PreImplantation Factor (PIF*) endogenously prevents preeclampsia: Promotes trophoblast invasion and reduces oxidative stress.

Preeclampsia is a unique pregnancy disorder whose patho-physiology is initiated early in gestation, while clinical manifestations typically occur in mid-to-late pregnancy. Thus, prevention should optimally be initiated in early gestation. The intimate interaction between PIF, secreted early by viable embryos, and its host-mother provides insight into putative mechanisms of preeclampsia prevention. PIF is instrumental at the two critical events underlying preeclampsia. At first, shallow implantation leads to impaired placentation, oxidative stress, protein misfolding, and endothelial dysfunction. Later in gestation, hyper-oxygenation due to overflow of maternally derived oxygenated blood compromises the placenta. The first is likely involved in early preeclampsia occurrence due to reduced effectiveness of trophoblast/uterus interaction. The latter is observed with later-onset preeclampsia, caused by a breakdown in placental blood flow regulation. We reported that 1. PIF promotes implantation, endometrium receptivity, trophoblast invasion and increases pro-tolerance trophoblastic HLA-G expression and, 2. PIF protects against oxidative stress and protein misfolding, interacting with specific targets in embryo, 3. PIF regulates systemic immunity to reduce oxidative stress. Using PIF as an early preventative preeclampsia intervention could ameliorate or even prevent the disease, whose current main solution is early delivery.

Immune regulatory and neuroprotective properties of preimplantation factor: From newborn to adult.

Embryonic-maternal interaction from the earliest stages of gestation has a key, sustained role in neurologic development, persisting into adulthood. Early adverse events may be detrimental in adulthood. Protective factors present during gestation could significantly impact post-natal therapy. The role of PreImplantation Factor (PIF) within this context is herein examined. Secreted by viable early embryos, PIF establishes effective embryonic-maternal communication and exerts essential trophic and protective roles by reducing oxidative stress and protein misfolding and by blunting the nocive let-7 microRNA related pathway. PIF's effects on systemic immunity lead to comprehensive immune modulation, not immune suppression. We examine PIF's role in protecting embryos from adverse maternal environment, which can lead to neurological disorders that may only manifest post-nataly: Synthetic PIF successfully translates endogenous PIF features in both pregnant and non-pregnant clinically relevant models. Specifically PIF has neuroprotective effects in neonatal prematurity. In adult relapsing-remitting neuroinflammation, PIF reverses advanced paralysis while promoting neurogenesis. PIF reversed Mycobacterium smegmatis induced brain infection. In graft-vs.-host disease, PIF reduced skin ulceration, liver inflammation and colon ulceration while maintaining beneficial anti-cancer, graft-vs.-leukemia effect. Clinical-grade PIF has high-safety profile even at supraphysiological doses. The FDA awarded Fast-Track designation, and university-sponsored clinical trials for autoimmune disorder are ongoing. Altogether, PIF properties point to its determining regulatory role in immunity, inflammation and transplant acceptance. Specific plans for using PIF for the treatment of complex neurological disorders (ie. traumatic brain injury, progressive paralysis), including neuroprotection from newborn to adult, are presented.

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling.

A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

Bruxism and oral parafunctional hyperactivity in social phobia outpatients.

Anxiety and selective serotonin reuptake inhibitors (SSRIs) are considered aggravating factors for bruxism. We examined the influence of anxiety, depression and SSRI on bruxism in social phobia (SP). Twenty-three drug naïve, 17 SSRI-treated SP patients and 33 healthy controls underwent a psychiatric assessment and completed Leibowitz Social Anxiety Scale and Beck Depression Inventory. Oral parafunctional activity (PF) was evaluated by TM-dental examination and by a questionnaire. Drug- naïve and SSRI-treated SP patients did not differ on demographic and clinical measures. Awake bruxism, 'JAW PLAY' and at least one PF were more prevalent in SP than in controls. Severity of SP predicted the presence of PF. SP, but not depression, was associated with higher risk of oral PF and awake bruxism. Chronic SSRI treatment of SP did not affect sleep and awake bruxism. Dental and anxiety screening may improve the prognosis psychiatric and dental patients. Effective treatment of SP may mitigate bruxism.

Correlation between fetal heart rate reactivity and mortality and severe neurological morbidity in extremely low birth weight infants.

