deleted or amplified in ovarian cancer are known, how these pathways initiate and drive specific morphological phenotypes and tumor outcomes remain unclear. We recently generated Pten(fl/fl); Kras(G12D); Amhr2-Cre mice to disrupt the Pten gene and express a stable mutant form of Kras(G12D) in ovarian surface epithelial (OSE) cells. On the basis of histopathologic criteria, the mutant mice developed low-grade ovarian serous papillary adenocarcinomas at an early age and with 100% penetrance. This highly reproducible phenotype provides the first mouse model in which to study this ovarian cancer subtype. OSE cells isolated from ovaries of mutant mice at 5 and 10 weeks of age exhibit temporal changes in the expression of specific Mullerian epithelial marker genes, grow in soft agar and develop ectopic invasive tumors in recipient mice, indicating that the cells are transformed. Gene profiling identified specific mRNAs and microRNAs differentially expressed in purified OSE cells derived from tumors of the mutant mice compared with wild-type OSE cells. Mapping of transcripts or genes between the mouse OSE mutant data sets, the Kras signature from human cancer cell lines and the human ovarian tumor array data sets, documented significant overlap, indicating that KRAS is a key driver of OSE transformation in this context. Two key hallmarks of the mutant OSE cells in these mice are the elevated expression of the tumor-suppressor Trp53 (p53) and its microRNA target, miR-34a-c. We propose that elevated TRP53 and miR-34a-c may exert negatively regulatory effects that reduce the proliferative potential of OSE cells leading to the low-grade serous adenocarcinoma phenotype.

Reliability and validity of the International Spinal Cord Injury Basic Pain Data Set items as self-report measures.

OBJECTIVE: To evaluate the psychometric properties of a subset of International Spinal Cord Injury Basic Pain Data Set (ISCIBPDS) items that could be used as self-report measures in surveys, longitudinal studies and clinical trials. SETTING: Community. METHODS: A subset of the ISCIBPDS items and measures of two validity criteria were administered in a postal survey to 184 individuals with spinal cord injury (SCI) and pain. The responses of the participants were evaluated to determine: (1) item response rates (as an estimate of ease of item completion); (2) internal consistency (as an estimate of the reliability of the multiple-item measures); and (3) concurrent validity. RESULTS: The results support the utility and validity of the ISCIBPDS items and scales that measure pain interference, intensity, site(s), frequency, duration and timing (time of day of worst pain) in individuals with SCI and chronic pain. The results also provide psychometric information that can be used to select from among the ISCIBPDS items in settings that require even fewer items than are in the basic data set.

Poor to modest agreement between rheumatoid arthritis response measures in clinical practice.

OBJECTIVE: To evaluate the agreement among several rheumatoid arthritis (RA) response measures in a clinical setting. METHODS: 529 patients with RA were seen at 2 regular visits where the following response measures were determined: ACR-20, EULAR good or moderate (EULAR-GM), Simplified Disease Activity Index moderate (SDAI-M), Clinical DAI moderate (CDAI-M), and Patient Reported Outcomes Index-M 20 (PRO-IM-20). Each measure was modified to include a "worse" response, i.e. the inverse of the respective guidelines for a positive improvement response.Introduced for comparison was the Real-time Assessment of Disease Activity in Rheumatoid Arthritis (RADARA), a response measure that registers improvement if the patient's tender and swollen joint counts and HAQ score all improve and worsening if all three increase. Contingency tables comparing the three responses (worse, no change, and improvement) along with Cohen's kappa were calculated. RESULTS: The mean (SD) baseline characteristics of the patients included: age 66.5 (10.7) years, RA duration 12.9 (11.0) years, 91.3% male, 84.1% rheumatoid factor positive, and a Disease Activity Score-28 of 3.5 (1.3). The percentage of patients who improved/worsened were as follows: ACR-20 4.7/9.1, EULAR-GM 23.4/26.3, SDAI-M 16.1/20.6, CDAI-M 16.3/20.0, PRO-IM-20 22.5/34.4, and RADARA 7.0/11.5. Agreement (kappa) was poor to slight (

The international spinal cord injury pain basic data set.

