Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition.

BACKGROUND: Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. RESULTS: In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416. CONCLUSIONS: Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced.

Conditional survival and standardized mortality ratios of patients with severe aplastic anemia surviving at least one year after hematopoietic cell transplantation or immunosuppressive therapy.

Immunosuppressive treatment (IST) and hematopoietic cell transplant (HCT) are standard therapies for severe aplastic anemia (SAA). We report on conditional survival and standardized mortality ratios (SMR), which compare the mortality risk with the general population adjusted for age, gender, and race/ethnicity, in patients with SAA alive for at least 12 months after treatment with IST or HCT between 2000 and 2018. Given changes to treatment regimens and differences in length of follow-up, two treatment periods were defined a priori: 2000-2010 and 2011-2018. The SMR of patients treated during the period 2000-2010 and who survived one year were 3.50 (95% confidence interval [CI]: 2.62-4.58), 4.12 (95% CI: 3.20-5.21), and 8.62 (95% CI: 6.88-10.67) after IST, matched related donor HCT, and alternative donor HCT, respectively. For the period 2011-2018, the corresponding SMR were 2.89 (95% CI: 1.54-4.94), 3.12 (95% CI: 1.90-4.82), and 4.75 (95% CI: 3.45-6.38), respectively. For IST patients, their mortality risk decreased over time, and became comparable to the general population by five years. For patients who underwent HCT during 2000-2010 and 2011-2018, their mortality risk became comparable to the general population after ten years and after five years, respectively. Thus, 1-year survivors after IST or HCT can expect their longevity beyond five years to be comparable to that of the general US population.

Uranium and lanthanum in Norwegian drinking water - Is there cause for concern?

Due to natural conditions such as geology, topography, and climate, and historical features such as resource utilization, land use, and settlement patterns, the drinking water supply in Norway is separated into many public and private water supply systems. This survey sheds light on whether the Drinking Water Regulation's limit values provide a sufficient basis for ensuring safe drinking water for the Norwegian population. Participating waterworks, both private and public, were spread throughout the country, in 21 municipalities with different geological conditions. The median value for the number of persons supplied by the participating waterworks was 155. The two largest waterworks, both of which supply >10,000 people, have water sources from unconsolidated surficial sediments of latest Quaternary age. Fourteen waterworks have water sources from bedrock aquifers. Raw and treated water were analysed for 64 elements and selected anions. The concentration of manganese, iron, arsenic, aluminium, uranium, and fluoride exceeded the respective drinking water regulations' parametric value given in Directive (EU) 2020/2184. Regarding the rare earth elements, neither WHO, EU, USA nor Canada have established any limit values. However, concentration of lanthanum in groundwater from a sedimentary well exceeded the health-based guideline value that applies in Australia. Results from this study raise the question of whether increased precipitation can have an impact on the mobility and concentration of uranium in groundwater from bedrock aquifers. Furthermore, findings of high levels of lanthanum in groundwater create uncertainty as to whether the current quality control of Norwegian drinking water is sufficient.

Protocol for indirect and direct co-culture between human cancer cells and endothelial cells.

The cross talk between cancer cells and endothelial cells (ECs) within the tumor microenvironment plays a critical role in tumor progression, recurrence, and cancer stemness. Here, we present a protocol containing two in vitro approaches to study such interactions. We first describe an indirect co-culture system to study the regulation of stemness markers in cancer cells by secreted factors from ECs. We then detail a direct co-culture system to study juxtracrine communications between the cell types. For complete details on the use and execution of this protocol, please refer to Sewell-Loftin et al.1 and Guo et al.2.

What Causes Aplastic Anaemia: Results of Transplants from Genetically-Identical Twins.

