Pilot study of a community pharmacist led program to treat hepatitis C virus among people who inject drugs.

Background: People who inject drugs (PWID) are a key population for treatment with direct-acting antiviral medications (DAAs) to eliminate hepatitis C virus (HCV). We developed a Pharmacist, Physician, and Patient Navigator Collaborative Care Model (PPP-CCM) for delivery of HCV treatment; this study describes clinical outcomes related to HCV treatment (initial evaluation, treatment initiation, completion, and cure), as well as patient satisfaction. Methods: We conducted a single-arm prospective pilot study of adult PWID living with HCV. Participants completed baseline and six-month follow-up surveys, and treatment and outcomes were abstracted from electronic health records. Primary outcome was linkage to pharmacist for HCV evaluation; secondary outcomes included DAA initiation, completion, and cure, as well as patient-reported satisfaction. Results: Of the 40 PWID enrolled, mean age was 43.6 years, 12 (30 %) were female, 20 (50 %) were non-white, and 15 (38 %) were unhoused. Thirty-eight (95 %) were successfully linked to the pharmacist for initial evaluation. Of those, 21/38 (55 %) initiated DAAs, and 16/21 (76 %) completed treatment. Among those completing treatment who had viral load data to document whether they achieved "sustained virologic response", i.e. cure, 10/11 (91 %) were found to be cured. There was high satisfaction with 100 % responding "agree or strongly agree" that they had a positive experience with the pharmacist. Conclusion: Nearly all participants in this pilot were successfully linked to the pharmacist for evaluation, and more than half were started on DAAs; results provide preliminary evidence of feasibility of pharmacist-led models of HCV treatment for PWID. Clinicaltrialsgov registration number: NCT04698629.

Effects of repeated hypoglycemia on cognitive function: a psychometrically validated reanalysis of the Diabetes Control and Complications Trial data.

OBJECTIVE: To test the conclusion that there is no association between multiple episodes of severe hypoglycemia and cognitive decrements by reanalyzing the data from the Diabetes Control and Complications Trial (DCCT) with psychometrically validated cognitive factors and to conduct a novel analysis of the association between individual differences in baseline cognitive ability and episodes of severe hypoglycemia documented after baseline. RESEARCH DESIGN AND METHODS: The factor structure of cognitive ability in the neuropsychological data from the DCCT study was derived. Four cognitive factors (spatial ability, processing speed, memory, and verbal ability) were extracted. Changes in patients' cognitive scores for each year of follow-up were obtained, and paired comparisons of these change scores were performed between groups experiencing zero and five or more hypoglycemic episodes. The association between cognitive ability at baseline and number of subsequent episodes of severe hypoglycemia was also examined. RESULTS: Repeated episodes of hypoglycemia were found not to be associated with cognitive decline in any of the validated cognitive factors. No significant association was found between prospectively documented numbers of severe hypoglycemic episodes and baseline cognitive ability level. CONCLUSIONS: Repeated episodes of hypoglycemia were not related to cognitive decrement, and initial mental ability level was not associated with eventual numbers of hypoglycemic episodes in this group of patients.

Periodic saccadic oscillations and tinnitus.

A man with essential hypertension developed stereotyped cycles of oscillopsia and bilateral "sparking" tinnitus. Eye movement recordings showed cycles of disconjugate opsoclonus, square-wave jerks, and saccadic dynamic overshoot disrupting stable fixation. Neuroimaging studies were normal. We postulate a lesion episodically disturbing saccade-related neurons and central auditory neurons in the pons.

Etiology and prognosis of alpha coma.

We reviewed our experience with alpha coma, the finding of predominantly alpha-frequency rhythms in the EEGs of unconscious patients, and identified 50 patients. Cardiac arrest, either inside (n = 25) or outside (n = 24) the hospital, was the cause of unconsciousness in all except one patient who had hyperglycemic, hyperosmolar coma. After out-of-hospital cardiac arrest, the risk of never regaining consciousness or dying during hospitalization did not differ significantly between unconscious patients with (n = 24) and without (n = 69) alpha frequencies in their EEGs. A review of the literature supports our findings that alpha coma most commonly follows cardiac arrest and does not preclude the possibility of neurologic recovery. We conclude that alpha coma is a descriptive term and lacks prognostic significance in itself.