OBJECTIVE: To develop a basic pain data set (International Spinal Cord Injury Basic Pain Data Set, ISCIPDS:B) within the framework of the International spinal cord injury (SCI) data sets that would facilitate consistent collection and reporting of pain in the SCI population. SETTING: International. METHODS: The ISCIPDS:B was developed by a working group consisting of individuals with published evidence of expertise in SCI-related pain regarding taxonomy, psychophysics, psychology, epidemiology and assessment, and one representative of the Executive Committee of the International SCI Standards and Data Sets. The members were appointed by four major organizations with an interest in SCI-related pain (International Spinal Cord Society, ISCoS; American Spinal Injury Association, ASIA; American Pain Society, APS and International Association for the Study of Pain, IASP). The initial ISCIPDS:B was revised based on suggestions from members of the Executive Committee of the International SCI Standards and Data Sets, the ISCoS Scientific Committee, ASIA and APS Boards, and the Neuropathic Pain Special Interest Group of the IASP, individual reviewers and societies and the ISCoS Council. RESULTS: The final ISCIPDS:B contains core questions about clinically relevant information concerning SCI-related pain that can be collected by health-care professionals with expertise in SCI in various clinical settings. The questions concern pain severity, physical and emotional function and include a pain-intensity rating, a pain classification and questions related to the temporal pattern of pain for each specific pain problem. The impact of pain on physical, social and emotional function, and sleep is evaluated for each pain.

Obesity intervention in persons with spinal cord injury.

STUDY DESIGN: A single group uncontrolled trial. OBJECTIVES: Despite widespread emphasis on the obesity-related health risks in persons with spinal cord injury (SCI), limited research has been carried out to intervene in this problem. This study was conducted to assess the initial effectiveness of a weight loss program on various health outcomes in persons with SCI. SETTING: A rehabilitation center in Birmingham, Alabama, United States. METHODS: A total of 16 individuals with chronic SCI who were overweight or obese participated in a weight management program that consisted of 12 weekly classes, covering nutrition, exercise, and behavior modification. Various outcomes were examined over a 6-month period (baseline, week 12, and week 24), including body composition measured by dual energy X-ray absorptiometry, physiologic measures, diet behavior, and psychosocial and physical functioning. Of these, 13 participants returned for the week 24 follow-up. RESULTS: Weight loss averaged 3.5+/-3.1 kg (3.8% of the initial weight) at week 12 and 2.9+/-3.7 kg (3.0% of the initial weight) at week 24. There was a significant reduction from baseline values at weeks 12 and 24 in body mass index, anthropometric measurements, and fat mass and improvement in diet behavior and psychosocial and physical functioning, while lean mass and blood albumin and hemoglobin levels were maintained. A correlation analysis showed that a greater weight loss was importantly (r>0.4) associated with a greater reduction in total cholesterol at weeks 12 and 24 and in systolic and diastolic blood pressure at week 24. Several factors were important (r>0.4 or r<-0.4) in determining the success in weight loss, including age, race, marital and employment status, family history of overweight/obesity, level and duration of injury, and cholesterol level at baseline. CONCLUSIONS: This is the first demonstration that a carefully planned program with time-calorie displacement diet is effective for overweight/obese individuals with SCI to lose weight without compromising total lean mass and overall health. It provides foundation for a future large clinical trial for weight loss of persons with SCI or other spinal cord dysfunction.

Regulation of transcripts encoding ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin-like motifs-1) and progesterone receptor by human chorionic gonadotropin in equine preovulatory follicles.

One member of a new family of metalloproteinases, a disintegrin and metalloproteinase with thrombospondin-like motifs-1 (ADAMTS-1), has been found to be expressed and hormonally induced in granulosa cells of ovulating rodent follicles. Furthermore, the targeted disruption of the ADAMTS-1 gene resulted in ovarian defects associated with severely impaired fertility. While these data demonstrate the importance of ADAMTS-1 in rodent ovarian physiology, the potential role of ADAMTS-1 in the ovulatory process of monoovulatory species remains unknown. The objectives of this study were to clone the equine ADAMTS-1 primary transcript and to study its regulation during human chorionic gonadotropin (hCG)-induced ovulation. A 3573 bp follicular cDNA library clone was isolated and found to encode a nearly complete, highly conserved ADAMTS-1 homologue. Real-time RT-PCR analysis detected this transcript in diverse tIssues, including previously unreported sites of ADAMTS-1 expression such as the male reproductive tract, the follicular theca interna and the mature corpus luteum. The tIssue distribution of the progesterone receptor (PR), a known regulator of ADAMTS-1 expression in rodent preovulatory follicles, was found to overlap that of ADAMTS-1 in some tIssues. A study of the regulation of follicular ADAMTS-1 and PR mRNAs during the hCG-induced ovulatory process revealed distinct patterns of regulation in granulosa cells and in theca interna. In granulosa cells, ADAMTS-1 mRNA was found to be induced at 12 h post-hCG (P<0.05), followed by a return to basal levels by 30 h and a re-increase at 33-39 h (P<0.05). A concomitant increase in PR mRNA (P<0.05) was observed at 12 h post-hCG. In theca interna, abundant ADAMTS-1 mRNA was detected at all timepoints, and levels increased transiently at 33 h post-hCG (P<0.05), whereas no significant change was observed in PR mRNA. Together, these data demonstrate for the first time the hormonally regulated ovarian expression of ADAMTS-1 in a monoovulatory species, and identify a novel biphasic regulation of ADAMTS-1 in granulosa cells and a regulated expression in theca interna that were not previously observed in rodents.

