Development of Bone Targeting Drugs.

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca(2+). The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments

Recognition, Investigation, and Control of Communicable-Disease Outbreaks in Child Day-Care Settings

As increasing numbers of young children attend day-care centers in the US, the elevated risk of acquiring infectious diseases in this setting has emerged as an important public health issue.1 Outbreaks of infectious diseases occur frequently within the daycare setting,2 and enteric and respiratory pathogens may be readily transmitted to household members and others in the community.1,2 The economic burden of these outbreaks is considerable; for example, parents of children in day care miss an average of I to 4 weeks of work each year to care for their sick children.1 Investigations of communicable-disease outbreaks in day-care centers have provided a wealth of information useful in developing and implementing infection-control policies and guidelines. While documented experiences with outbreaks in day-care settings have been relatively recent, they have rapidly expanded our understanding of reservoirs of infectious agents, routes of transmission, clinical characteristics of illness, risk factors for infection, the effectiveness of interventions, and recognition of pathogens previously not reportable or thought to be unimportant. Outbreak investigations in day-care centers reported in the literature have focused primarily on the etiologic agents listed in the Table. The purpose of this paper is to provide a brief overview of methodologic issues pertinent to such investigations

NO-Donating NSAIDs, PPARδ, and Cancer: Does PPARδ Contribute to Colon Carcinogenesis?

The chemopreventive NO-donating NSAIDs (NO-NSAIDs; NSAIDs with an NO-releasing moiety) modulate PPARδ and offer the opportunity to revisit the controversial role of PPARδ in carcinogenesis (several papers report that PPARδ either promotes or inhibits cancer). This review summarizes the pharmacology of NO-NSAIDs, PPARδ cancer biology, and the relationship between the two. In particular, a study of the chemopreventive effect of two isomers of NO-aspirin on intestinal neoplasia in Min mice showed that, compared to wild-type controls, PPARδ is overexpressed in the intestinal mucosa of Min mice; PPARδ responds to m- and p-NO-ASA proportionally to their antitumor effect (p- > m-). This effect is accompanied by the induction of epithelial cell death, which correlates with the antineoplastic effect of NO-aspirin; and NO-aspirin's effect on PPARδ is specific (no changes in PPARα or PPARγ). Although these data support the notion that PPARδ promotes intestinal carcinogenesis and its inhibition could be therapeutically useful, more work is needed before a firm conclusion is reached

Recognition, Investigation, and Control of Communicable-Disease Outbreaks in Child Day-Care Settings

As increasing numbers of young children attend day-care centers in the US, the elevated risk of acquiring infectious diseases in this setting has emerged as an important public health issue.1 Outbreaks of infectious diseases occur frequently within the daycare setting,2 and enteric and respiratory pathogens may be readily transmitted to household members and others in the community.1,2 The economic burden of these outbreaks is considerable; for example, parents of children in day care miss an average of I to 4 weeks of work each year to care for their sick children.1 Investigations of communicable-disease outbreaks in day-care centers have provided a wealth of information useful in developing and implementing infection-control policies and guidelines. While documented experiences with outbreaks in day-care settings have been relatively recent, they have rapidly expanded our understanding of reservoirs of infectious agents, routes of transmission, clinical characteristics of illness, risk factors for infection, the effectiveness of interventions, and recognition of pathogens previously not reportable or thought to be unimportant. Outbreak investigations in day-care centers reported in the literature have focused primarily on the etiologic agents listed in the Table. The purpose of this paper is to provide a brief overview of methodologic issues pertinent to such investigations

Orthopedic management of the extremities in patients with Morquio A syndrome.

BackgroundMusculoskeletal involvement in Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) contributes significantly to morbidity and mortality. While the spinal manifestations of the disorder have received considerable attention in the literature, there have been few reported studies to date to guide the management of the orthopedic problems associated with the lower and upper extremities.PurposeThe objective was to develop recommendations for the management of the extremities in patients with Morquio A syndrome.MethodsA group of specialists in orthopedics, pediatrics and genetics with experience in the management of Morquio A patients convened to review and discuss current clinical practices and to develop preliminary recommendations. Evidence from the literature was retrieved. Recommendations were further refined until consensus was reached.Results and conclusionsThis present article provides a detailed review and discussion of the lower and upper extremity deformities in Morquio A syndrome and presents recommendations for the assessment and treatment of these complications. Key issues, including the importance of early diagnosis and the implications of medical therapy, are also addressed. The recommendations herein represent an attempt to develop a uniform and practical approach to managing patients with Morquio A syndrome and improving their outcomes

