Overview of the relevance of PI3K pathway in HR-positive breast cancer.

One of the hallmarks of hormone receptor (HR)-positive breast cancer is its dependence on the phosphatidylinositol-3-kinase (PI3K) pathway. Here, we review the epidemiologic, functional, and pharmacologic interactions between oncogenic PI3K and the estrogen receptor (ER). We discuss the epidemiology of PI3K pathway alterations, mechanisms of resistance to PI3K inhibitors, and the current mechanistic landscape of crosstalk between PI3K and ER, which provide the rationale for dual ER and PI3K inhibition and is now a standard of care in the treatment of ER+ PIK3CA-mutant metastatic breast cancer. We outline newer studies in this field that delineate the clinically relevant overlaps between PI3K and parallel signaling pathways, insulin signaling, and ER epigenetic modifiers. We also identify several caveats with the current data and propose new strategies to overcome these bottlenecks.

Effects of astrocytic dynamics on spatiotemporal hemodynamics: Modeling and enhanced data analysis.

The effects of astrocytic dynamics on the blood oxygen-level dependent (BOLD) response are modeled. The dynamics are represented via an astrocytic response function that approximates the effects of astrocytic activity, including delay between neural activity and hemodynamic response. The astrocytic response function is incorporated into a spatiotemporal hemodynamic model to predict the BOLD response measured using functional magnetic resonance imaging (fMRI). Adding astrocytic dynamics is shown to significantly improve the ability of the model to robustly reproduce the spatiotemporal properties of the experimental data such as characteristic frequency and time-to-peak. Moreover, the results are consistent across different astrocytic response functions, thus a simple impulsive form suffices to model the effective time delay of astrocytic responses. Finally, the results yield improved estimates of previously reported hemodynamic parameters, such as natural frequency and decay rate of the flow signal, which are consistent with experimentally verified physiological limits. The techniques developed in this study will contribute to improved analysis of BOLD-fMRI data.

Unilateral ectopic insertion of the pectoralis minor: Clinical and functional significance.

During routine dissection of a 70-year-old female, we observed a unilateral ectopic insertion of the left pectoralis minor muscle. The tendon was cord-like and passed through a tendon sheath superior to the coracoid process to insert on the greater tubercle of the humerus. Additionally, an aponeurosis extended from the distal aspect of the muscle's tendon and passed medially to insert near the base of the coracoid process. This is the first report of an additional aponeurosis extending from the tendon of the pectoralis minor and attaching to the coracoid process. We also observed that the pectoralis minor tendon caused an unusually smooth deep indentation on the superior aspect of the coracoid process; considering its insertion on the humerus, we hypothesize that the muscle acted as an abductor of the shoulder along with the supraspinatus. The medial extension of an aponeurotic tendon from the pectoralis minor tendon near its insertion, to the base of the coracoid process further suggests that the muscle provided stability to the glenohumeral joint while acting as an abductor. Pectoralis minor variations have been described since 1897; however, few studies have demonstrated functional or clinical significance. The redundancy of the actions of this muscle along with its long tendon suggests a potential source for autograft.

Hypogenetic right lung with partial anomalous pulmonary venous return and accessory diaphragm: a case of "scimitar lung".