Test-retest reliability of the Donovan spinal cord injury pain classification scheme.

STUDY DESIGN: Videotape rating by independent viewers. OBJECTIVE: To determine the test-retest reliability of the Donovan spinal cord injury (SCI) pain classification scheme. SETTING: Rehabilitation Centre, Alabama, USA. METHODS: A total of 28 individuals with SCI reported 60 pain sites. A structured interview and physical exam were used to illicit information to classify each pain site according to the Donovan criteria. All structured interviews and exams were videotaped. Three independent raters viewed the videotapes on two occasions, separated by a 3-month interval, and classified each pain site using the Donovan pain classification scheme. RESULTS: Considering all three raters together, 78% of the pain sites were consistently classified from one period to the next. Within each rater, consistent classification ranged from 67 to 83%. However, inter-rater agreement for the classification of each pain site into the various types of pain was low for both periods (about 50-60%). CONCLUSIONS: Pain classification within each rater generally showed adequate test-retest reliability when using the Donovan SCI pain classification scheme. However, reliability estimates of agreement across raters highlight the ongoing need to exam and improve the psychometric characteristics of the various pain classification schemes.

Metallothionein-1 messenger RNA transcription in steroid-secreting cells of the rat ovary during the periovulatory period.

An increase in metallothionein 1 (MT-1) mRNA was detected in the ovaries of immature Wistar rats that were primed with s.c. injection of 10 IU eCG followed 48 h later by 10 IU hCG s.c. to initiate the ovulatory process. Ovarian RNA was extracted at 0, 2, 4, 8, 12, 24, 72, 144, and 288 h after the primed animals were injected with hCG. These extracts were used for reverse transcription polymerase chain reaction (RT-PCR) differential display and Northern analyses that yielded complementary gene fragments for MT-1. Expression of MT-1 mRNA increased significantly by 24 h after hCG treatment and reached a peak at 144 h after hCG. In contrast, a disintegrin and metalloproteinase with thrombospondin motifs and a tissue inhibitor of metalloproteinase 1, which were also detected by the RT-PCR differential display procedure, reached a peak at 12 h after hCG and returned to control levels in the ovaries by 72 h after hCG. In situ hybridization indicated that most of the MT-1 mRNA was expressed in the vicinity of the theca interna of preovulatory follicles and in the lutein granulosa of postovulatory follicles. Thus, MT-1 mRNA expression is primarily in the vicinity of steroid-secreting areas of the ovary. The substantial increase in MT-1 mRNA expression might be important in protecting the ovarian tissues from oxidative stress generated by ovarian inflammatory events during the ovulatory process and luteinization.

Delivery of the oocyte from the follicle to the oviduct: a time of vulnerability.

The multiplicity of genes regulated by the actions of LH in specific granulosa cell and cumulus cell microenvironments of the follicle during ovulation has now revealed how complex and finely tuned the ovulation process is. Although many proteases are expressed in the ovary and are hormonally regulated, the novel proteases ADAMTS-1 and cathepsin L, rather than the MMPs, have gained particular recognition. These may play critical roles in the eventual rupture of the follicle at the ovarian surface. Rupture is only one part of ovulation. Another important aspect is the actual release of the oocyte from the ovulation pore. Several recent studies have shown that the production of the matrix that is evidenced by cumulus expansion is somehow critical for extrusion to occur and for the oocyte to travel into the oviduct. At any point the oocyte may be trapped within a non-ovulating structure. Lastly, if the events of ovulation fail to occur before the events of luteinization are complete, oocytes are destined to degenerate within the non-ovulating structures.