Background: Aplastic anaemia has diverse aetiologies. Distinguishing between these is, in part, testable by analyzing results of haematopoietic cells transplants between genetically-identical twins one of whom has aplastic anaemia. Objective: Describe outcomes of genetically-identical twin transplants for aplastic anaemia with and without pretransplant conditioning. Methods: We interrogated data from an observational database of 59 consecutive recipients of genetically-identical twin transplants for aplastic anaemia reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) 2000-2019. Results: 38 subjects were male. Median age was 18 years (Interquartile Range [IQR], 11-32 years). Median interval from diagnosis to transplant was 2 months (IQR 1-3 months). 11 subjects received a 1st transplant without pretransplant conditioning. 2 of recovered normal bone marrow function. The other 9 received a 2nd transplant with pretransplant conditioning 7 of whom recovered. 48 subjects received pretransplant conditioning before a 1st or 2nd transplant all of whom recovered. Conclusion: Only some genetically-identical twins with aplastic anaemia recover normal bone marrow function after a 1st haematopoietic cell transplant without pretransplant conditioning whereas most subjects recover when a transplant is preceded by pretransplant conditioning. These data are consistent with an immune-mediated aetiology of aplastic anaemia in most cases.

Graphene oxide: efficiency of reducing agents.

The efficiency of reducing agents for the reduction of graphene oxide (GO) could be probed by scanning Raman spectroscopy. A film of graphene flakes derived from GO was probed to be graphene like. We also focus on the surface quality of reduced GO (rGO).

Wet chemical synthesis of graphene.

A suitable technology for the preparation of graphene based on versatile wet chemistry is presented for the first time. The protocol allows the wet chemical synthesis of graphene from a new form of graphene oxide that consists of an intact hexagonal σ-framework of C-atoms. Thus, it can be easily reduced to graphene that is no longer dominated by defects.

Functional and environmental factors affecting work status in individuals with longstanding poliomyelitis.

INTRODUCTION: Remunerative employment is a major concern of individuals with chronic disabilities, among them, those with longstanding poliomyelitis (LSP). Although LSP is not rare there are almost no data related to work participation. PURPOSE: The aims of the current study were to determine the effects of a number of social and functional variables as barriers or facilitators to work participation in persons with LSP. PATIENTS AND METHODS: Charts of 123 LSP patients of working age that were seen in the post-polio outpatient clinic, between the years 2000 and 2005 were reviewed for the study. Data on age, gender, family status, level of function in activities of daily living, basic, and extended (B-ADL and E-ADL), and mobility were then analyzed for correlation to the vocational status. RESULTS: Seventy-two people (58.5%) were employed at the time of the survey. Gender and marital status were not found to significantly differ as regard to employment. Using assistive devices for mobility or being dependent for basic ADL were associated with lower levels of employment. Driving was positively associated with the employment status of the LSP individuals. CONCLUSION: Persons with LSP encounter important barriers to work participation, particularly on the International Classification of Functioning, Disability, and Health (ICF) components of activity and environment.

Satisfaction rates amongst elderly amputees provided with a static prosthetic foot.

AIM: Persons in Israel losing a lower limb owing to disease and have an ambulatory potential are provided with an artificial limb financed by the Ministry of Health. The choice of foot provided depends upon the physicians' assessment of the amputees' ambulatory potential. The present study investigates the patients' satisfaction with the provided limb. METHOD: A telephone survey was carried out and patients were asked to reply to a number of relevant questions. RESULTS: The less disabled patients', who received their prosthesis early, were the most satisfied. Increasing patient disability correlated with less prosthetic usage and hence greater dis-satisfaction. CONCLUSIONS: Solid ankle cushion heel (SACH) feet, which are cheap, are adequate for amputees with limited walking ability. Just over 10% of the patients who received an artificial limb could not continue using it and further studies should be conducted to investigate whether any predictive features can be found in order to minimise the financial waste.

Patients education of a self-reduction technique for anterior glenohumeral dislocation of shoulder.

