Mark Corson

By C. Gnar. International College.

Bacillary hemoglobinuria caused by monly associated with acute disease buy atorvastatin 10mg low cost, thrombocytopenia generic atorvastatin 5mg on-line, Clostridium novyi type D (Clostridium hemolyticum) is and blood loss generic atorvastatin 5mg online. Hemoglobinuria gener- cause of diffuse neoplasia, nonregenerative anemia ally is observed in those with these diseases. Iron deciency anemia may rarely cause severe weak- Autoimmune hemolytic anemia, as described in other ness in milk-fed calves. Concurrent erythrolysis does not occur naturally in cattle, but the inammatory diseases may alter this typical stress leu- disorder has been observed when cattle were vaccinated kogram. Subsequent passive transfer of maternal an- a normal neutrophil count because of glucocorticoid- tibodies against specic blood types to calves from these induced neutrophilia counterbalancing the expected cattle results in some calves showing isoerythrolysis. Cattle and their leukograms are ex- although several other factors may be involved. A single Determination of when an anemic patient requires injection of 20 mg or more dexamethasone usually re- whole blood transfusion must be made primarily based sults in a stress leukogram characterized by neutrophilia, on the physical examination and secondarily based on lymphopenia, and eosinopenia within 24 hours. In ad- weakness, and other general signs that would indicate dition to altering numbers of neutrophils, corticosteroids the need for a transfusion. Neutrophil function may be impaired during greater than 100 beats/min, respiratory rates of greater the periparturient period and in cattle with retained fetal than 60 breaths/min, obvious mucous membrane pal- membranes. Heart rates that are greater than A degenerative left shift wherein neutropenia coex- 120 beats/min and pounding, respiratory rates over ists with the appearance of band neutrophils is typical of 60 breaths/min, and obvious pallor all dictate a need for cattle with severe acute inammation or endotoxemia. Although the degenerative left shift remains a Cattle are unique in regard to the leukogram and its negative prognostic indicator and a positive indicator of response to various diseases and stresses. Cattle that have a degenerative left shift will may be associated with normal or variable leukograms often have a return to normal neutrophil numbers within that shed little light on which disease the patient has. This time lapse may simply reect the time bovine patients in an academic referral hospital, we nd necessary for resolution of a severe infection. If the infec- that the majority of these leukograms, regardless of the tion requires more than 1 week for resolution, rebound cause of illness, have been within normal limits. Stress and glucocorticoids reliably alter the leukogram Certainly some cattle with chronic infections have neu- to create neutrophilia, lymphopenia, and eosinopenia. It is rare to see an adult cow with more than consistent with stress or exogenous corticosteroid ad- 18,000 to 20,000 neutrophils unless exogenous cortico- ministration. Although monocytosis is not a consis- potential for greater morbidity and mortality to be tent nding in the peripheral blood of ruminants associated with concurrent infectious diseases such as infected with Listeria monocytogenes, as in humans and Salmonellosis or Pasteurellosis should not be over- rodents so infected, some cattle with listeriosis do have looked diagnostically during a herd outbreak of enteric a classical monocytosis. Frequently it is difcult to know Bovine Leukocyte Adhesion Deciency whether the lymphopenia is associated directly with the (Bovine Granulocytopathy Syndrome) disease or simply represents stress associated with a dis- ease. Although eosinopenia should accompany lympho- Etiology penia when the cause is stress or corticosteroid adminis- A fatal syndrome consisting of poor growth, chronic or tration, eosinophil counts have limited value in this recurrent infections, and persistent extreme neutrophilia regard. Absolute lymphocytosis that is transient is rare in has been observed in Holstein calves since the late dairy cattle and when present usually is associated with 1970s. Affected calves had persistent neutrophil counts a neutrophilia in patients recovering from acute infec- exceeding 30,000/ l, and some had counts exceeding tion. Lymphocyte counts may range from 30,000 to humans brought about further suspicion of an inher- 100,000 in such cases, and immature lymphocytes and ited disorder in leukemoid calves. Recessive homozygotes are expected as a result of parasite loads and other con- affected, and heterozygote carriers have intermediate ditions. Denitive diagnosis alongside identication