Subperiosteal Midface Lift with Sub-Superficial Musculoaponeuritic System Rhytidectomy.

The subperiosteal midface lift is a powerful tool that allows the surgeon to reposition the SOOF and malar fat pad in a vertical direction. Additionally, it significantly softens deep nasolabial folds. Its effect, however, is minimal with regards to addressing the jowl, jawline, gonial angle and cervicomental angle. Combining the subperiosteal midface lift with an extended sub-SMAS rhytidectomy addresses the pre-jowl sulcus by releasing the mandibular ligament. The jawline and gonial angle become more defined with the transposition and suspension of the SMAS flap. The SMAS transposition flap along with the suspension of the platysma flap to the mastoid fascia support the submandibular glands and deepen the cervicomental angle. These two approaches are valuable additions to the surgeons armamentarium and can yield excellent results in carefully selected patients.

Embryonic and Fetal Human Hemoglobins: Structures, Oxygen Binding, and Physiological Roles.

During the past two decades, significant advances have been made in our understanding of the human fetal and embryonic hemoglobins made possible by the availability of pure, highly characterized materials and novel methods, e.g., nano gel filtration, to study their properties and to correct some misconceptions. For example, whereas the structures of the human adult, fetal, and embryonic hemoglobins are very similar, it has generally been assumed that functional differences between them are due to primary sequence effects. However, more recent studies indicate that the strengths of the interactions between their subunits are very different leading to changes in their oxygen binding properties compared to adult hemoglobin. Fetal hemoglobin in the oxy conformation is a much stronger tetramer than adult hemoglobin and dissociates to dimers 70-times less than adult hemoglobin. This property may form the basis for its protective effect against malaria. A major source of the increased strength of fetal hemoglobin resides within the A-helix of its gamma subunit as demonstrated in studies with the hybrid hemoglobin Felix and related hybrids. Re-activating fetal hemoglobin synthesis in vivo is currently a major focus of clinical efforts designed to treat sickle cell anemia since it inhibits the aggregation of sickle hemoglobin. The mechanisms for both the increased oxygen affinity of fetal hemoglobin and its decreased response to DPG have been clarified. Acetylated fetal hemoglobin, which makes up 10-20% of total fetal hemoglobin, has a significantly weakened tetramer structure suggesting a similar role for other kinds of protein acetylation. Embryonic hemoglobins have the weakest tetramer and dimer structures. In general, the progressively increasing strength of the subunit interfaces of the hemoglobin family during development from the embryonic to the fetal and ultimately to the adult types correlates with their temporal appearance and disappearance in vivo, i.e., ontogeny.

Cranioplasty.

Calvarial defects are commonly encountered after neurosurgical procedures, trauma, and ablative procedures of advanced head neck cancers. The goals of cranioplasty are to provide a protective barrier for the intracranial contents, to restore form, and prevent syndrome of the trephined. Autologous and alloplastic techniques are available, each with their advantages and drawbacks. A multitude of materials are available for cranioplasty, and proper timing of reconstruction with attention to the overlying skin envelope is important in minimizing complications.

Nano gel filtration reveals how fish hemoglobins release oxygen: The Root Effect.

The Root Effect is to many species of fish what the Bohr Effect is to humans regarding the release of O2 from their hemoglobins at low pH. However, Root Effect hemoglobins accomplish this more extensively than human adult hemoglobin in order to satisfy the diverse oxygen requirements in fish. To understand this difference between fish and human hemoglobins, we studied their subunit interface strengths using very low (nanomolar) concentrations, referred to as nano gel filtration. Root Effect hemoglobins in their CO form dissociate in a tetramer-monomer equilibrium. In contrast, tetramers and dimers but no monomers are found for adult human hemoglobin consistent with its well known tetramer-dimer equilibrium. By analogy to the human variant Hb Kansas and a similar recombinant Hb, both of which readily release oxygen due to an unstable oxygenated structure, the mechanism proposed is that oxygenated Root Effect tetramers release their oxygen to form energetically stable deoxygenated tetramers rather than dissociate to energetically unfavorable oxygenated dimers with labile interfaces. In contrast, the strong binding of CO permits observation of dissociation to monomers, thus revealing an intrinsic property of Root Effect fish hemoglobins enabling it to function as an oxygen pump.