BACKGROUND: : Anterior dislocation of the shoulder (glenohumeral joint) is one of the most prevalent dislocations. Following a first dislocation recurrence rates of up to 80% have been reported. Many patients will seek medical assistance for reduction of the shoulder after each of these recurrent dislocations. We describe the results of reduction of anterior glenohumeral dislocation using a modified self manipulated Milch technique that can be performed by the patients themselves after simple guidance and demonstration. This method is directed to patients who are not willing or cannot have surgical stabilization and may be in a place where medical assistance is not available. PATIENTS: : The patient is placed in a supine position, and begins slowly to actively abduct and externally rotate the dislocated shoulder until the arm is overhead. Once the overhead position has been achieved, the arm is gently lowered back to the side of the body. Simultaneously, the patient has to apply pressure to the front of the shoulder with the other hand to maintain position until the reduction is complete. RESULTS: : Thirty-two dislocated shoulders in 33 consecutive patients suffering from recurrent dislocations were successfully reduced by this technique. Mean reduction time was 10 minutes. DISCUSSION: : The results illustrate the fact that most patients are able to reliably and reproducibly reduce glenohumeral dislocations by themselves. Subsequent dislocations can be reduced promptly decreasing the dislocation time thus avoiding further damage to the shoulder, achieving immediate pain relief, and removing the immediate necessity for medical attendance.

Trans-metatarsal amputation in patients with a diabetic foot: reviewing 10 years experience.

Considerable disagreement exists whether trans-metatarsal amputations are indicated in persons with diabetes. A previous study reported that statistically the success rate of Syme's amputation in diabetic patients over 65 years of age resulted in a very poor results. The purpose of this study was to investigate the results of trans-metatarsal amputations, in patients with diabetes and to seek markers which could shed light upon the advantages/disadvantages of this procedure. The records of 46 patients covering a 10-year period (1996-2006) were used as a database. Twelve needed higher amputation level and another 10 needed a wound revision. All the patients that maintained the original amputation level walk without a need for a prosthesis and kept their previous abode. TMA in diabetic patients, although at a high risk for an extrasurgical procedure, once successful, the patient will regain his previous lifestyle.

Thoracic and lumbar spine radiographs for walking trauma patients--is it necessary?

Numerous patients ambulating independently arrive in the Emergency Department complaining of back pain after being involved in a motor vehicle crash (MVC). We examined the yield of routine screening radiographs of the lumbar and thoracic spine in these patients. A retrospective review was carried out of the records of 3173 patients who were involved in a MVC during a 1-year period and presented to a single medical center. Radiographs of the lumbar spine, thoracic spine, or both were obtained in all patients complaining of back pain. Of 3173 ambulating MVC trauma patients, 35% (1110 patients) complained of thoracic or lumbar back pain. None of the lumbar and thoracic spine radiographs that were obtained in these patients was positive for a fracture or dislocation. The current study suggests that the yield of the routine use of spinal radiographs is very low in patients ambulating independently and complaining of back pain after a MVC.

[Total contact cast for management of neuropathic ulceration of the foot].

Neuropathic foot ulcers are common in diabetic patients. One etiological factor is neural dysfunction. These ulcers are a major cause leading to limb loss and exist in 85% of diabetic patients undergoing amputations. A treatment modality of neuropathic ulcers is by weight-bearing relief of the affected area, which facilitates natural healing. The best way of providing such treatment is by the application of a total contact healing plaster cast which dissipates the pressure over the entire sole and shin. The method is successful in more than 70% of the cases. The major drawbacks of this process are the frequent need to change the plaster cast, which is extremely time consuming, and the need for a skilled artisan. This treatment protocol is dependent on the availability of conditions that will permit the artisan to create these total contact casts.

Range of joint movement in female dancers and nondancers aged 8 to 16 years: anatomical and clinical implications.