Quahogs in Eastern North America: Part II, History by Province and State

The northern quahog, Mercenaria mercenaria, ranges along the Atlantic Coast of North America from the Canadian Maritimes to Florida, while the southern quahog, M. campechiensis, ranges mostly from Florida to southern Mexico. The northern quahog was fished by native North Americans during prehistoric periods. They used the meats as food and the shells as scrapers and as utensils. The European colonists copied the Indians treading method, and they also used short rakes for harvesting quahogs. The Indians of southern New England and Long Island, N.Y., made wampum from quahog shells, used it for ornaments and sold it to the colonists, who, in turn, traded it to other Indians for furs. During the late 1600’s, 1700’s, and 1800’s, wampum was made in small factories for eventual trading with Indians farther west for furs. The quahoging industry has provided people in many coastal communities with a means of earning a livelihood and has given consumers a tasty, wholesome food whether eaten raw, steamed, cooked in chowders, or as stuffed quahogs. More than a dozen methods and types of gear have been used in the last two centuries for harvesting quahogs. They include treading and using various types of rakes and dredges, both of which have undergone continuous improvements in design. Modern dredges are equipped with hydraulic jets and one type has an escalator to bring the quahogs continuously to the boats. In the early 1900’s, most provinces and states established regulations to conserve and maximize yields of their quahog stocks. They include a minimum size, now almost universally a 38-mm shell width, and can include gear limitations and daily quotas. The United States produces far more quahogs than either Canada or Mexico. The leading producer in Canada is Prince Edward Island. In the United States, New York, New Jersey, and Rhode Island lead in quahog production in the north, while Virginia and North Carolina lead in the south. Connecticut and Florida were large producers in the 1990’s. The State of Tabasco leads in Mexican production. In the northeastern United States, the bays with large openings, and thus large exchanges of bay waters with ocean waters, have much larger stocks of quahogs and fisheries than bays with small openings and water exchanges. Quahog stocks in certified beds have been enhanced by transplanting stocks to them from stocks in uncertified waters and by planting seed grown in hatcheries, which grew in number from Massachusetts to Florida in the 1980’s and 1990’s

International guidelines for the management and treatment of Morquio A syndrome.

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom-based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome

Outcome following mini-open lower limb fasciotomy for chronic exertional compartment syndrome

PURPOSE: The aim of this study was to report outcomes following mini-open lower limb fasciotomy (MLLF) in active adults with chronic exertional compartment syndrome (CECS). METHODS: From 2013–2018, 38 consecutive patients (mean age 31 years [16–60], 71% [n = 27/38] male) underwent MLLF. There were 21 unilateral procedures, 10 simultaneous bilateral and 7 staged bilateral. There were 22 anterior fasciotomies, five posterior and 11 four-compartment. Early complications were determined from medical records of 37/38 patients (97%) at a mean of four months (1–19). Patient-reported outcomes (including EuroQol scores [EQ-5D/EQ-VAS], return to sport and satisfaction) were obtained via postal survey from 27/38 respondents (71%) at a mean of 3.7 years (0.3–6.4). RESULTS: Complications occurred in 16% (n = 6/37): superficial infection (11%, n = 4/37), deep infection (3%, n = 1/37) and wound dehiscence (3%, n = 1/37). Eight per cent (n = 3/37) required revision fasciotomy for recurrent leg pain. At longer-term follow-up, 30% (n = 8/27) were asymptomatic and another 56% (n = 15/27) reported improved symptoms. The mean pain score improved from 6.1 to 2.5 during normal activity and 9.1 to 4.7 during sport (both p < 0.001). The mean EQ-5D was 0.781 (0.130–1) and EQ-VAS 77 (33–95). Of 25 patients playing sport preoperatively, 64% (n = 16/25) returned, 75% (n = 12/16) reporting improved exercise tolerance. Seventy-four per cent (n = 20/27) were satisfied and 81% (n = 22/27) would recommend the procedure. CONCLUSION: MLLF is safe and effective for active adults with CECS. The revision rate is low, and although recurrent symptoms are common most achieve symptomatic improvement, with reduced activity-related leg pain and good health-related quality of life. The majority return to sport and are satisfied with their outcome

Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants.

Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick's disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied

Genetic Connectivity and Diversity of a Protected, Habitat-Forming Species:Evidence Demonstrating the Need for Wider Environmental Protection and Integration of the Marine Protected Area Network

Funding Information: This work was largely funded by Heriot-Watt University (James Watt Scholarship) and NatureScot (formerly Scottish Natural Heritage). Additional funding was received from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) and their support is gratefully acknowledged. MASTS was funded by the Scottish Funding Council (grant reference HR09011) and contributing institutions.Peer reviewedPublisher PD