Phosphorylation of Serine Induces Lysine p Ka Increases in Histone N-Termini and Signaling for Acetylation. Transcription Implications.

The mild acetylating agent, methyl acetyl phosphate, is used to estimate the p Ka values of some of the amine groups in peptides with sequences corresponding to a segment of the N-terminal tail of histone H4. When Ser-1 is not phosphorylated, the Lys ε amines have p Ka values in the range of 7.8-8.3, which are much lower than the currently assumed values. When Ser-1 is phosphorylated, the p Ka values of these Lys amines are elevated to the range of 8.8-10.3, thus providing the rationale for reports that they are then better substrates for acetyltransferases. Thus, reversal of suppressed p Ka values of Lys ε amines by Ser phosphorylation represents the basis for signaling in histone N-terminal tails to promote hyperacetylation, which is a hallmark of transcriptionally active euchromatin. In contrast, a state of hypoacetylation is present in the absence of phosphorylation as in transcriptionally inactive heterochromatin. A novel approach for estimating p Ka values based on a linkage between the Henderson-Hasselbalch and Michaelis-Menten equations indicates that the p Ka values of the Lys ε amines in H3 and H4 N-terminal tails have a highly variable charge gradient dependent on the location and proximity to the phosphorylation site.

A comparison of Selective Aortic Arch Perfusion and Resuscitative Endovascular Balloon Occlusion of the Aorta for the management of hemorrhage-induced traumatic cardiac arrest: A translational model in large swine.

BACKGROUND: Survival rates remain low after hemorrhage-induced traumatic cardiac arrest (TCA). Noncompressible torso hemorrhage (NCTH) is a major cause of potentially survivable trauma death. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) at the thoracic aorta (Zone 1) can limit subdiaphragmatic blood loss and allow for IV fluid resuscitation when intrinsic cardiac activity is still present. Selective Aortic Arch Perfusion (SAAP) combines thoracic aortic balloon hemorrhage control with intra-aortic oxygenated perfusion to achieve return of spontaneous circulation (ROSC) when cardiac arrest has occurred. METHODS AND FINDINGS: Male Yorkshire Landrace cross swine (80.0 ± 6.0 kg) underwent anesthesia, instrumentation for monitoring, and splenectomy. TCA was induced by laparoscopic liver lobe resection combined with arterial catheter blood withdrawal to achieve a sustained systolic blood pressure <10 mmHg, cardiac arrest. After 3 min of arrest, swine were allocated to one of three interventions: (1) REBOA plus 4 units of IV fresh whole blood (FWB), (2) SAAP with oxygenated lactated Ringer's (LR), 1,600 mL/2 min, or (3) SAAP with oxygenated FWB 1,600 mL/2 min. Primary endpoint was survival to the end of 60 min of resuscitation, a simulated prehospital phase. Thirty animals were allocated to 3 groups (10 per group)-5 protocol exclusions resulted in a total of 35 animals being used. Baseline measurements and time to cardiac arrest were not different amongst groups. ROSC was achieved in 0/10 (0%, 95% CI 0.00-30.9) REBOA, 6/10 (60%, 95% CI 26.2-87.8) SAAP-LR and 10/10 (100%, 95% CI 69.2-100.0) SAAP-FWB animals, p < 0.001. Survival to end of simulated 60-minute prehospital resuscitation was 0/10 (0%, 95% CI 0.00-30.9) for REBOA, 1/10 (10%, 95% CI 0.25-44.5) for SAAP-LR and 9/10 (90%, 95% CI 55.5-99.7) for SAAP-FWB, p < 0.001. Total FWB infusion volume was similar for REBOA (2,452 ± 0 mL) and SAAP-FWB (2,250 ± 594 mL). This study was undertaken in laboratory conditions, and as such may have practical limitations when applied clinically. Cardiac arrest in this study was defined by intra-aortic pressure monitoring that is not feasible in clinical practice, and as such limits the generalizability of findings. Clinical trials are needed to determine if the beneficial effects of SAAP-FWB observed in this laboratory study will translate into improved survival in clinical practice. CONCLUSIONS: SAAP conferred a superior short-term survival over REBOA in this large animal model of hemorrhage-induced traumatic cardiac arrest with NCTH. SAAP using an oxygen-carrying perfusate was more effective in this study than non-oxygen carrying solutions in TCA. SAAP can effect ROSC from hemorrhage-induced electrocardiographic asystole in large swine.