Partial anomalous pulmonary venous return (PAPVR) is a rare congenital cardiovascular condition in which some of the pulmonary veins drain into the systemic circulation. We report on the cadaveric dissection of a 71-year-old Caucasian male donor who died of chronic obstructive pulmonary disease with hypertension. We noted a faint incisional scar on the thorax extending from the parasternal region at the 4th intercostal level to the midaxillary line. Since the straight-line incision followed the ribs and the scar was quite faint, surgery probably occurred when the donor was young. We also observed numerous surgical interventions of the heart, lungs, and vasculature to correct various defects. The morphology of the heart was normal, but was shifted more to the right side. An atrial septal defect (ASD) was closed with sutures. The right superior pulmonary vein that drained into the superior vena cava (SVC) was ligated close to the SVC and the right inferior, left superior, and inferior pulmonary veins all drained directly into the left atrium. We noticed a dilated coronary sinus entering the right atrium adjacent to the ASD; the ostium of the coronary sinus noticeably lacked the normal valve-like structure. We initially thought the right lung was a "horseshoe" lung, but realised that it was a "hypogenetic" lung with PAPVR and an accessory diaphragm. Compared to the left, the right secondary bronchi were much narrower and branched uncharacteristically, as seen in hypogenetic lung syndrome. The inferior lobe was highly disorganised, severely hypoplastic, and exhibited uncharacteristic morphology. The superior bronchopulmonary segment was markedly hypoplastic. The posterior and medial basal segments were not only hypoplastic and slender, but also extended like a tail to the left pulmonary cavity behind the heart/pericardium and in front of the oesophagus and aorta. The right lung, though hypoplastic, demonstrated patent bronchi and the lobes were inflatable. Based on the hypogenetic lung and PAPVR, we conclude that the donor exhibited 'scimitar' lung.

Evaluating the utility of pre-operative airway assessment for intubation management in difficult airway patients.

OBJECTIVE: To assess intubation management in difficult airway patients by performing a multidisciplinary pre-operative examination of the airway using a flexible fibre-optic laryngoscope. METHODS: Patients with a known but stable difficult airway were evaluated prior to surgery in the pre-operative holding suite by both an ENT surgeon and an anaesthesiologist via a fibre-optic laryngeal examination. RESULTS: Performing a pre-operative fibre-optic examination of the difficult airway led to a change in intubation strategy in 6 out of 12 cases. Intubation 'first-pass' success occurred in 9 out of 12 (75 per cent) of our patients. CONCLUSION: By performing a multidisciplinary airway examination immediately prior to surgery, a safe plan to intubate on the initial attempt was developed. This resulted in improved first-pass success at intubation compared to historical data.

Surgeon-performed intubation in awake patients utilising an anterior commissure laryngoscope with bougie: a retrospective case series.

OBJECTIVE: This retrospective case series examined the outcomes of surgeon-performed intubation using the anterior commissure rigid laryngoscope and bougie in adults with a difficult airway, including awake patients. METHODS: This study comprised a series of adult patients who underwent surgeon-performed intubation over a 10-year period. They were identified by a records search for the Current Procedural Terminology ('CPT') code 31500 - 'intubation by surgeon'. RESULTS: Forty-nine intubations performed in the operating theatre were reviewed. Intubation performed by the surgeon using the rigid anterior commissure laryngoscope was successful in 47 of the cases (96 per cent). Over half of the patients had experienced failed intubation attempts with other methods by other providers prior to the surgeon performing direct laryngoscopy. Twenty intubations were performed without paralytics and with the patient awake. CONCLUSION: In properly selected adults who need an urgent, secure airway in the operating theatre, surgeon-performed anterior commissure laryngoscopic intubation using a bougie should be considered a safe, reliable procedure. In most cases, this procedure can be performed in selected patients whilst awake, with sedation.

Alterations in the rat renal glycosaminoglycans in streptozotocin-induced diabetes.

The effect of streptozotocin-induced diabetes on the glycosaminoglycan composition of rat renal cortical tissue was evaluated. Glycosaminoglycans were isolated and purified from the kidney cortex of control and diabetic rats by means of digestion with collagenase, pronase and ethanol precipitation. Subsequent fractionation was performed by ion exchange chromatography on Dowex 1-X2 Cl using various concentrations of sodium chloride solution. The glycosaminoglycan in each fraction was characterized by digestion with hyaluronidase, chondroitinase AC and ABC. The undigested glycosaminoglycans were separated after each enzyme digestion and quantitated. The glycosaminoglycan composition of each fraction was computed from the enzyme digestion profile. The results indicate that in renal cortex of streptozotocin induced diabetic rats there was a significant reduction in the levels of dermatan sulfate, heparan sulfate and hyaluronic acid, while the chondroitin sulfate remained unaffected. In light of this finding, the significance of these anionic polysaccharides in renal functions is discussed.

Alterations of renal cortex and medullary glycosaminoglycans in aging dog kidney.