migration into tissue sites of inammation. Infections thought to be clinically minor re- Treatment spond poorly or not at all to appropriate therapy. Recur- Treatment is only palliative, and most affected calves die rence of signs and multiple problems are typical. To date those that survive to develop chronic disease associated most affected calves studied have had greater than with poor growth are suspected to have the disease. Al- cause variable expression of the glycoprotein deciency though myelogenous leukemia is a consideration, is possible in homozygote recessives and in heterozy- neutrophil function tests differentiate these diseases gotes, it also is possible that mild forms of disease and because neutrophils in myelogenous leukemic patients prolonged survival occur. Affected calves must recessives bleed excessively or repeatedly following inju- be differentiated from calves with chronic abscessation ries or routine surgical procedures such as castration or of the thorax or abdomen and calves persistently in- dehorning. Thrombocytopenia is the most common cause of abnormal coagulation in dairy cattle. Thrombocytope- is most commonly observed in association with neonatal nia and leukopenia tend to be profound long before calf septicemia. Similar thrombocytopenia caused by usually affect platelet survival rather than production. Infec- bocytopenia has been reproduced experimentally, most tious diseases cause decreased platelet survival via sev- thrombocytopenia cases are sporadic and associated with eral mechanisms. The calf completely recovered following a fection show a return to normal platelet numbers in whole blood transfusion and replacement of the prop- conjunction with an increase in serum antibody titers tosed globe. Platelet count (usually less than 50,000/ l) pertains to cattle because, in general, specic reagents 2. Bleeding time and clot retraction occur from small vessels anywhere in the body typify are abnormal. Bleeding may occur from the skin at sites of Once the diagnosis of thrombocytopenia is conrmed injections or insect bites. Venipuncture causes bleeding, by laboratory studies, clues to the cause of this disorder hematoma formation, and possible venous thrombosis. Septicemia, endotoxemia, and recent Epistaxis is common in cattle with thrombocytopenia trauma may be clinically obvious, whereas ingested tox- and other signs of bleeding frequently accompanying ins or parenteral drugs may require careful historical data inammation or injury to specic sites. Melena and hematuria also are pos- ever the etiology of thrombocytopenia remains obscure, sible signs. Obviously stress, trauma, and bleeding requires therapy with a fresh whole blood hydration factors may affect the incidence of bleeding at transfusion and treatment of any primary condition.

When mitochondria are not functioning properly order 20mg atorvastatin visa, tissues that have high energy demands suffer rst cheap atorvastatin 10mg mastercard. This is manifest in genetic mitochondrial disorders atorvastatin 40mg generic, which mostly affect the nervous system, heart and skeletal muscle [21]. It is notable that inadequate energy support, excessive and unopposed oxidative stress as well as chronic inammation have all been associated with the syndrome of frailty and with almost all chronic diseases whose incidence and preva- lence increase with aging as well as with sarcopenia, gait disorders, and brain dys- function. The translation of these biological events into both multi-morbidity and frailty is direct and intuitive. Further, it is easy to see how age-associated mitochondrial dysfunction can produce a number of vicious cycles that further impair mitochondrial physiology, for example, by causing ischemia or metabolic derangement. There are now many other examples implicating a single biological mechanism that, while driving the development of aging as a phenotype and aging- related frailty, also causes multi-morbidity. What is important here is that the trian- gle of aging-multimorbidity-and frailty may derive from the same root cause and, plausibly, they may all respond to the same interventions. We develop further here the concept and the evidence that underlying mechanism(s) of aging as exemplied 46 L. Ferrucci above by the example of mitochondrial changes - may lead to this syndrome of frailty. Frailty is associated with a dysregulation of the complex adaptive mecha- nisms that support organismal resilience; the dysregulation leading to loss of homeostatic capabilities and increased susceptibility to stress. The net result is the emergence of a distinct clinical syndrome with a characteristic phenotype that is predictive of a range of adverse clinical outcomes. We will rst describe frailty as a prototypical constellation