Gel filtration of dilute human embryonic hemoglobins reveals basis for their increased oxygen binding.

This report establishes a correlation between two known properties of the human embryonic hemoglobins-- their weak subunit assemblies as demonstrated here by gel filtration at very dilute protein concentrations and their high oxygen affinities and reduced cooperativities reported previously by others but without a mechanistic basis. We demonstrate here that their high oxygen affinities are a consequence of their weak assemblies. Weak vs strong hemoglobin tetramers represent a regulatory mechanism to modulate oxygen binding capacity by altering the equilibrium between the various steps in the assembly process that can be described as an inverse allosteric effect.

Catalytic C-H functionalization by metal carbenoid and nitrenoid insertion.

Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.

Dilemmas in the diagnosis and management of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by thrombosis (which may be venous, arterial, or microvascular) and/or pregnancy morbidity in association with persistently positive antiphospholipid antibodies. Although thrombosis and pregnancy morbidity are the main clinical criteria for a diagnosis of APS in the revised Sapporo (Sydney) criteria, recently published American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for APS have significantly refined the diagnostic algorithm to include a scoring system clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular thrombosis, obstetric, cardiac valve, and hematologic). Diagnosis of APS is complicated by the fact that significant heterogeneity exists in patients' clinical presentation, underlying vascular risk factors, and methods of detecting antiphospholipid antibodies. Despite the autoimmune nature of APS, anticoagulation remains the main strategy for secondary prevention of thrombosis. Furthermore, optimal antithrombotic treatment in APS patients with arterial thrombosis remains controversial due to a paucity of data from randomized controlled studies. In this paper, we present 2 cases and highlight the diagnostic and therapeutic challenges they pose and how we approach them in the light of current evidence.

Preoperative Imaging and Surgical Findings in Pediatric Frontonasal Dermoids.

OBJECTIVE: To review cases of congenital frontonasal dermoids to gain insight into the accuracy of preoperative computed tomography (CT) and magnetic resonance imaging (MRI) in predicting intracranial extension. METHODS: This retrospective study included all patients who underwent primary excision of frontonasal dermoids at an academic children's hospital over a 23-year period. Preoperative presentation, imaging, and operative findings were reviewed. Receiver operating characteristic (ROC) statistics were generated to determine CT and MRI accuracy in detecting intracranial extension. RESULTS: Search queries yielded 129 patients who underwent surgical removal of frontonasal dermoids over the study period with an average age of presentation of 12 months. Preoperative imaging was performed on 122 patients, with 19 patients receiving both CT and MRI. CT and MRI were concordant in the prediction of intracranial extension in 18 out of 19 patients. Intraoperatively, intracranial extension requiring craniotomy was seen in 11 patients (8.5%). CT was 87.5% sensitive and 97.4% specific for predicting intracranial extension with an ROC of 0.925 (95% CI [0.801, 1]), whereas MRI was 60.0% sensitive and 97.8% specific with an ROC of 0.789 (95% CI [0.627, 0.950]). CONCLUSION: This is the largest case series in the literature describing a single institution's experience with frontonasal dermoids. Intracranial extension is rare and few patients required craniotomy in our series. CT and MRI have comparable accuracy at detecting intracranial extension. Single-modality imaging is recommended preoperatively in the absence of other clinical indications. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1961-1966, 2024.

Prehospital Resuscitation: What Should It Be?

Prehospital resuscitation is a dynamic field now being energized by new technologies and a shift in thinking regarding intravascular resuscitation. Growing evidence discourages use of intravenous (IV) crystalloid and colloid solutions in trauma, whereas blood products, particularly whole blood, are becoming preferred. Although randomized clinical trials validating definitive resuscitative protocols are still lacking, most preclinical and clinical indicators support this approach. In addition, emerging technologies such as external and endovascular hemorrhage control devices and extracorporeal perfusion are now being used routinely, even in the prehospital setting in many countries, generating new lines of emerging investigations for trauma specialists.

Developing bottom drifters to better understand the stranding locations of cold-stunned sea turtles in Cape Cod Bay, Massachusetts.

