PHOSPHO1 is essential for normal bone fracture healing: An Animal Study.

OBJECTIVES: Bone fracture healing is regulated by a series of complex physicochemical and biochemical processes. One of these processes is bone mineralization, which is vital for normal bone development. Phosphatase, orphan 1 (PHOSPHO1), a skeletal tissue-specific phosphatase, has been shown to be involved in the mineralization of the extracellular matrix and to maintain the structural integrity of bone. In this study, we examined how PHOSPHO1 deficiency might affect the healing and quality of fracture callus in mice. METHODS: Tibial fractures were created and then stabilized in control wild-type (WT) and Phospho1-/- mice (n = 16 for each group; mixed gender, each group carrying equal number of male and female mice) at eight weeks of age. Fractures were allowed to heal for four weeks and then the mice were euthanized and their tibias analyzed using radiographs, micro-CT (µCT), histology, histomorphometry and three-point bending tests. RESULTS: The µCT and radiographic analyses revealed a mild reduction of bone volume in Phospho1-/- callus, although it was not statistically significant. An increase in trabecular number and a decrease in trabecular thickness and separation were observed in Phospho1-/- callus in comparison with the WT callus. Histomorphometric analyses showed that there was a marked increase of osteoid volume over bone volume in the Phospho1-/- callus. The three-point bending test showed that Phospho1-/- fractured bone had more of an elastic characteristic than the WT bone. CONCLUSION: Our work suggests that PHOSPHO1 plays an integral role during bone fracture repair and may be a therapeutic target to improve the fracture healing process.Cite this article: M. W. Morcos, H. Al-Jallad, J. Li, C. Farquharson, J. L. Millán, R. C. Hamdy, M. Murshed. PHOSPHO1 is essential for normal bone fracture healing: An Animal Study. Bone Joint Res 2018;7:397-405. DOI: 10.1302/2046-3758.76.BJR-2017-0140.R2.

Driving and Patients With Dementia.

Driving is a symbol of autonomy and independence, eagerly awaited during adolescence, cherished during adulthood and reluctantly rescinded during old age. It is nevertheless an individual's privilege, not right, especially as driving may affect other drivers and pedestrians on the road. It is therefore not only the individual patient who is at stake but essentially the entire community. In this case scenario, we describe the situation that arose when a patient with multi-infarct dementia wanted to go for a drive and his son and grandson tried to convince him that he could no longer drive. What went wrong in the caregivers/patient interaction is presented. The futility of arguing with patients who have dementia is highlighted as well as the suspiciousness it may generate. Alternate actions that can be useful to avoid/avert the situation from escalating and having a catastrophic ending are discussed. Testing/evaluating patients with dementia for fitness to drive is also reviewed and a list of select resources is included.

Agnosia Interferes With Daily Hygiene in Patients With Dementia.

Patients with dementia, particularly Alzheimer's disease, may not recognize that their clothes are dirty. They may see the food stains and discoloration of the clothes and yet because of their agnosia are unable to integrate these observations and deduce that their clothes are dirty and need to be changed. They will, therefore, resist attempts to get them to change clothes, especially if these clothes happen to be their favorite ones. This often causes caregivers to become frustrated, especially, if it represents a change in the patient's previous habits of only wearing clean clothes. In this case study, we present a 72-year-old woman with moderate Alzheimer's disease who lives with her daughter, who adamantly refuses to change the clothes she has been wearing for a few days and which are now clearly dirty. We report the interaction, highlight what went wrong in the patient-daughter interaction, and discuss how the catastrophic ending could have been avoided or averted.

Insomnia and Mild Cognitive Impairment.

Insomnia is a common problem in older people, especially in patients with mild cognitive impairment (MCI) whose circadian rhythm is often compromised. Insomnia exerts such a toll on caregivers that it is frequently the primary reason for seeking to institutionalize their loved ones. Three different types of insomnia are recognized: sleep-onset or initial insomnia, sleep maintenance or middle insomnia, and early morning awakening or late insomnia. Nocturnal hypoglycemia, as a cause of middle insomnia, is the main focus of this case study. Other types of insomnia are also briefly reviewed. The management of insomnia is then discussed including sleep hygiene, the usefulness and potential drawbacks of dietary supplements, nonprescription over-the-counter preparations and prescription hypnotics. Sleep architecture is then briefly reviewed, emphasizing the importance of its integrity and the role of each sleep stage.

Visual Hallucinations and Paranoid Delusions.