Recurrences of cerebellar astrocytomas: a violation of Collins' law.

Cerebellar astrocytomas generally carry an excellent prognosis when managed with surgical treatment alone. However, these tumors may violate Collins' Law in two opposite ways: by recurring late or by being "cured" with incomplete excision. In a study of 41 cases of cerebellar astrocytoma and a review of the literature, no gross or microscopic factors that correlated with either of these two outcomes could be identified other than brain-stem involvement. The effect of radiation therapy in the treatment of primary or recurrent cerebellar astrocytomas was not detectable when analyzed the same way. Malignant recurrence of cerebellar astrocytoma and primary malignant tumors of the cerebellum are so rare that the possibility should not be taken as a reason to substitute radiation therapy for surgical excision repeated as necessary.

A reliable method to retrieve accident & emergency data stored on a free-text basis.

Accident & Emergency (A & E) data on asthma-related attendances are useful for studies on the effectiveness of asthma interventions, and to determine the relationship of environmental factors to asthma and asthma epidemics. The final diagnoses made in the A & E departments are not usually coded when entered into hospital databases in the U.K., although the "presenting complaint' can be retrieved from the computerized Hospital Information & Support Systems (HISS), from a free-text attendance diagnosis field entered by the reception clerk when the patient arrives at the A & E department. The validity of this as an indication of the final diagnosis is unevaluated. The aim of this study was to measure the validity of the string "asth' in the A & E attendance diagnosis field for identifying patients attending the A & E departments of two hospitals for asthma-related conditions. A list of patients who attended the A & E department of two hospitals was retrieved from the HISS along with the attendance diagnosis field. If the attendance diagnosis field contained the text string "asth', mentioned wheeze or breathing problems, or the patients were referred by their GP without any diagnostic information entered on HISS, the records were selected for evaluation. The remaining attendances, which were not evaluated further, were attributed to another diagnosis based on the evidence of the recorded attendance diagnosis. The results indicated that the string "asth' in the attendance diagnosis field had a sensitivity of 80.3% (95% CI 75.1-85.5%) and a specificity of 96.7% (95% CI 95.6-97.8%) for a final diagnosis of asthma. It is concluded that free-text attendance diagnosis fields in hospital databases can be searched with suitable strings to obtain reliable data on attendance with asthma. As part of another investigation, the present authors attempted to retrieve a list of the attendances with asthma at the same two A & E departments at a time that was reportedly associated with an epidemic of asthma following a thunderstorm. On this occasion, the string "asth' proved to be significantly less sensitive. The possible reasons for this and the implications for using this method for identifying cases are discussed.

Neuropathologic observations in congenital phrenic nerve palsy.

A right phrenic nerve palsy with severe respiratory and feeding difficulties throughout the patient's 2 1/2 years of survival was found at autopsy to relate to grossly complete atrophy of the muscle of the right diaphragm. An oblique fibrotic scar transected the right phrenic nerve at the level of the brachial plexus. There was marked reduction of the number of anterior motor neurons in the right central portion of cervical segments 2, 3, and 4. The lesion in the phrenic nerve is what would be expected following stretching during delivery.

The final stages of dominant follicle selection in cattle.

The final stages of ovarian follicle growth in cattle are typically characterized by the ultrasound-detectable emergence of a cohort of small (3-5mm in diameter) antral follicles, followed by a selection process during which the number of follicles continuing to grow decreases. Finally, only one follicle (the dominant follicle; DF) shows an enhanced growth rate and estradiol synthesis when it attains 8.5mm compared to its closest competitor (the largest subordinate follicle; SF). Cohort emergence is caused by a transient FSH rise, while DF selection occurs during declining FSH indicating differential FSH dependence of DF and SF. In order to elucidate the mechanisms underlying DF survival or SF atresia, this review aims to (i) describe follicular changes in the local production and regulation of members of the inhibin family of proteins and the insulin-like growth factor (IGF) system in relation to FSH deprivation leading to DF selection, and (ii) develop a model for DF selection outlining the putative involvement of inhibins, activin and follistatin on the one hand, and bioavailable IGFs regulated by IGF binding proteins (IGFBPs) and IGFBP proteases on the other hand. It is concluded, that the first indications of differential FSH dependence are seen within 33h of the FSH peak, and high amounts of precursor forms of inhibin and free activin, and low amounts of the lower molecular weight (MW) IGFBPs are related to follicle survival in terms of enhanced growth and estradiol synthesis, and suppression of granulosa cell apoptosis. In addition, maintenance of low amounts of intrafollicular IGFBP4 may constitute an important mechanism in the future DF to attain FSH independence.