of signs and symp- toms that allows a clinical diagnosis and then, working backwards in the causal pathway to etiology, we will consider how what we currently know about frailty informs understanding of aging and accelerated aging. When a critical number of such signs and symptoms occur in the same individual they identify the frailty syn- drome [23]. It is noteworthy that studies have demonstrated that the phenotypic criteria of frailty co-occur in ways that are consistent with the denition of a medi- cal syndrome [24]. That they predict the clinical outcomes associated with being frail provides criterion validity. This susceptibility to adverse outcomes occurs frequently in the context of a stressor, such as illness, hospitaliza- tion or surgery. Clinical frailty develops progressively, so that testing positive for one or two criteria predicts the development of the full syndrome, with weakness and slowed gait being the most common earliest predictors [27]. Studies have found that the greater frailty is associated with greater risk for disability and loss of independence, for example, in the absence of an acute precipitant [28 ]. Clinical frailty is also associated with the presence of specic chronic diseases, particularly those with an inammatory etiology, and the risk of frailty rises with the number of such diseases present [29]. Further, new evidence indicates that obesity and aggregate risk for coronary artery disease in midlife predicts the development of pre-frailty and frailty 26 years later. Together these observations may implicate a shared etiology of aging (the process) and frailty (the clinical syndrome) [29]. Etiological Role of Aging in Chronic Diseases: From Epidemiological Evidence 47 45 Non-frail 40 Pre-frail Frail 35 30 25 20 15 10 5 0 Fig. A large body of evidence indicates that frailty in all its clinical manifestations could be driven by a specic, although complex, pathophysiology that leads to dys- regulation of multiple physiologic systems. Since aging is pervasive across the entire body, the more systems that are dysregulated, the greater the likelihood that the clinical manifestation is the result of accelerated aging or frailty rather than to specic disease. Longitudinal studies have found that dysregulation and loss of function tends to occur harmonically across multiple systems (Fig. Further, the relationship goes beyond any particular dysregulated sys- tem: simply counting the number of systems dysregulated predicts the frailty 48 L. Ferrucci phenotype, and the risk increases exponentially with the number of physiological systems involved [31]. The latter is consistent with the fraying of a complex dynam- ical and adaptive system that is essential for a resilient and robust organism. In other terms, we can hypothesize that some fundamental housekeeping mechanism impor- tant for homeostasis and probably related to energetics becomes impaired and diminishes the functionality of important physiological systems at the organismal level. To generate frailty, the level of physiological impairment should be severe enough to impair other downstream compensatory mechanisms towards a down- ward spiral that leads to the clinical presentation of frailty [23], an emergent state which tends be irreversible. The alteration of specic physiologic functions may be involved in the vulnera- bility to adverse outcomes characteristic of frailty. Further, frail women showed a pattern of elevation in glucose- raising hormones and decrease in glucose-lowering hormones not seen in the non-frail [33]. These ndings indicate that the entire physiological network of signals that regulate glucose homeostasis tends to be altered in frailty. Importantly, the dimin- ished regulation of physiological responses to a stressor identies the frail. This suggests that nd- ings of frailty are at the more severe end of dysregulation associated broadly with aging, and that the dysregulation of aging is interpretable, in this case, as disease [4]. The ndings summarized above suggest that some specic cellular alterations might be key to maintaining the robust complex dynamic system of the human organism which is essential for health and resilience. The case of mitochondrial dysfunction described above is just an example of the many potential mechanisms that could be involved. The true underlying mechanisms of biological alteration that lead to frailty, and aging itself, remain unknown. The existence of a common causal pathway between aging and frailty could explain why the prevalence of frailty increases geometrically with aging and why the criteria used to dene the frailty syndrome clinically include dimensions, such as sarcopenia and mobility, that are strongly modied by aging in all individuals and across species.

