Monica A. Pessina

Effects of ovariectomy and steroid hormones on vaginal smooth muscle contractility

The role of steroid hormones in regulating vaginal smooth muscle contractility was investigated. Rabbits were kept intact or ovariectomized. After 2 weeks, animals were continuously infused with vehicle or supraphysiological levels of testosterone (100 μg/day), or estradiol (200 μg/day), for an additional 2 weeks. The distal vaginal tissue was used to assess contractility in organ baths and changes in tissue structure were assessed by histology. Ovariectomized animals infused with vehicle exhibited significant atrophy of the muscularis and decreased epithelial height, resulting in thinning of the vaginal wall. Estradiol infusion increased epithelial height, comparable to that of intact animals, but only partially restored the muscularis layer. In contrast, testosterone infusion completely restored the muscularis layer, but only partially restored the epithelial height. In vaginal tissue strips contracted with norepinephrine and treated with bretylium, electrical field stimulation (EFS) caused frequency-dependent relaxation that was slightly attenuated with vehicle, significantly inhibited with estradiol and significantly enhanced with testosterone. VIP-induced relaxation was slightly attenuated in tissues from vehicle and estradiol-infused groups, but was enhanced in tissues from testosterone-infused animals. Contraction elicited by EFS or exogenous norepinephrine was not significantly altered with ovariectomy or steroid hormone infusion when data were normalized to potassium contraction. However, the tissue from testosterone-infused animals developed significantly greater contractile force to norepinephrine. These observations suggest that steroid hormones may be important regulators of vaginal tissue structure and contractility.

ORIGINAL RESEARCH—BASIC SCIENCE: Differential Regulation of the Expression of Estrogen, Progesterone, and Androgen Receptors by Sex Steroid Hormones in the Vagina: Immunohistochemical Studies

OBJECTIVE Significant structural changes occur in the rat vagina in response to sex steroid hormone deprivation and replacement. However, the mechanism by which these changes occur is not clearly understood and our current hypothesis is that these effects are mediated, at least in part, by the expression of sex steroid hormone receptors. The goal of this study was to assess changes in steroid hormone receptor expression and distribution in response to sex steroid hormone deprivation and administration. METHODS Female rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or hormone combinations. Using immunohistochemistry, hormone receptor distribution was assessed in all layers of the vaginal wall. RESULTS After ovariectomy, estrogen receptor alpha (ERalpha) was up-regulated and progesterone receptor (PR) was down-regulated. Estradiol replacement restored these ovariectomy-induced changes, and this effect was dose-dependent. Androgen receptor (AR) expression was unaffected by ovariectomy or estradiol replacement. However, testosterone treatment resulted in increased AR density in the muscularis. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. CONCLUSION Estradiol down-regulated ERalpha and up-regulated PR expression in the vagina, suggesting this may be a mechanism to prevent continued proliferation of the epithelium by surges of estradiol during the estrous cycle.

Recovery from ischemia in the middle-aged brain: a nonhuman primate model

Studies of recovery from stroke mainly utilize rodent models and focus primarily on young subjects despite the increased prevalence of stroke with age and the fact that recovery of function is more limited in the aged brain. In the present study, a nonhuman primate model of cortical ischemia was developed to allow the comparison of impairments in young and middle-aged monkeys. Animals were pretrained on a fine motor task of the hand and digits and then underwent a surgical procedure to map and lesion the hand-digit representation in the dominant motor cortex. Animals were retested until performance returned to preoperative levels. To assess the recovery of grasp patterns, performance was videotaped and rated using a scale adapted from human occupational therapy. Results demonstrated that the impaired hand recovers to baseline in young animals in 65-80 days and in middle-aged animals in 130-150 days. However, analysis of grasp patterns revealed that neither group recover preoperative finger thumb grasp patterns, rather they develop compensatory movements.

Assessment of motor function of the hand in aged rhesus monkeys

In the elderly, intact motor functions of the upper extremity are critical for the completion of activities of daily living. Many studies have provided insight into age-related changes in motor function. However, the precise nature and extent of motor impairments of the upper extremity remains unclear. In the current study we have modified two tasks to assess hand/digit function in both young and aged rhesus monkeys. We tested monkeys from 9 to 26 years of age on these tasks to determine the level of fine motor performance across the adult age range. Compared to young monkeys (9–12 years of age), aged monkeys (15–26 years of age) were mildly impaired on fine motor control of the digits. These findings are consistent with previous studies that have found age-related impairment in fine motor function. However, the magnitude and extent of impairment in the current study does differ from previous findings and is likely due to methodological differences in the degree of task complexity.

Recovery of fine motor performance after ischemic damage to motor cortex is facilitated by cell therapy in the rhesus monkey

Abstract We investigated the efficacy on recovery of function following controlled cortical ischemia in the monkey of the investigational cell drug product, CNTO 0007. This drug contains a cellular component, human umbilical tissue-derived cells, in a proprietary thaw and inject formulation. Results demonstrate significantly better recovery of motor function in the treatment group with no difference between groups in the volume or surface area of ischemic damage, suggesting that the cells stimulated plasticity.