Exogenous hormonal manipulation of ovarian activity in cattle.

To achieve precise control of the oestrous cycle in cattle it is necessary to control both the life span of the corpus luteum and the follicle wave status at the end of the treatment. Antral follicle growth in cattle occurs in distinct wavelike patterns during the ovarian cycle and the postpartum anoestrous period. The emergence of each new wave is stimulated by a transient increase in FSH. Each follicle wave has an inherent life span of 7-10 days as it progresses through the different stages of development, viz., emergence, selection, dominance and atresia or ovulation. The dominant follicle (DF) is distinguishable from other subordinate follicles by its enhanced capacity to produce oestradiol, maintenance of low intrafollicular concentrations of insulin-like growth factor binding proteins-2, -4 and -5 and follistatin and an increase in free intrafollicular concentrations of IGF-I as well as an increase in size. Three approaches can be taken to control ovarian activity and regulate the oestrous cycle in cattle: (i) use of the luteolytic agent prostaglandin F2alpha (PGF2alpha) alone or one of its potent analogues, (ii) administration of exogenous progesterone-progestagen treatments combined with the use of exogenous oestradiol or gonadotrophin releasing hormone (GnRH) to control new follicle wave emergence and shorten the life span of the corpus luteum, and (iii) prior follicle wave synchrony followed by induced luteolysis. A number of different oestrous synchronisation regimens, viz., PGF2alpha-based only, short-term progesterone with prior follicle wave synchrony using oestradiol or GnRH have been developed but the problem of obtaining good follicle wave synchrony and CL regression limit their widespread application. GnRH-prostaglandin-GnRH regimens have recently been developed for beef and dairy cows. However, their success is variable. A better understanding of the hormonal control of follicle growth is a prerequisite in order to obtain more precise control the oestrous cycle allowing one AI at a predetermined time giving high pregnancy rates without recourse to detection of oestrus.

The effect of estradiol benzoate on synchrony of estrus and fertility in cattle after removal of a progesterone-releasing intravaginal device.

The aim was to determine the effect of estradiol benzoate (EDB) given after removal of a progesterone-releasing intravaginal device (PRID) at either emergence or dominance of a follicle wave, on the interval to estrus, variation in its onset and pregnancy rate in heifers. Heifers (n=186) were assigned randomly to four treatments in a 2 x 2 factorial design; emergence or dominance of a follicle wave at PRID removal, with or without 0.5 mg EDB 24 h after PRID removal. Ovarian ultrasonography was performed to confirm follicular status; data from heifers of undeterminable follicular status were excluded (n=36). Mean size of the largest follicle of the new wave at PRID removal was smaller (P < 0.01) in heifers given EDB at emergence (6.3 +/- 0.09 mm) compared with those given it at dominance (10.9 +/- 0.30 mm). The onset of estrus was earlier (P < 0.01) in heifers given EDB at dominance (median 42 h, range 13 h) compared with those not given EDB at dominance (median 43 h, range 42 h). The median interval to estrus was decreased (P < 0.01) in heifers given EDB at emergence (median 48 h, range 73 h) compared with those not given EDB at emergence (median 66 h, range 45 h). Variation in onset of estrus was reduced (P < 0.05) in heifers given EDB compared with those not given EDB. The pregnancy rate was not affected when EDB was given at dominance, however, it was decreased (P < 0.05) when given at emergence (23 of 40 vs 26 of 32, respectively). To determine the effect of EDB on follicular dynamics in heifers treated with EDB at emergence, heifers (n=37) were assigned to two treatments: at emergence with or without EDB and their ovaries were examined daily using ultrasonography. Follicular dynamics were not different (P > 0.05) in EDB-heifers compared with untreated controls. Mean serum estradiol was greater (P < 0.01) in EDB-treated heifers compared with controls. In conclusion, 0.5 mg EDB given 24 h after PRID removal to heifers decreased the interval to estrous onset at emergence or dominance, decreased variation in onset of estrus and decreased pregnancy rates when given at emergence of a follicle wave.