BACKGROUND: Little data are available on changes that occur with age in joint range of motion in dancers and nondancers. HYPOTHESIS: In dancers, joint range of motion will increase with age, whereas it will decrease in nondancers, independent of the joint studied. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The study population included 1320 female dancers, aged 8 to 16 years, who participated in different types of dancing classes (classical ballet, modern dance, jazz, etc) and 226 nondancers of similar age. Range of motion was measured for the hip, knee, ankle, foot, and spinal joints. RESULTS: The pattern of differences in range of motion with age varied in different joints and types of movement. (1) For combined ankle and foot plantar flexion (pointe), ankle plantar flexion, and hip external rotation, there was no change in range of motion in dancers, whereas range of motion diminished with age in the nondancers. (2) For ankle dorsiflexion, neither group showed any change with age, and range of motion was significantly greater in the nondancer group. (3) For knee flexion, hip flexion, and hip internal rotation, range of motion decreased with age in both groups. (4) For hip abduction, range of motion decreased with age in dancers and remained constant in the nondancers. (5) For hip extension, range of motion increased in both groups. (6) For lower back and hamstrings, range of motion increased among dancers with age and remained constant among nondancers. CONCLUSION: Dancers and teachers should realize that passive joint range of motion is unlikely to improve with age. Therefore, the major goal of a dancing program should focus on exercises that retain the natural flexibility of the dancers' joints rather than trying to improve them.

Hemophilia orthopedic management with emphasis on developing countries.

The articular problems of patients with hemophilia begin in infancy when minor injuries result in hemarthroses. Early continuous prophylaxis (from cradle to college) is of paramount importance because the immature skeleton is very sensitive to the complications of hemophilia; severe structural deficiencies may develop quickly. If continuous prophylaxis is not feasible owing to the expense of the clotting material or lack of venous access, then a major hemarthrosis must be treated aggressively to prevent the development of synovitis, recurrent joint bleeds, and ultimately end-stage arthritis. Once synovitis has developed, which bleeding will make inevitable, the aim should be to treat it as soon as possible. There are conservative (synoviorthesis) and operative (open or arthroscopic synovectomy) methods. Between the second and fourth decades, many patients with hemophilia develop articular complications. Once this has occurred, treatment modalities such as alignment osteotomies, joint debridement, arthrodesis, and arthroplasties are possible. Should surgery be required, one should consider multiple procedures.

Trans-femoral amputee pilots: criteria for return to the fighter cockpit.

Proximal lower limb amputations (trans-femoral) usually leave amputees with significant functional disturbances. This article contains information regarding three pilots with trans-femoral amputations that returned swiftly to continue their aeronautical careers despite their disabilities. Adaptations are needed in the limb prostheses to enable the amputees to access the minimally spaced cockpit.

[Medical footwear].

Medical footwear provides solutions for structural or functional foot problems. Individuals with normal feet do not require medical footwear. In diabetic patients with neuropathy and foot deformity, the use of medical footwear protects the foot, reduces the plantar pressures and significantly reduces the rate of ulcers formation and amputations. Shoes have different designs, heights, and may be constructed of differing materials depending upon the nature of the needed corrections. Structurally, shoes can be viewed as consisting of a sole and an upper portion. Both these entities can be further sub-divided into components and shapes, each one providing a different corrective feature. Ordering medical footwear requires the same specificity as with the provision of medications. In Israel, shoes are provided by the Ministry of Health to patients according to specific criteria. The provision and quality control is conducted through a selected panel of doctors, chosen by the Lewis National Institute of Rehabilitation, and working in public hospitals.

Blood transfusion requirements in elderly hip fracture patients.

The purpose of this study was to investigate blood transfusion patterns in elderly hip fractured patients and to determine the clinical predictive criteria for blood utilization. This retrospective study involved data analysis of 302 patients, undergoing surgical repair of pertrochanteric and subcapital fractures. Patients of the transfused group had significantly lower admission hemoglobin (P < 0.0001) and significantly more pertrochanteric fractures. About 80% of patients of the lowermost quartile of admission hemoglobin were transfused, compared with < 20% of the uppermost group (P < 0.0001). Admission hemoglobin levels < 12 g% and pertrochanteric fractures were independently associated with transfusions (odds ratio (O.R.) 0.475, C.I. 0.377-0.598, P < 0.0001 and O.R. 1.885, C.I. 1.05-3.215, P = 0.02, respectively). The results support the adoption of a policy considering primarily these two factors. Other factors we studied had no predictive power. Cross-matching may be reserved only for patients presenting with hemoglobin < 12 g% and pertrochanteric fractures. This practice seems safe and should help in reducing the extent of unnecessary blood ordering.