OBJECTIVE: To determine the correlation between specific fetal heart rate (FHR) abnormalities and the incidence of death, severe (grade 3-4) intraventricular hemorrhage (IVH) and periventricular echogenicity (PVE) in extremely low birth weight infants (ELBW) within the first 4 days after birth. METHODS: The study included live-born ELBW infants ≤ 30 weeks' gestation who were born in 2000-2007 at Kaplan Medical Center, Rehovot, Israel, and, who had FHR monitoring during the 24 h before delivery and cranial ultrasound during the first 4 days of life. FHR pattern was analyzed for the presence of baseline rate, reactivity, variability and decelerations. RESULTS: 96 infants with mean birth weight 757 ± 150 g and mean gestational age 25.8 ± 1.5 weeks were included. By 4 days of life, 23/96 (24%) died, 17/96 (18%) developed severe IVH and 31/96 (32%) had PVE. Absence of reactivity was significantly associated with increase in both death (p = 0.02, OR 3.45, 95% CI: 1.22-9.47 and severe IVH (p = 0.029, OR 3.33, 95% CI: 1.25-10) but not with PVE. Other FHR parameters were not associated with adverse outcome. CONCLUSION: These results suggest that FHR reactivity may be of value in predicting short-term outcome in ELBW infants. This may be helpful in counseling parents with imminent extremely preterm birth.

[Crestal core elevation technique--case series and literature review].

Sinus floor augmentation is the most common surgical procedure for gaining bone volume in the posterior maxilla. The purpose of this procedure is to enable implant placement un edentulous ridges. The most common techniques for sinus augmentation are: 1. Bone added osteotome sinus floor elevation (BAOSFE). 2. Crestal core elevation (CCE). 3. Lateral window technique (LWT). Since the early 80's many articles describing the successful use of different augmentation materials for sinus elevation have been published. Although many articles have been published on the lateral window technique and the osteotome technique as described by Summers, few articles have been published on the crestsal core sinus elevation technique. This technique, first described by Summers, includes the use of wide diameter osteotomes and trephine bur with a diameter of 6 m"m. This technique is implemented in situations when the available bone for implant placement is less than 6 m"m , which impairs the possibility of achieving primary stability of the implant. In those cases crestal core elevation is performed and implant placement is postponed 3-8 months later. Modification of the technique described by Summers was published by Fugazzoto, this technique is implemented concomitant with the extraction of the upper molars. The crestal core elevation technique (CCE), which is based on the BAOSFE (Bone Added Osteotome Sinus Floor Elevation), is based on the principle of hydraulic force acting on fluids and particles which transfer the vector of force to all direction, in this case the sinus membrane. The detached core of interradicular bone prior to osteotome placement and malleting significantly reduces surgical trauma to the patient especially in cases where a significant portion of the pre-disease interradicular bone remains. The concomitant placement of particulate material and a membrane at the time of tooth extraction offers the advantage of minimizing if not eliminating significant 3-dimensional alveolar resorption. In this article 3 cases treated using the crestal core elevation technique are presented. Advantages and disadvantages of the technique and indication for use will be discussed.

[Alveolar ridge augmentation with hip corticocancellous allogenic block graft prior to implant placement].

The use of autogenous block bone grafts in bone regeneration procedures for alveolar ridge augmentation can be limited by donor-site morbidity and complications. In this study, allogeneic block grafts were used for ridge augmentation prior to implant placement. Thirty six patients with severe ridge width and height deficiency underwent augmentation using an allogeneic corticocancellous iliac block bone graft. After rigid fixation of the graft, the site was covered with a freeze dried allogeneic dura mater membrane or restorable collagen membrane and then tension-free closure was performed. Implants were placed three to four months after surgery. Three to six months after implant placement, panoramic radiographs were taken and implants were uncovered for prosthetic restoration. Out of the 70 implants placed, one implant failed to integrate. Out of the 49 grafts placed one graft showed three millimeters of bone resorbtion at the superior buccal aspect of the graft. No other clinical problems were observed. The block grafts were clinically well integrated into the recipient site. The augmented bone remained stable throughout implant placement procedures. Clinical outcome evidence demonstrates that allogeneic block bone grafts in conjunction with G.B.R principles might be a viable alternative to autogenous grafts in selected patients with alveolar ridge deficiencies.

[Full arch impression techniques utilizing addition type poly vinyl siloxane for fabrication of tooth born fixed partial dentures].