The effect of estradiol benzoate or a synthetic gonadotropin-releasing hormone used at the start of a progesterone treatment on estrous response in cattle.

The aim was to compare the estrous response in heifers given either gonadotropin-releasing hormone (GnRH) or estradiol benzoate (EDB) at the start of a progesterone treatment initiated at emergence or dominance of the first or second follicular wave of the estrous cycle. Cross-bred beef heifers (n=134) were assigned to 1 of 3 treatments; 0.75 mg EDB given at insertion of a progesterone-releasing intravaginal device (PRID) treatment of 10 days duration (10dE2), 0.75 mg EDB at insertion of a PRID treatment of 8 days duration with 15 mg luprostiol (PGF) a luteolytic agent, given 1 day before PRID removal (8dE2) or 250 microg GnRH at insertion of a PRID treatment of 8 days duration with 15 mg PGF given 1 day before PRID removal (8dGnRH). Treatments were initiated on Days 2, 5, 10 or 13 of the estrous cycle. Estrous detection was conducted six times daily. Twice daily blood samples were taken, from 2 days before PRID insertion until detection of estrus. The proportion of heifers detected in estrus was higher (P < 0.05) for heifers in the 8dE2 treatment group (40/40) compared with those in the 8dGnRH group (38/42) and tended to be higher (P = 0.08) than heifers in the 10dE2 group (38/41). The onset of estrus was earlier (P < 0.05) for heifers in the 10dE2 treatment group (median 41 h, range 92 h) compared with either the 8dE2 (median 49 h, range 64 h) or 8dGnRH groups (median 49 h, range 92 h). Submission rate at 72 h was higher (P < 0.01) in the 8dE2 (95%) group than for those in the 10dE2 (74%) and 8dGnRH (69%) groups. In conclusion, EDB given at PRID insertion, with PGF given 1 day before PRID removal, was more effective at synchronizing estrus than was GnRH at PRID insertion. Decreasing the length of treatment and the use of PGF 1 day before the end of an EDB and progesterone treatment improved estrous synchrony.

Effect of duration of dominance of the ovulatory follicle on onset of estrus and fertility in heifers.

In cattle, prolonged progestogen treatments following luteolysis result in persistent dominant follicles (DF) that are associated with precise onset of estrus but marked reductions in pregnancy rate (PR). The aim was to determine whether increasing duration of dominance of the ovulatory follicle in heifers affected 1) precision of onset of estrus and 2) the timing and nature of the decline in PR. In Exp. 1, duration of dominance of the ovulatory follicle was controlled by causing corpus luteum (CL) regression at emergence of the second follicle wave (mean duration of dominance of 2.1+/-.3 d, Dm2, n = 11) or first day of dominance of the second DF of the cycle; the latter was combined with insertion of a 3-mg norgestomet ear implant for 2 to 10 d to maintain the second DF for 4 (Dm4, n = 32), 6 (Dm6, n = 19), 8 (Dm8, n = 49), 10 (Dm10, n = 28), or 12 d (Dm12, n = 20). Heifers detected in estrus were inseminated approximately 12 h later with frozen-thawed semen. Durations of dominance of the ovulatory follicle of up to 8 d did not affect (P>.05) PR (Dm2 8/9, Dm4 19/28, Dm6 14/18, and Dm8 34/48 heifers pregnant), but PR in Dm10 heifers (12/23 heifers pregnant) was reduced (P = .05) compared with Dm2 heifers; PR in Dm12 heifers (2/17 pregnant) was less compared with all other treatments (P<.01). Fitting a logistic regression model to the pooled PR data to examine the trend in PR showed that extending the duration of dominance from 2 to 9 d and from 10 to 12 d resulted in a predicted decline in PR of 10 to 25% and a further decline of 35 to 75%, respectively. Onset of estrus was delayed in heifers assigned to Dm4 treatment relative to all other treatments (P<.001); it was less variable than that for heifers on Dm6, Dm8, and Dm10 treatments (P<.1). In Exp. 2, heifers received a PGF2alpha analogue and a norgestomet implant on d 12 of the cycle for 3 or 7 d to give approximate durations of dominance of the preovulatory follicle of 2 to 4 d (Dm2-4, n = 29) or 6 to 8 d (Dm6-8, n = 24), respectively. The PR did not differ (P>.05) between heifers on Dm2-4 (22/29) and Dm6-8 (15/24) treatments, but the interval to onset of estrus was delayed (P<.05) by 7 h in the Dm2-4 heifers. In conclusion, restricting the duration of dominance of the preovulatory follicle to < or =4 d at estrus, results in a precise onset of estrus and a high PR following a single AI at a detected estrus.