Every fall, juvenile sea turtles in the Northwest Atlantic Ocean are threatened by rapidly declining water temperatures. When sea turtles become hypothermic, or cold-stunned, they lose mobility-either at the surface, subsurface, or the bottom of the water column-and eventually strand at the shoreline where rescue teams associated with the Sea Turtle Stranding and Salvage Network may search for them. Understanding the effects of ocean currents on the potential stranding locations of cold-stunned sea turtles is essential to better understand stranding hotspots and increase the probability of successful discovery and recovery of turtles before they die in the cold temperatures. Traditional oceanographic drifters-instruments used to track currents-have been used to examine relationships between current and stranding locations in Cape Cod Bay, but these drifters are not representative of sea turtle morphology and do not assess how bottom currents affect stranding locations. To address these knowledge gaps, we designed new drifters that represent the shape and dimensions of sea turtles-one that can float at the surface and one that sinks to the bottom-to track both surface and bottom currents in Cape Cod Bay. We found a marked difference between the trajectories of our new drifter models and those that were previously used for similar research. These findings bring us one step closer to identifying the transport pathways for cold-stunned sea turtles and optimizing cold-stunned sea turtle search and rescue efforts in Cape Cod.

Pregnancy outcomes in women receiving eculizumab for the management of paroxysmal nocturnal haemoglobinuria.

Aims: To report pregnancy outcomes and complications in women receiving eculizumab for the management of paroxysmal nocturnal haemoglobinuria. Methods: A service evaluation of routinely collected medical records across 49 pregnancies in 21 women. Results: Eculizumab was used in 37 pregnancies, 31 of which (83.8%) ended in live birth. Eight infants (25.8%) were born prematurely. Over half (54%) of women required increases in their dose of eculizumab to control their haemolysis. There were no reported cases of maternal thrombosis. Major ante/postpartum bleeding necessitating urgent intervention was reported in 10.8% of pregnancies. There were two cases of intrauterine death and three miscarriages. There were no maternal or neonatal deaths. Three newborns required prolonged hospital stays. Conclusions: Eculizumab appears to benefit pregnant women with paroxysmal nocturnal haemoglobinuria and pregnancy outcomes following its use are largely good.

Spreading pathways of Pilgrim Nuclear Power Station wastewater in and around Cape Cod Bay: Estimates from ocean drifter observations.

Near-surface drifter observations were used to study the spreading pathways in and around the Cape Cod Bay from a source region located just offshore of the Pilgrim Nuclear Power Station. The study was motivated by the recent closing of the power plant and a possible release of accumulated wastewater. The investigation applies several different techniques to the drifter data set to estimate and quantify various aspects of the circulation and spreading. Our goal was two-fold: first, to better understand and predict the fate of the Pilgrim wastewater should it be released; and second, to review, compare, and contrast several useful techniques that can be applied to drifter datasets in other parts of the global ocean. Our analysis suggests weaker spreading of the wastewater plume inside the Bay than outside, and sensitivity of the advection pathways to the location of the release. Statistical techniques predicted that part of the plume would likely be advected cyclonically around the inner coastline of the Bay towards the more quiescent eastern regions, while another part of the plume would likely pass close to the tip of Cape Cod and the beaches of the Outer Cape. For the soluble radionuclides, the levels observed in our statistical model offshore of Provincetown and Dennis/Brewster will be at least 100 times smaller than the initial concentrations.

Femoral vascular access for endovascular resuscitation.

ABSTRACT: Endovascular resuscitation is an emerging area in the resuscitation of both severe traumatic hemorrhage and nontraumatic cardiac arrest. Vascular access is the critical first procedural step that must be accomplished to initiate endovascular resuscitation. The endovascular interventions presently available and emerging are routinely or potentially performed via the femoral vessels. This may require either femoral arterial access alone or access to both the femoral artery and vein. The time-critical nature of resuscitation necessitates that medical specialists performing endovascular resuscitation be well-trained in vascular access techniques. Keen knowledge of femoral vascular anatomy and skill with vascular access techniques are required to meet the needs of critically ill patients for whom endovascular resuscitation can prove lifesaving. This review article addresses the critical importance of femoral vascular access in endovascular resuscitation, focusing on the pertinent femoral vascular anatomy and technical aspects of ultrasound-guided percutaneous vascular access and femoral vessel cutdown that may prove helpful for successful endovascular resuscitation.

Chiral discrimination among aminotransferases: inactivation by 4-amino-4,5-dihydrothiophenecarboxylic acid.