A precise impression is necessary for fabricating an accurately fitting cast restoration. For this purpose, Polyvinyl Siloxane (PVS) impression materials are extremely popular because of their combination of excellent physical properties, handling characteristics and dimensional stability. Its excellent clinical features remain unaffected if simple measures are guarded. This review presents several impression techniques using PVS and recommends the one that provides the most accurate impression, utilizing the superior qualities of the PVS. The one step impression technique where no control of wash bulk and thickness exists, is considered to be the least accurate impression method with measured discrepancies as large as 7 times the original inter preparation distance and 40 times the original cross arch dimensions. Furthermore, the direct contact between the less refined putty material and the tooth preparation, as well as the high prevalence of air bubble entrapment, seriously compromises restoration longevity. The two stage impression technique has proved to produce the most accurate and reliable impressions due to complete control of the wash bulk and thickness entailed. The ideal wash bulk thickness should range between 1 to 2.5 mm all around the abutment tooth in order to minimize distortion of its subsequent die. Using a "Putty Tray" at the first stage with a predetermined space encircling the abutments will allow the wash to flow to its ideal uniform bulk size at the second stage. A uniform bulk size will prevent differential setting contraction and uneven changes at the dimensions of the die. The easiest and most clinically applicable method to achieve the desired space around the preparations is by loading the Putty material with the temporary crowns in place, followed by their removal at the second stage and occupation of the created space by the wash. In general, less control of wash bulk will result in either insufficient or excessive wash material which will determine uneven dimensional changes in the impression. This, in turn, will produce ill fitting cast restoration.

Relationship between the craniofacial complex and size of the resorbed mandible in complete denture wearers.

A cephalometric study was conducted on 34 complete denture wearers to examine the relationship between the area of the mandible and the skeletal facial form, the area of the mandible and the gonial angle, and the area of the mandible and the length of the mandible. No significant correlation was found between the area of the mandible and the skeletal facial types or the gonial angle. A statistically significant correlation (P < 0.0028) was found between the length of the mandible and the area of the mandible. Residual resorption of the mandible appears to be independent of skeletal facial form and the gonial angle.

Relationship between occlusal plane determinants and craniofacial structures.

A cephalometric study was conducted on 34 complete denture wearers to investigate the relationship between the anatomical structures commonly used to determine the occlusal plane and the facial skeletal shape. The results showed no correlation between the shape of the skeletal face, the gonial angle and the length of the mandible versus the location of the retromolar pad, the occlusal plane and Camper's plane. However, a statistically significant linear correlation (P < 0.0001) was found between the facial skeletal shape designated SN POG and the location of Camper's plane. Cephalometric analysis alone cannot determine the location of the occlusal plane in edentulous patients. Intra-oral structures should also be considered.

Embryo maternal dialogue: From pregnancy recognition to proliferation control.

Embryo-maternal dialogue starts shortly after fertilization and is exerted through both local and systemic signaling. We have discovered specific embryo derived pre-implantation factors (PIF), novel peptides that are secreted already at the two cell stage and which modulate cellular immunity. In the fallopian tube the embryo, a partial allograft, is tolerated by the mother. Embryo derived peripheral signaling (PIF) is also detected prior to implantation in maternal sera. This signal may also help prime the endometrium to facilitate implantation. Upon implantation, embryo-endometrial communication becomes direct and highly amplified. When the immune privilege appears to be secured, embryogenesis proper initiates. This requires proliferation/differentiation to be tightly controlled. Knowledge of proliferation promoters is ample while the factors involved in its control remain less understood. We have identified a class of novel proteins/peptides, developmental proteins (DPs), that are present in the embryo before a mature immune system has developed. Their role is to create a balance between pro and antiproliferative forces, to promote normal proliferation while controlling abnormal cell proliferation (i.e. due to carcinogens, toxins, viruses, and ionic radiation). DPs, may also redirect growth towards functionality through differentiation. DPs appear to act through a specific receptor negating growth factors action through promotion of tumor suppressors and inhibition of tumor promoters at 2 minutes, blocking DNA synthesis at ~24 hours, and promoting apoptosis at ~48 hours. When an embryo becomes incompatible with life, DPs may lead to growth arrest, PIF-like compounds decline, the immune system to be restored and the pregnancy is rejected. Final identification and use of PIF and DPs is likely to help both managing early pregnancy disorders and aid in treatment of proliferative disorders due to cancer and viral infection.

Synergy of SF1 and RAR in activation of Oct-3/4 promoter.