Oestrous synchronisation in cattle--current options following the EU regulations restricting use of oestrogenic compounds in food-producing animals: a review.

Oestrous synchronisation is an important strategy to improve reproductive management of cattle. The use of oestradiol-17beta, and its related ester derivatives, in food-producing cattle for the purposes of oestrous synchronisation is prohibited in the European Union since October 2006; a serious limitation in the implementation of large-scale use of cost effective synchronisation regimens in both dairy and beef herds. This has obvious consequences within the EU and also in other countries that have restricted the use of oestradiol following the EU ban. Oestrous synchronisation is an important facilitator for the use of artificial insemination, a necessary part of any national herd genetic improvement scheme. Presently, only 35% of the Irish dairy herd is bred by artificial insemination; and facilitation rather than restriction is required to increase this percentage. Ideally synchronisation of oestrus should increase submission rates, improve or at least not affect conception rates, and thus, increase overall pregnancy rate at the end of the breeding season. This should reduce the proportion of cows to be culled. This paper aims to review the oestrous synchrony options available in EU countries and other countries affected by the European ban on oestrogenic compounds being used for oestrous synchrony protocols. Currently, the options available for oestrous synchronisation are generally not as effective, efficient or cost effective as those that incorporated use of oestrogenic compounds.

Follicle wave growth in cattle.

Ovarian follicle growth in cattle culminates in the selection of a single dominant follicle which attains the ability for final maturation and ovulation once or twice during the luteal phase and at the end of the oestrous cycle, as well as during other reproductive states. This review will describe in detail the first follicle wave of the cycle leading to selection of the first wave dominant follicle, indicating the specific gonadotrophin dependencies of cohort and dominant follicles, and relating follicle fate to steroidogenesis. As a differential gonadotrophin response of growing antral follicles during the follies-stimulating hormone (FSH) decline may determine which follicle becomes selected, first wave follicles are also characterized in relation to intrafollicular growth factors, which may modify the gonadotrophin response, such as inhibins and members of the insulin-like growth factor (IGF) family. Subsequently, the follicular control of the transient FSH rise and decline so crucial to dominant follicle selection will be discussed. It is concluded that successful hormonal manipulation of follicle wave growth and dominant follicle selection will depend on our detailed understanding of the gonadotrophin requirements of differentiating wave follicles.

Potentially misleading extratemporal lobe lesions in patients with temporal lobe epilepsy.

From a series of 217 consecutive temporal resections for intractable epilepsy between 1993 and 2000, we identified all patients with large non-neoplastic extratemporal lesions. Only patients with known postsurgical outcomes with follow up for more than two years were included. Fifteen patients were identified. All patients had a history of medically refractory epilepsy with clinical and ictal evidence of mesial temporal seizure onset. Eleven patients had extratemporal lesions ipsilateral to the seizure focus, whereas four patients had the lesions contralateral to the seizure focus. Nine of the 15 patients had evidence of hippocampal atrophy on magnetic resonance imaging (MRI). Following temporal resection, nine of these patients (60%) became seizure free (Engel class 1A), two patients were free of disabling seizures only (Engel class 1B), and two patients had a few early seizures but then became seizure free for at least two years (Engel class 1C). Two patients had significant improvement (Engel class 2). Thus, the finding of large extratemporal lesions on MRI was potentially misleading. When clinical semiology and ictal EEG recordings provide evidence of temporal onset seizures, anterior temporal resection should be considered in patients with extratemporal lesions.

Carryover bias in visual assessment.