It is uncertain how progressive but modest muscle loss directly affects the skeleton and in particular the periosteum order 20 mg atorvastatin otc. Targeted therapy with myokine ago- nists or antagonists are soon to be developed for frailty buy 10mg atorvastatin free shipping, yet we know little about the mechanisms at the bone-muscle interface buy atorvastatin 20 mg on line. Understanding the role of neuropeptides at the bone-muscle interface provides another targeted area for research, particularly with aging. Remarkably, Cthrc1 is highly expressed in the pituitary and hypothalamus and circulates in mea- sureable quantities. The new discipline of Geroscience attempts to merge the physiology of aging with an understanding of the pathophysiology of age-related diseases and the delin- eation of the pillars that dene age-associated disorders. We can no longer afford to study major organ systems in isolation with age, and a major thrust for future stud- ies will be in dening regulation of the bone-muscle interface and the downstream consequences that result from impairment in either tissue. Reeve J, Loveridge N (2014) The fragile elderly hip: mechanisms associated with age-related loss of strength and toughness. Seeman E (2013) Age- and menopause-related bone loss compromise cortical and trabecular microstructure. Ferretti C, Mattioli-Belmonte M (2014) Periosteum derived stem cells for regenerative medi- cine proposals: boosting current knowledge. Vokes 1 Clinical Aspects of Osteoporosis Osteoporosis is a generalized skeletal disorder in which decrease in bone mass and deterioration of bone quality lead to bone fragility and increased risk of fracture. Osteoporosis is primarily a disease of the elderly, with more than 70 % of fractures being sustained by those 65 or older [1]. Fragility fractures, also termed osteoporotic fractures or low trauma fractures, occur when falling from a standing height during usual physical activity [3]. Fractures result from an interaction between bone strength and the mechanical force applied to it, usually during a fall. Younger individuals may experience fragility fractures when they have diseases or take medications that have harmful effects on bone. However, bone strength is inuenced by bone quantity (mass) and bone quality, both of which decrease with age, thus leading to an increase in fragility fractures among the elderly. In addition, elders have an increased risk for falls, which further contributes to increased fracture incidence. Because the risk of osteoporotic fractures increases with age [2], this population growth will likely result in increased numbers of fractures and associated health care costs. Osteoporotic fractures result in signicant morbidity, mortality, and reduced quality of life [3]. Hip fractures are associated with increased mortality, loss of independent living, and decline in functional status [4 6]. Osteoporotic fractures accounted for nearly 50 % of hospitalizations among women 75 years and older. Although the hospitalization rates for all other diseases declined during this 11 year observation period, the rate of hospitalization for non-hip fractures actually increased [11 ]. From [2] Hip Radiographic vertebral Wrist 300 200 100 0 400 Women 300 200 100 0 Age(years) 280 J. Fracture risk increases with age in all populations studied [2] and women have approxi- mately twice as many fractures as men although female-to-male ratios vary depend- ing on the skeletal site of fracture and the geographic region (Fig. There are signicant geographic, racial, and ethnic differences in fracture rates, the reasons for which have not been clearly identied. Although some of these differences may be due to under-reporting of fractures in countries with less developed medical care, there are probably true differences in fracture risk that are due to genetic as well as environmental factors. The best-studied geographic differences are for hip fracture rates because those fractures are most likely to be reported accurately (Fig. Age- standardized rates of hip fractures reported from over 60 countries around the world vary by over 200-fold in women and 140-fold in men [12]. Even within the same continent there are sig- nicant differences between countries. Similarly, in the Middle East, the rates of hip fracture are 8 times higher in Iran than in Tunisia (Fig. In contrast to hip fractures, vertebral fractures do not show as much geographic variability. This is particularly true for morphometric (radiographic) vertebral frac- tures, which have similar prevalence in studies from different regions of the world [12 14]. It is likely that genetic differences account for at least some of the observed disparity. Finally, regional differences in fall risk have been reported and may contribute to differences in fracture rates [15, 16 ]. The most peculiar observation regarding geographic differences in fracture rates is a recent nding of hip fracture rates increasing in the east (China) while decreas- ing in the west (Western Europe, North America, and Oceania) [17]. Decreasing fracture rates in the west may be due to increasing body weight (which is usually associated with higher bone mass and also may provide more mechanical cushioning when falling on the hip), decrease in unhealthy behaviors such as smoking, increased use of therapies for osteoporosis, or a cohort effect where later generations had better nutrition in utero and during childhood resulting in higher peak bone mass. Increasing urbanization and employment in sedentary occupations are associated with decreased physical activity, sitting on chairs rather than on the oor, use of western style toilets rather than squatting, all of which may result in decreased muscle strength and higher fall risk. Peak bone mass is accrued during childhood and adolescence and those with low peak bone mass will be at an increased fracture risk later in life, such as is the case with those who develop eating disorders, use medications (glucocorti- coids), or have diseases that affect bone during their formative years. Bone mass in the elderly also depends on the magnitude of bone loss after peak bone mass is achieved; those rates differ between trabecular and cortical bone, and between men and women [18 20]. Women have a more pronounced rate of loss during early menopause [18], which together with lower peak bone mass results in greater risk of fractures observed in elderly women [1, 6].