Mechanism-based inhibitors such as cycloserine and gabaculine can inactivate aminotransferases via reactions of the compounds with the pyridoxal phosphate cofactor forming an irreversible adduct. The reaction is chirally specific in that any one enzyme usually only recognizes one enantiomer of the inactivator. For instance, l-aspartate aminotransferase (l-AspAT) is inactivated by 4-amino-4,5-dihydro-2-thiophenecarboxylic acid (ADTA), however, only by the S-isomer. We have now shown that d-amino acid aminotransferase (d-a-AT) is irreversibly inactivated by the R-isomer of the same compound. The X-ray crystal structure (PDB code: 3LQS ) of the inactivated enzyme shows that in the product the enzyme no longer makes a Schiff base linkage to the pyridoxal 5'-phosphate (PLP) cofactor, and instead the compound has formed a derivative of the cofactor. The adduct is similar to that formed between d-cycloserine and d-a-AT or alanine racemase (Ala-Rac) in that the thiophene ring of R-ADTA is intact and seems to be aromatic. The plane of the ring is rotated by nearly 90 degrees with respect to the plane of the pyridine ring of the cofactor, in comparison with the enzyme inactivated by cycloserine. Based on the structure of the product, the mechanism of inactivation most probably involves a transamination followed by aromatization to form an aromatic thiophene ring.

Production of the biotechnologically relevant AFP from Aspergillus giganteus in the yeast Pichia pastoris.

The mould Aspergillus giganteus produces a basic, low molecular weight protein (AFP) showing in vitro and in vivo antifungal properties against important plant pathogens. AFP is secreted as an inactive precursor containing an amino-terminal extension of six amino acids (lf-AFP) which is later removed to produce the active protein. The molecular basis to explain this behavior and the features that determine the fungal specificity of this protein are not completely solved. In this work, the mature AFP (AFP *) and a version of AFP with an extended amino-terminal (proAFP) have been cloned and produced in the yeast Pichia pastoris. The two proteins have been purified to homogeneity and characterized from structural and functional points of view. Recombinant AFP * produced is practically indistinguishable from the natural fungal protein in terms of its spectroscopic and antifungal properties while proAFP is mostly inactive under identical assay conditions. The availability of an active AFP protein produced in P. pastoris will permit investigation of the mode of action and targeting specificity of AFP by using site-directed mutagenesis approaches.

Emerging hemorrhage control and resuscitation strategies in trauma: Endovascular to extracorporeal.

This article reviews four emerging endovascular hemorrhage control and extracorporeal perfusion techniques for management of trauma patients with profound hemorrhagic shock including hemorrhage-induced traumatic cardiac arrest: resuscitative endovascular balloon occlusion of the aorta, selective aortic arch perfusion, extracorporeal life support, and emergency preservation and resuscitation. The preclinical and clinical studies underpinning each of these techniques are summarized. We also present an integrated conceptual framework for how these emerging technologies may be used in the future care of trauma patients in both resource-rich and austere environments.

The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for non-traumatic cardiac arrest: A review.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been proposed as a novel approach to managing non-traumatic cardiac arrest (NTCA). During cardiac arrest, cardiac output ceases and perfusion of vital organs is compromised. Traditional advanced cardiac life support (ACLS) measures and cardiopulmonary resuscitation are often unable to achieve return of spontaneous circulation (ROSC). During insertion of REBOA a balloon-tipped catheter is placed into the femoral artery and advanced in a retrograde manner into the aorta while the patient is undergoing cardiopulmonary resuscitation (CPR). The balloon is then inflated to fully occlude the aorta. The literature surrounding the use of aortic occlusion in non-traumatic cardiac arrest is limited to animal studies, case reports and one recent non-controlled feasibility trial. In both human and animal studies, preliminary data show that REBOA may improve coronary and cerebral perfusion pressures and key physiologic parameters during cardiac arrest resuscitation, and animal data have demonstrated improved rates of ROSC. Multiple questions remain before REBOA can be considered as an adjunct to ACLS. If demonstrated to be effective clinically, REBOA represents a potentially cost-effective and generalizable intervention that may improve quality of life for patients with non-traumatic cardiac arrest.

Discovery of AM-6494: A Potent and Orally Efficacious ß-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2.

ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid ß (Aß) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aß40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.