Visual well-formed hallucinations, fluctuations in the level of cognition, and alertness and extrapyramidal signs are core features of dementia with Lewy bodies. Some patients realize that what they are seeing or hearing are just hallucinations and learn to accept them. Others, however experience these hallucinations as quite real and cannot be dissuaded from the firm belief that they are. In fact, efforts to dissuade them often serve only to confirm the often associated paranoid delusions and this may lead to a catastrophic ending. Hence, it is best not to contradict the patient. Instead, attempts should be made to distract the patient and change the focus of her or his attention. In this case scenario, we present a 68-year-old man who has been diagnosed with dementia with Lewy bodies. He lives with his daughter. He has visual hallucinations and paranoid delusions that worsen at night: He thinks there are people outside the house plotting to kill him. We discuss what went wrong in the patient/caregiver interaction and how the catastrophic ending could have been avoided or averted.

Repetitive Questioning II.

Repetitive questioning is a major problem for caregivers, particularly taxing if they are unable to recognize and understand the reasons why their loved one keeps asking the same question over and over again. Caregivers may be tempted to believe that the patient does not even try to remember the answer given or is just getting obnoxious. This is incorrect. Repetitive questioning is due to the underlying disease: The patient's short term memory is impaired and he is unable to register, encode, retain and retrieve the answer. If he is concerned about a particular topic, he will keep asking the same question over and over again. To the patient each time she asks the question, it is as if she asked it for the first time. Just answering repetitive questioning by providing repeatedly the same answer is not sufficient. Caregivers should try to identify the underlying cause for this repetitive questioning. In an earlier case study, the patient was concerned about her and her family's safety and kept asking whether the doors are locked. In this present case study, the patient does not know how to handle the awkward situation he finds himself in. He just does not know what to do. He is not able to adjust to the new unexpected situation. So he repeatedly wants to reassure himself that he is not intruding by asking the same question over and over again. We discuss how the patient's son-in-law could have avoided this situation and averted the catastrophic ending.

FRAX calculated without BMD does not correctly identify Caucasian men with densitometric evidence of osteoporosis.

The FRAX algorithm assesses the patient's probability of sustaining an osteoporotic fracture and can be calculated with or without densitometric data. This study seeks to determine whether in men, FRAX scores calculated without BMD, correctly identify patients with BMD-defined osteoporosis. INTRODUCTION: The diagnosis of osteoporosis is based on densitometric data, the presence of a fragility fracture or increased fracture risk. The FRAX algorithm estimates the patient's 10-year probability of sustaining an osteoporotic fracture and can be calculated with or without BMD data. The purpose of this study is to determine whether in men, FRAX calculated without BMD, can correctly identify patients with BMD-defined osteoporosis. METHODS: Retrospectively retrieved data from 726 consecutive Caucasian males, 50 to 70 years old referred to our Osteoporosis Center. RESULTS: In the population studied, 11.8 and 25.3% had BMD-defined osteoporosis when female and male reference populations were used respectively. When the National Osteoporosis Foundation thresholds to initiate treatment are used, only 27% of patients with BMD-defined osteoporosis, but 4% with normal BMD reached/exceeded these thresholds. Lowering the threshold increased sensitivity, but decreased specificity. CONCLUSIONS: Our results suggest that FRAX without BMD is not sensitive/specific enough to be used to identify Caucasian men 50 to 70 years old with BMD-defined osteoporosis.

Repetitive Questioning Exasperates Caregivers.

Repetitive questioning is due to an impaired episodic memory and is a frequent, often presenting, problem in patients with Alzheimer's disease (amnestic type). It is due to the patients' difficulties learning new information, retaining it, and recalling it, and is often aggravated by a poor attention span and easy distractibility. A number of factors may trigger and maintain repetitive questioning. Caregivers should try to identify and address these triggers. In the case discussion presented, it is due to the patient's concerns about her and her family's safety triggered by watching a particularly violent movie aired on TV. What went wrong in the patient/caregiver interaction and how it could have been avoided or averted are explored. Also reviewed are the impact of repetitive questioning, the challenges it raises for caregivers, and some effective intervention strategies that may be useful to diffuse the angst that caregivers experience with repetitive questioning.

Fronto-Temporal Dementia, Diabetes Mellitus and Excessive Eating.

Diabetes mellitus is common among older people. Hypoglycemia is a sign of poorly controlled diabetes mellitus and may lead to irritability, agitation, anxiety, hunger, and an excessive food intake, which in turn may make the control of diabetes more difficult. Excessive, inappropriate food intake is also a sign of Fronto-Temporal Dementia (behavioral variant: bvFTD). In this case study, we describe the events leading to an altercation that developed between an older diabetic patient with bvFTD and the staff in an Assisted Living Facility. His first dose of insulin was given early that morning while he was still asleep. He, subsequently, woke up feeling hungry, agitated, and irritable. This, in turn, exacerbated the hyperorality associated with bvFTD. We examine what went wrong in the patient/caregiver interaction and how this potentially catastrophic situation could have been avoided or defused.

Patients with Dementia Are Easily Distracted.