Partner notification for sexually transmitted diseases: proposed practice guidelines cheap atorvastatin 20mg overnight delivery. The role of sexual partnership networks in the epidemiology of gonorrhea order 10 mg atorvastatin with mastercard, Sex Transm Dis 1997; 24(1):45-56 atorvastatin 20 mg line. This chapter describes how health advisers use interview structure and techniques to minimise resistance and encourage participation. It is important that all members of the multidisciplinary team are supportive of partner notification, and that an efficient internal referral system is in place. The health adviser therefore has a role in ensuring that: All staff understand which patients are to be seen by the health adviser All staff understand the rationale, process and importance of partner notification All staff understand their particular role in facilitating the interview Referrals are worded positively ( It will be helpful for you to see the health adviser is better than I m afraid you ve got to see the health adviser. However, if the patient is unlikely to wait after treatment has been given, it may be useful to offer the interview beforehand. Medication can be given at the same time, to streamline care, if the health adviser is approved to dispense. Some index patients are informed of their diagnosis over the telephone when being recalled for treatment. Arranging for the patient and the regular partner to attend on the same day could reduce the risk of re-infection. The patient can be advised of the need to avoid exposure to untreated partners whilst being reassured that they do not need to notify anybody at this stage. Preliminary discussion about who may need to be notified if an infection were found can be a useful preparation for the patient, and can yield valuable information for the health adviser. It is worth remembering that the patient may not return, particularly if he or she has already received medication. In this situation it is much easier to follow-up partner notification issues by telephone when preliminary face-to-face discussions have already taken place. Interpreters may also be necessary if there are language difficulties (see Ch 36: Working with Interpreters. It is also an opportunity to build the trust, goodwill and rapport necessary for co-operation with partner notification. This could make it difficult for the individual to absorb information given by the doctor or nurse at the time. It is important to clarify the patient s understanding early in the interview because subsequent misconceptions may lead to unnecessary anxieties or reduce compliance with treatment. Furthermore, awareness of routes of transmission and incubation periods is necessary to help identify contacts at risk and prevent re-infection. Knowing the serious consequences of untreated infection may encourage co-operation with partner notification. Questioning style The patient s level of understanding can be assessed most effectively by using open questions that encourage the sharing of details, such as: What has already been explained about. This enables the health adviser to pitch further information and discussion at an appropriate level, without mystifying or patronising the patient. Information tailored to the specific needs of the individual is more likely to be taken on board. It is essential to build rapport at this early stage by personalising the discussion and encouraging dialogue: if the health adviser is doing all the talking, and information is given in standardised form, the patient may disengage; this could make it more difficult to involve the patient in discussion about partners. It is also important to avoid overloading a person with more information than is needed, or can be absorbed, at an emotionally stressful time. If difficulties are identified, discuss with the doctor and/or make alternative arrangements. Motivating the patient to take part is therefore the central challenge of the interview. The following techniques may be useful: Establishing rapport The patient will be more likely to discuss partners if s/he can talk to the health adviser easily. Building good rapport depends upon an ability to show interest, empathy and respect; to listen effectively; to encourage dialogue; to identify shared values and to express approval of positive behaviours or intentions. Negative signals such as boredom, irritation, shock and distaste will inhibit rapport. Ensuring the patient feels in control Fear of what partner notification might entail could discourage some people from discussing partners. This barrier may be overcome by emphasising choice and offering early reassurance that the person will not be forced to do anything against his or her will. It would be unethical to coerce, bully, threaten or blackmail a patient into giving names or notifying partners. Testing resistance The health adviser needs to make an early assessment of the patient s willingness to discuss partners in order to structure and pace the interview appropriately. A useful approach is to ask open questions that allow the patient to say as much or as little, as s/he wishes. These questions allow the index patient to withhold information s/he is not ready to give, without seeming rude. As a result, the patient develops a sense of being in control and the health adviser gains insight into the patient s level of resistance without having created conflict. At this stage, most people will be willing to give a first name and describe the type of relationship (regular, ex, casual). Questions about where and how they met (if recent) are usually non-threatening, and can help to develop a 2 relaxed rapport while giving insight into the patient s social and sexual milieu.