The Oct-3/4 transcription factor is expressed in the earliest stages of embryogenesis, and is thus likely to play an important role in regulation of initial decisions in development. For the first time, we have shown that SF1 and Oct-3/4 are co-expressed in embryonal carcinoma (EC) P19 cells, and their expression is down-regulated with very similar kinetics following retinoic acid (RA) induced differentiation of these cells, suggesting a functional relationship between the two. Previously, we have shown that the Oct-3/4 promoter harbors an RA-responsive element, RAREoct, which functions in EC cells as a binding site for positive regulators of transcription, such as RAR and RXR. In this study we have identified in the Oct-3/4 promoter two novel SF1-binding sites: SF1(a) and SF1(b). The proximal site, SF1(a), is located within the RAREoct, and the distal site, SF1(b), is located between nucleotide -193 and -209 of the Oct-3/4 promoter. Both sites contribute to activation of Oct-3/4 promoter in EC cells, with SF1(a) playing a more crucial role. SF1, and its isoforms ELP2 and ELP3 bind to both SF1 sites and activate the Oct-3/4 promoter. This activation depends on the presence of SF1 DNA-binding domain. Thus, Oct-3/4 is the first EC-specific gene reported that is regulated by SF1. Interestingly, SF1 and RAR form a novel complex on the RAREoct sequence that synergistically activate the Oct-3/4 promoter. Both RARE and SF1 cis regulatory elements, as well as the SF1 DNA-binding domain, are needed for this synergism. SF1 and Oct-3/4 transcription factors play a role in the same developmental regulatory cascade.

Progress in characterization of pre-implantation factor in embryo cultures and in vivo.

PROBLEM: Pre-implantation factor (PIF), a small, embryo-derived peptide is detected in the maternal serum prior to implantation and is associated with successful pregnancy outcome. However, its identity is not known. METHOD OF STUDY: PIF was isolated from mouse embryo conditioned media and from pregnant porcine sera, using high-performance liquid chromatography (HPLC) followed by mass spectrometry. RESULTS: Conditioned culture media was separated by gel filtration chromatography followed by reversed phase chromatography. At each step, PIF activity was determined by the lymphocyte/platelet binding autorosette assay (LPBA). Mass spectrometry yielded a single peak with a mass of 1300 Da. The peptide is, however, present in very low concentrations (fM), which has so far precluded complete identification. Pregnant porcine sera that exhibit potent PIF activity were deproteinated by acetone and further fractionated by reversed phase HPLC. Active fractions contain peptides of molecular masses 523 and 551 Da. CONCLUSION: PIF, likely to be peptides, represents a novel substance related to pregnancy initiation and maintenance.

Daily scheduling of the golden spiny mouse under photoperiodic and social cues.

A most important function of the circadian system is to ensure that behaviors and metabolism are appropriately timed with respect to the light/dark cycle and photoperiod. Ecological constraints can perturb the daily schedules; would they also impair photoperiodic adaptations? A natural model exists in the golden spiny mouse (Acomys russatus), which is nocturnal, but driven into diurnal activity when sharing the habitat with its congener, A. cahirinus. We show here that the presence of A. cahirinus alters the diurnal rhythms of body temperature and urine volume, delays excretion of the major melatonin metabolite, 6-sulfatoxymelatonin (6-SMT), and increases 2-deoxyglucose uptake by the suprachiasmatic nuclei in A. russatus. Nevertheless, a clear photoperiod effect on urine volume and 6-SMT rhythms was observed. These results indicate that the circadian system can adapt to major changes in daily scheduling without impairing daylength measurement, and consequently seasonal adaptation.

The effect of parafunction on condylar asymmetry in patients with temporomandibular disorders.

This study was undertaken to examine the relationship between condylar asymmetry and parafunction in patients with temporomandibular disorders (TMD). Twenty-eight patients with TMD and parafunction and 30 patients with TMD but no parafunction were examined. A panoramic radiograph was obtained for each patient and from this the condylar asymmetry determined. The group with parafunction showed a significantly (P < 0.005) higher asymmetry index than did the group with no noticeable parafunction. Patients were grouped into the following age ranges: 10-19 years, 20-29 years, 30-39 years, and 40 + years. The mean asymmetry index was determined for each age range for both groups of patients. The group of patients with TMD and parafunction had a higher mean asymmetry index in all the age ranges studied. This suggests that muscle hyperactivity may be a factor in the increased asymmetry found in patients with TMD.