Carryover of stimuli in sequential judgments was studied for a visual assessment task involving estimation of the percentage cover of black circles on a white image. Seven image types with different levels of cover density were arranged in a sequentially balanced design in which each image type was preceded the same number of times by all image types. In the absence of carryover, when images were preceded by images with the same cover density, the response scores were well fitted by a power function of percentage cover with a mean exponent of 0.73 over subjects. Carryover took the form of an assimilation, so that the cover estimate for a target image was generally higher when preceded by an image with higher cover, and lower when preceded by an image with lower cover. However, the magnitude of the carryover effect showed little evidence of increasing with difference in cover between successive images. Nonparametric and parametric methods for testing for carryover are presented. The need for development of psychological models to explain the proposed statistical models is discussed.

Regulation of follicle waves to maximize fertility in cattle.

Cattle have recurrent follicular waves every 7-10 days in most physiological situations; an FSH increase is associated with emergence of the wave and LH pulse frequency determines the fate of the dominant follicle. To control oestrus with hormones it is necessary to ensure that either induced corpus luteum regression or the termination of a progestogen treatment coincides with the selection of the dominant follicle during the wave, to give a precise onset of oestrus and high fertility. The exogenous administration of progesterone or progestagen blocks the normal turnover of the dominant follicle once the corpus luteum regresses. Thus, the effects of duration of dominance of the preovulatory follicle on onset of oestrus and fertility were examined. The variation in onset of oestrus was reduced but occurred 5-9 h later after 4 versus 8 days of dominance; pregnancy rate was also affected with dominance periods of 2-4, 4-8 and > 10 days resulting in 0, 10-15% or 20-50% reduction in pregnancy rates, respectively. The necessity for short duration of dominance of the preovulatory follicle means that to ensure high fertility the follicular wave needs to be regulated when using hormones to control oestrus. Two approaches were examined, namely the use of GnRH or oestradiol at time of progesterone intravaginal releasing device insertion. The effect of 250 micrograms of synthetic GnRH on the fate of an existing follicle wave was to ovulate the dominant follicle (20/20 cows) and a new wave emerged 1.6 +/- 0.3 days later; however, there was no effect of GnRH on the wave if administered before dominant follicle selection. The effect of oestradiol concentrations on suppression of FSH in ovariectomized heifers showed that increasing oestradiol to 10-15 pg ml-1 caused a 37 +/- 6.9% decrease in FSH for 24 h, with a subsequent increase to pretreatment values by 57 +/- 13 h. In cyclic heifers, increasing oestradiol to > 10 pg ml-1 in conjunction with progesterone treatment at emergence of the first wave of the cycle affected the current follicle wave by either preventing dominant follicle selection or decreasing diameter of the dominant follicle, without consistently affecting the interval to new wave emergence. Increase of oestradiol after dominance, however, delayed new wave emergence by 2-5 days. A better understanding of the hormonal control of follicle waves will lead to development of improved hormonal regimens to control oestrus sufficiently to give high pregnancy rates to a single AI without recourse to detection of oestrus.

Effects of oestradiol and progesterone on secretion of gonadotrophins and health of first wave follicles during the oestrous cycle of beef heifers.

Antral follicle development in cattle is initially FSH dependent and then LH dependent. The aim of the present study was to determine the effects of oestradiol- and progesterone-induced suppression of FSH and LH on growth and differentiation of first wave follicles. Cyclic heifers (n = 45, n = 6-10 per group) received the following i.m. injections or treatments beginning 30 h after oestrus: (i) saline (controls); (ii) 0.75 mg oestradiol benzoate (ODB); (iii) insertion of a progesterone-releasing intravaginal device (PRID) for 42 h (progesterone); (iv) 0.75 mg oestradiol benzoate plus PRID (ODB plus progesterone); (v) 0.75 mg ODB plus injection of 1 mg Ovagen(TM) at 33, 39 and 45 h after onset of oestrus (ODB plus FSH). In Expt 1, follicle development was monitored by ovarian ultrasonography once a day. In Expt 2, heifers were ovariectomized. Emergence of the first follicle wave and dominant follicle selection were delayed in ODB plus progesterone-treated heifers compared with controls. Interval to nadir FSH concentration was shorter in ODB-, progesterone- and ODB plus progesterone-treated heifers compared with controls. Frequency of LH pulses was unaffected in ODB- or ODB plus FSH-treated heifers, decreased in progesterone-treated heifers and further decreased in ODB plus progesterone-treated heifers. Intrafollicular oestradiol concentrations were lower in the largest follicle from ODB plus progesterone-treated heifers compared with control (66 h) heifers, but follicle diameter and concentrations of insulin-like growth factor binding proteins (IGFBPs) and inhibin forms were unaffected. Treatment with ODB decreased follicular oestradiol concentration in smaller follicles in the cohort. It is concluded that growing cohort follicles are uniformly responsive to increased FSH concentration but differentially responsive to suppressed FSH and LH release, which is consistent with an LH-mediated survival advantage of the largest follicle in the cohort before cessation of the growth of remaining follicles in the cohort occurs.