Age-related changes in renal function have been attributed to alterations in the chemical composition of the kidney tissues. Hence, the glycosaminoglycan composition of the renal cortex and medulla at varying age intervals was investigated. Glycosaminoglycans were isolated from the tissues by means of digestion with collagenase and pronase and purified by ethanol precipitation. Subsequent separation of various polyanions was accomplished by ion exchange chromatography on a Dowex 1-X2 column, using sodium chloride buffers of increasing ionic strengths. The glycosaminoglycans in each fraction were identified and quantitated by digestion with specific enzymes, including hyaluronidase, chondroitinase AC and ABC. The enzyme resistant material was separated and further digested with nitrous acid to quantitate the proportion of heparon sulfate. The results indicate that the glycosaminoglycan content of the renal medulla was much higher than the cortex at all the age intervals studied, and age-induced reduction was mainly cortical. There was a significant reduction in the heparan sulfate content of the cortex in aging. Interestingly, the major glycosaminoglycan content of the medulla was hyaluronic acid, which showed a sharp increase during aging, whereas heparan sulfate declined. Chondroitin sulfate was not altered due to age in either tissue. The molecular weight of hyaluronic acid was determined by column chromatography. Results indicate that the size of hyaluronate in the cortex was small and did not vary with age. In the medulla of the younger age group, a considerable amount of large size hyaluronate was observed. As age increased, the size decreased. The results strongly suggest that alteration in the renal glycosaminoglycans may be partly responsible for the age related protinuria and ionic imbalance.

Suspected adverse events, 2013.

Increase in the number of reports of suspected adverse events in animals, Fewer reports of human adverse events to veterinary medicines, Notable increase in reports relating to products used for treating canine epilepsy. These are some of the results from the surveillance work carried out by the pharmacovigilance unit at the Veterinary Medicines Directorate (VMD), as discussed by Giles Davis and colleagues from the VMD.

Somite Chondrogenesis in vitro: Differential Induction by Modified Matrix- a Biochemical and Morphological Study*: (induction/chondrogenesis/proteoglycans/SEM analysis).

The stimulation of somite chondrogenesis by extracellular matrix components was studied by monitering the synthesis of cartilage-specific large proteoglycan aggregates. Chick embryonic sternal proteoglycans were separated into various components: monomers, hyaluronic acid, link protein and glycosaminoglycan side chains. The effects of these components, either individually or in various combinations, on somite chondrogenesis was examined. Proteoglycan monomers, alone or in a mixture with other components, induced chondrogenesis. The other components did not have any stimulating effect of their own. The results of these induction studies were also observed on a Sepharose CL-2B column and correlated using electron microscopy. Stimulation of somites resulted in an increase in the amount of proteoglycan aggregation (material excluded from the column) and was in agreement with the morphological appearance of the matrix in that there was increased accumulation of large proteoglycan granules. A matrix mixture of collagen and proteoglycans showed significant stimulation. When the matrix environment of the somites was altered to be unfavorable to the explants (medium containing hyaluronic acid) there was altered synthesis of cartilage-specific molecules. The results presented in this report strongly suggest that the composition of the extracellular matrix material is critical for somite chondrogenesis.

A preliminary study of mechanically stress-induced changes in the extracellular matrix of the canine intervertebral disc.

The intervertebral discs of a young (age, 3 years) and an old (age, 8 years) dog were isolated as motion segments and cyclically stressed in physiologic nondestructive axial compression loads. Chemical analysis of the matrix of the annulus fibrosus revealed a shift in proteoglycan molecular size from larger to smaller moieties for the older dog but not for the younger. These preliminary results may indicate an age-related inability of the disc to tolerate cyclic stress.

Cerebellopontine angle lymphoma presenting as chronic mastoiditis.

Middle-ear tumours are not uncommonly mistaken for mastoiditis on presentation. We report a case of cerebellopontine angle non-Hodgkin's B-cell lymphoma originally presenting as a middle-ear inflammatory process. In mastoiditis not resolving with conventional treatment it is important to look for an underlying cause.

Management of children with clefts of the lip or palate: an overview.