Mild cognitive impairment (MCI) is the middle ground between normal, age-appropriate memory impairment, and dementia. Whereas patients with MCI are able to cope with the memory deficit, those with dementia are not: Their memory impairment and other cognitive deficits are of sufficient magnitude to interfere with the patients' ability to cope independently with daily activities. In both MCI and dementia, there is evidence of declining cognitive functions from a previously higher level of functioning. In both the conditions, there is also an evidence of dysfunction in one or more cognitive domains. There are two subtypes of MCI depending on whether memory is predominantly affected: amnestic type and nonamnestic/behavioral type. Not all patients with MCI transition to dementia, some recover. In this case scenario, we present a 68-year-old man with MCI who lives with his wife. They are getting ready to host dinner. His wife asks him to vacuum the dining room while she runs an urgent errand. We describe how this simple task vacuuming a room ended in a catastrophe with the patient spending the night in jail and his wife hospitalized. We discuss what went wrong in the patient/wife interaction and how the catastrophic ending could have been avoided. OBJECTIVES: At the end of this case discussion readers will know the following:The differences between mild cognitive impairment (MCI), normal aging, and dementia.MCI is often a precursor of dementia and has an amnestic or nonamnestic/behavioral presentation. However, not all patients with MCI develop dementia, some even recover.MCI is an opportunity to discuss with the patient various issues that may arise, should it progress to dementia such as preparing a will, transitioning from driver to passenger, and addressing various financial and legal issues including end-of-life issues and selecting someone to have power of attorney.Patients with MCI should be regularly followed up to determine whether and when they will transition to dementia as this changes the level of care needed.Patients with MCI are at an increased risk of triggering accidents because of their cognitive impairment and often impaired judgment.It may be hazardous to leave patients with MCI alone, without supervision.The importance of support groups, social media, and cameras when providing care to patients with MCI and dementias.

Efficient in vitro delivery of Noggin siRNA enhances osteoblastogenesis.

Several types of serious bone defects would not heal without invasive clinical intervention. One approach to such defects is to enhance the capacity of bone-formation cells. Exogenous bone morphogenetic proteins (BMP) have been utilized to positively regulate matrix mineralization and osteoblastogenesis, however, numerous adverse effects are associated with this approach. Noggin, a potent antagonist of BMPs, is an ideal candidate to target and decrease the need for supraphysiological doses of BMPs. In the current research we report a novel siRNA-mediated gene knock-down strategy to down-regulate Noggin. We utilized a lipid nanoparticle (LNP) delivery strategy in pre-osteoblastic rat cells. In vitro LNP-siRNA treatment caused inconsequential cell toxicity and transfection was achieved in over 85% of cells. Noggin siRNA treatment successfully down-regulated cellular Noggin protein levels and enhanced BMP signal activity which in turn resulted in significantly increased osteoblast differentiation and extracellular matrix mineralization evidenced by histological assessments. Gene expression analysis showed that targeting Noggin specifically in bone cells would not lead to a compensatory effect from other BMP negative regulators such as Gremlin and Chordin. The results from this study support the notion that novel therapeutics targeting Noggin have the clinically relevant potential to enhance bone formation without the need for toxic doses of exogenous BMPs. Such treatments will undeniably provide safe and economical treatments for individuals whose poor bone repair results in permanent morbidity and disability.

Hallucinations Are Real to Patients With Dementia.

In this case study, we present a patient with preexistent posttraumatic stress disorder and psychosis who has been recently diagnosed with Dementia with Lewy Bodies. He is experiencing vivid hallucinations. What went wrong between him and his wife as a result of these hallucinations is presented. Alternative actions that could have been used are suggested. OBJECTIVES: At the end of this case study, readers will know the following:The characteristic clinical features of Dementia with Lewy Bodies (DLB).Patients experiencing hallucinations should not be contradicted, to them, these hallucinations are real.Easy distractibility and short attention span can be exploited to avert or defuse potentially catastrophic situations.Patients with dementia should not have access to loaded guns.

Patients With Dementia Are Easy Victims to Predators.

Patients with dementia, especially Alzheimer's disease and particularly those in early stages, are susceptible to become victims of predators: Their agnosia (see Case 1) prevents them from detecting and accurately interpreting subtle signals that otherwise would have alerted them that they are about to fall for a scam. Furthermore, their judgment is impaired very early in the disease process, often before other symptoms manifest themselves and usually before a diagnosis is made. Patients with early stages of dementia are therefore prime targets for unscrupulous predators, and it behooves caregivers and health care professionals to ensure the integrity of these patients. In this case study, we discuss how a man with mild Alzheimer's disease was about to fall for a scam were it not for his vigilant wife. We discuss what went wrong in the patient/caregiver interaction and how the catastrophic ending could have been avoided or averted.

Too Many Choices Confuse Patients With Dementia.