Unilateral Complete Congenital Serratus Anterior Muscle Aplasia: A Case Report

A 28-year-old white man was referred to the authors’ outpatient clinic by his primary care physician for evaluation of presumed scoliosis. The patient reported decreased range of motion of the left shoulder with overhead activities and not being able to raise his left upper extremity as high as the right one throughout his life. He noted some upper back pain when exercising, specifically when performing abdominal crunches but not while performing activities of daily living. His medical history was significant only for chickenpox. He had never been hospitalized and his birth history was uncomplicated. His family history revealed colon cancer in a grandfather, and coronary artery disease and congestive heart failure in a grandmother. There were no known congenital disorders in the family. The patient’s occupation was a physician, he was a nonsmoker, and review of systems was unremarkable. The physical examination revealed the thorax to be slightly asymmetric with mild flattening of the left trunk contour and asymmetric position of the scapulae. The left scapula was noticeably smaller, elevated, and more medially positioned than the right. Anterior chestmusclesweresymmetricalwithoutatrophy.Theleftshoulderdemonstratedabnormal scapularrotationwithlimitedactiveflexionandabductionto120°.Medialscapularwinging and medial displacement of the inferior angle of the scapula occurred with left shoulder flexion.Therightupperextremitydemonstratedfull,normalrangeofmotion.Therewasno tenderness along the spine, trunk or scapula. Strength testing of the neck, shoulder girdle andupperextremitieswasnormalexceptfortheserratusanterior.Therestoftheneurologic examination was unremarkable.

Inosine enhances recovery of grasp following cortical injury to the primary motor cortex of the rhesus monkey.

BACKGROUND Inosine, a naturally occurring purine nucleoside, has been shown to stimulate axonal growth in cell culture and promote corticospinal tract axons to sprout collateral branches after stroke, spinal cord injury and TBI in rodent models. OBJECTIVE To explore the effects of inosine on the recovery of motor function following cortical injury in the rhesus monkey. METHODS After being trained on a test of fine motor function of the hand, monkeys received a lesion limited to the area of the hand representation in primary motor cortex. Beginning 24 hours after this injury and continuing daily thereafter, monkeys received orally administered inosine (500 mg) or placebo. Retesting of motor function began on the 14th day after injury and continued for 12 weeks. RESULTS During the first 14 days after surgery, there was evidence of significant recovery within the inosine-treated group on measures of fine motor function of the hand, measures of hand strength and digit flexion. While there was no effect of treatment on the time to retrieve a reward, the treated monkeys returned to asymptotic levels of grasp performance significantly faster than the untreated monkeys. Additionally, the treated monkeys evidenced a greater degree of recovery in terms of maturity of grasp pattern. CONCLUSION These findings demonstrate that inosine can enhance recovery of function following cortical injury in monkeys.

Cell based therapy enhances activation of ventral premotor cortex to improve recovery following primary motor cortex injury

ABSTRACT Stroke results in enduring damage to the brain which is accompanied by innate neurorestorative processes, such as reorganization of surviving circuits. Nevertheless, patients are often left with permanent residual impairments. Cell based therapy is an emerging therapeutic that may function to enhance the innate neurorestorative capacity of the brain. We previously evaluated human umbilical tissue‐derived cells (hUTC) in our non‐human primate model of cortical injury limited to the hand area of primary motor cortex. Injection of hUTC 24h after injury resulted in significantly enhanced recovery of fine motor function compared to vehicle treated controls (Moore et al., 2013). These monkeys also received an injection of Bromodeoxyuridine (BrdU) 8days after cortical injury to label cells undergoing replication. This was followed by 12weeks of behavioral testing, which culminated 3h prior to perfusion in a final behavioral testing session using only the impaired hand. In this session, the neuronal activity initiating hand movements leads to the upregulation of the immediate early gene c‐Fos in activated cells. Following perfusion‐fixation of the brain, sections were processed using immunohistochemistry to label c‐Fos activated cells, pre‐synaptic vesicle protein synaptophysin, and BrdU labeled neuroprogenitor cells to investigate the hypothesis that hUTC treatment enhanced behavioral recovery by facilitating reorganization of surviving cortical tissues. Quantitative analysis revealed that c‐Fos activated cells were significantly increased in the ipsi‐ and contra‐lesional ventral premotor but not the dorsal premotor cortices in the hUTC treated monkeys compared to placebo controls. Furthermore, the increase in c‐Fos activated cells in the ipsi‐ and contra‐lesional ventral premotor cortex correlated with a decrease in recovery time and improved grasp topography. Interestingly, there was no difference between treatment groups in the number of synaptophysin positive puncta in either ipsi‐ or contra‐lesional ventral or dorsal premotor cortices. Nor was there a significant difference in the density of BrdU labeled cells in the subgranular zone of the hippocampus or the subventricular zone of the lateral ventricle. These findings support the hypothesis that hUTC treatment enhances the capacity of the brain to reorganize after cortical injury and that bilateral plasticity in ventral premotor cortex is a critical locus for this recovery of function. This reorganization may be accomplished through enhanced activation of pre‐existing circuits within ventral premotor, but it could also reflect ventral premotor projections to the brainstem or spinal cord. HIGHLIGHTSc‐Fos activation increases with hUTC treatment in PMv but not PMd after M1 injury.c‐Fos activation is positively associated with improved recovery after M1 injury.Density of synaptophysin in PM does not differ with hUTC treatment after M1 injury.