Patients with clefts of the lip and palate present a number of problems associated with speech and hearing during early childhood, dental anomalies and malocclusion in the developing dentition, and secondary facial deformities and emotional "burn out" in adolescence. Appreciation of the differences in velopharyngeal function, hearing, speech, growth, and dental development is important in understanding the detailed and sequential multidisciplinary management required for patients with clefts. The dentist is an important member of the cleft-palate team, providing an essential role in establishing a preventive plan, monitoring the dental needs of the patient, and motivating and educating the patient. A very favourable outcome is now possible for these individuals, largely as a result of a team approach to management.

Recurrent ameloblastoma in an autogenous bone graft after 28 years: a case report.

The growth characteristics of ameloblastoma is such that recurrence can occur regardless of treatment method, although recurrence rates following a block resection are considerably less than that following enucleation and curettage. A small number of recurrences in autogenous bone grafts have been reported in the literature. This report describes a recurrent ameloblastoma in an autogenous bone graft occurring 28 years following resection and reconstruction.

Analysis of perinotochordal materials. I. Studies on proteoglycans synthesis.

Perinotochordal proteoglycans have been shown to influence somite chondrogenic differentiation. However, information concerning the composition of the proteoglycan molecules synthesized by the notochord, or the exact type of molecule necessary for the induction of somite chondrogenesis is not known. The results of the present study indicate that the proteoglycan extracted from the 8 day old notochord culture consists of predominantly small proteoglycans, while the large aggregates form less than 30% of the total. The chondroitin sulfate composition also shows a cartilage type of proteoglycan molecules synthesized by the notochord.

Proteoglycans in normal and severely osteoarthritic human cartilage.

Proteoglycans from osteoarthritic cartilage were compared with those from normal articular cartilage. Normal proteoglycan aggregates are larger in size and more homogeneous than those in osteoarthritis. Proteoglycan monomers from both sources gave two peaks on controlled pore glass-bead chromatography. Although the retarded material from normal cartilage showed an affinity for hyaluronate, the same material from osteoarthritic cartilage did not. The hyaluronate-binding capacity of the material which is partly in the void volume and partly retarded was similar in both types of cartilage. These results suggest that in osteoarthritic cartilage the proteoglycan aggregates are smaller and more heterogeneous and that the chondroitin sulphate side chains are shorter. They also indicate that there are two populations of proteoglycan, one with its hyaluronate-binding-protein region of core protein intact and the other either possessing an inactive binding region or totally lacking it.

Management of ectodermal dysplasia in children--an overview.

Oral rehabilitation is often difficult for the young child with ectodermal dysplasia. Most affected children require extensive dental treatment in order to restore their appearance and function. Early intervention also helps children develop a positive self-image. This paper will review the dental management and timing of different treatment modalities for children with ectodermal dysplasia.

Effects of physical stress on the synthesis and degradation of cartilage matrix.

The effects of mechanical stress on the metabolism of dog femoral head cartilage have been investigated. The model involves exercising the dog on a treadmill for an 8-month period and isolating the cartilage proteoglycans from three different anatomical regions of the femoral head. These regions are 1) the articulating area, which shows degenerative changes, 2) the area surrounding the articulating area, and 3) the non-articulating area. The hexosamine analysis of cartilage from the exercised animals, indicates 43% and 21% decreases in regions 1 and 2, respectively, while in region 3 no significant change was observed. The size of the proteoglycan aggregates and monomers also decreased with exercise in regions 1 and 2, and the cartilage from these two regions also incorporated more radioactive sulfate, suggesting a possible attempt to repair the degenerative alterations. The proteoglycan monomer (D1) from the articulating region of exercised dogs failed to interact with hyaluronic acid, while the monomers from other regions in the same animal did interact. Glycosaminoglycan chains from region 1 were smaller than in the control tissue, and there was an increase in chondroitin-4-sulfate synthesis. The results of the present study indicate that the cartilage from the articulating area and the surrounding area resist mechanical deformation by increasing synthetic activity. These observations suggest that the exercised animal can be a valuable model and provide increased understanding of the mechanism of cartilage degeneration.