Choices are often difficult to make by patients with Alzheimer Dementia. They often become acutely confused when faced with too many options because they are not able to retain in their working memory enough information about the various individual choices available. In this case study, we describe how an essentially simple benign task (choosing a dress to wear) can rapidly escalate and result in a catastrophic outcome. We examine what went wrong in the patient/caregiver interaction and how that potentially catastrophic situation could have been avoided or defused.

The effect of systemic administration of sclerostin antibody in a mouse model of distraction osteogenesis.

Distraction osteogenesis (DO) is a successful technique for bone lengthening, but one problem is the need to keep an external fixator in place until bone completely regenerates. We hypothesized that the systemic administration of sclerostin antibodies (Scl-Ab) can accelerate bone regeneration in a mouse model of DO. A total of 110 mice were randomized to receive one intravenous injection per week of either Scl-Ab (100 mg per kg body weight) or saline after DO surgery. Mice were sacrificed on day 11, 17, 34 or 51 post-surgery. Microcomputed tomography showed that bone volume per tissue volume of the Scl-Ab treated group was significantly higher on day 11 (P=0.009). Histological examinations indicated that chondrocytes and fibrocartilage predominated in the Scl-Ab group at day 11. The radiographic score of bone healing was also higher in Scl-Ab treated animals at day 11. There was a trend towards higher ultimate force and work to failure in Scl-Ab treated groups on day 34 and 51 (P>0.05). These data suggest the potential utility of Scl-Ab to reduce the time during DO when an external fixator is required.

An immunohistochemical analysis of the temporal and spatial expression of growth factors FGF 1, 2 and 18, IGF 1 and 2, and TGFbeta1 during distraction osteogenesis.

Distraction osteogenesis (DO) is a well established surgical technique that generates new bone by gradual distraction of two bony segments. In this study, we investigated the temporal and spatial profile of FGF 1, 2 and 18, IGF 1 and 2, and TGFbeta1 during distraction osteogenesis using immunohistochemistry. An osteotomy was performed on the right tibia of 13 white male New Zealand rabbits. After a delay of 7 days, distraction was started at a rate of 0.25 mm/12 hrs for 3 weeks which was followed by a 3 week period of consolidation. Immunohistochemical analysis was performed on a weekly interval to determine the expression of the growth factors. Staining of all growth factors was apparent at various levels in the centre and callus region in fibroblasts and chondrocyte cells. FGF2 however, showed continued high expression in osteoblasts. Within two weeks after the end of distraction all growth factors showed a reduction in expression except for FGF18 which maintained high levels of expression (up to 100% staining) throughout the distraction and consolidation phases. The study suggests that in comparison to the other investigated growth factors, FGF18 may play in important role throughout the entire process of distraction osteogenesis.

A review of FGF18: Its expression, signaling pathways and possible functions during embryogenesis and post-natal development.

FGF18 is a novel growth factor first reported in 1998. Current evidence suggests that FGF18 may play a prominent role in chondrogenesis and osteogenesis during skeletal development and growth. However, its function extends to many other biological processes. Although there remains much to be discovered and investigated on the functions and mechanisms of FGF18, it may play a role as a useful therapeutic target for various applications. The following review summarizes the current knowledge on FGF18 with special emphasis on its skeletal functions and highlights its potential areas for future research.

Overview of the radiology, histology, and bone morphogenetic protein expression during distraction osteogenesis of the mandible.

INTRODUCTION: Distraction osteogenesis (DO) is a form of in vivo tissue engineering during which an osteotomy and controlled distraction are used to lengthen bone. The molecular signals that govern distraction-induced bone formation have not been fully elucidated. Specifically, the role of bone morphogenetic proteins (BMPs) in DO of the mandible remains unclear. OBJECTIVE: To characterize the radiologic and histologic evolution of newly formed bone during DO of the mandible and to relate these changes to the expression of BMPs. METHODS: Fourteen skeletally mature male rabbits were used. A distractor device was surgically applied to one side of the mandible following osteotomy. After 1 week (latency period), distraction was started at a rate of 0.25 mm every 12 hours for 3 weeks (distraction period) and was followed by a 3-week consolidation period. Two animals were sacrificed each week after surgery (weeks 1 to 7). The mandible was resected and the new bone assessed by radiography and histology. The expression of BMPs was also analyzed using immunohistochemistry. RESULTS: There was radiographic and histologic evidence of bone formation during the distraction period. By week 6, there was mature woven bone within the distraction zone. Bone morphogenetic proteins 2 and 4 were strongly expressed in osteoblasts during distraction and in chondrocytes during consolidation. The expression of BMP-7 was relatively minor. CONCLUSION: The temporal and spatial pattern of BMP expression suggests that these proteins are important mediators of mandibular DO. Understanding the expression of BMPs may facilitate the use of recombinant proteins to enhance the rate and quality of bone generation during craniofacial DO.