Alterations in intrafollicular regulatory factors and apoptosis during selection of follicles in the first follicular wave of the bovine estrous cycle.

Changes in follicular fluid (FF) concentrations of estradiol, inhibin forms, and insulin-like growth factor binding proteins (IGFBPs), percentage of apoptotic granulosa cells (%A), and follicular size for individual follicles in a growing cohort were determined throughout the first wave of follicular development during the bovine estrous cycle and related to FSH decline. Four groups of heifers (n = 31) were ovariectomized between Days 1.5 and 4.5 of the estrous cycle at 5 +/- 1, 33 +/- 2, 53 +/- 1, and 84 +/- 2 h after the periovulatory peak in FSH concentrations. Follicles > or = 2.5 mm were dissected, measured, and FF aspirated. The five largest follicles were ranked based on their diameter (F1 to F5). Diameters of F1 to F5 were positively correlated with interval from FSH peak (r > or = 0.6, P < 0.05). Five hours after the FSH peak, follicular diameter and FF concentrations of estradiol, inhibins, and IGFBPs were similar for F1 to F5. From 5 to 33 h, amounts of the six precursor inhibin forms (> or = 48 kDa) increased (P < 0.05) in F1 follicles. The IGFBPs in F1 follicles remained low at all time periods. At 33 h, amounts of IGFBP-4 and -5 were higher (P < 0.05) in F4 and F5 compared with F1 follicles. At 84 h, IGFBP-2, -4, and -5 were increased (P < 0.05) in F3, F4, and F5 compared with F1. At 5, 33, or 53 h, %A was not different between follicles in any size class. At 84 h %A was increased (P < 0.05) in follicles <6 mm in diameter. However, at that time, %A did not differ between the selected DF and the largest subordinate follicle. For individual heifers, the selected DF at 84 h was largest in size, highest in estradiol, and lowest in IGFBP-2 and -4. The F1 follicle had highest estradiol in 23 of 27 heifers irrespective of stage of the wave and lowest IGFBP-4 in 19 of 21 heifers from 33 h. We concluded that the earliest intrafollicular changes that differentiate a dominant-like follicle from the growing cohort are enhanced capacity to produce estradiol and maintenance of low levels of IGFBPs.

Identification of potential intrafollicular factors involved in selection of dominant follicles in heifers.

A surgical procedure to aspirate follicular fluid concurrently from individual follicles from the same heifer was validated and used to determine if intrafollicular amounts of estradiol, progesterone, inhibins, activin-A, follistatins, and insulin-like growth factor binding proteins (IGFBP) differed for the future dominant compared with subordinate follicles during selection of the first wave dominant follicle. Heifers were subjected to surgery and aspiration of follicular fluid from the two or three largest follicles on Day 3 of the estrous cycle (approximately 1.5 days after emergence). Ultrasound was used to determine the fate of each aspirated follicle after surgery. At aspiration, diameter of the future dominant and largest subordinate follicle was similar in heifers. However, estradiol was higher, whereas IGFBP-4 was lower in the future dominant compared with the largest or next largest subordinate follicles. Also, the future dominant follicle in most cohorts had the highest estradiol and lowest IGFBP-4 compared with future subordinate follicles. We concluded that: IGFBP-4 and estradiol may have key roles in determining the physiological fate of follicles during selection of the first wave dominant follicle in heifers, and that both are reliable markers to predict which follicle in a growing cohort of 5- to 8.5-mm follicles becomes dominant.