CLASSIFICATION OF DIABETES

Diabetes Mellitus: Introduction

Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Several distinct types of DM exist and are caused by a complex interaction of genetics and environmental factors

Depending on the etiology of the DM, factors contributing to hyperglycemia include

· reduced insulin secretion,

· decreased glucose utilization, and

· increased glucose production.

The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on the individual with diabetes and on the health care system.

In the United States, DM is the leading cause of end-stage renal disease (ESRD), nontraumatic lower extremity amputations, and adult blindness. It also predisposes to cardiovascular diseases. With an increasing incidence worldwide, DM will be a leading cause of morbidity and mortality for the foreseeable future

Classification

DM is classified on the basis of the pathogenic process that leads to hyperglycemia, as opposed to earlier criteria such as age of onset or type of therapy

The two broad categories of DM are designated

· type 1 and

· type 2 (Table 338-1).

Both types of diabetes are preceded by a phase of abnormal glucose homeostasis as the pathogenic processes progresses.

Type 1 diabetes is the result of complete or near-total insulin deficiency.

Type 2 DM is a heterogeneous group of disorders characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Distinct genetic and metabolic defects in insulin action and/or secretion give rise to the common phenotype of hyperglycemia in type 2 DM and have important potential therapeutic implications now that pharmacologic agents are available to target specific metabolic derangements. Type 2 DM is preceded by a period of abnormal glucose homeostasis classified as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).

Table 338-1 Etiologic Classification of Diabetes Mellitus

I. Type 1 diabetes (Beta-cell destruction, usually leading to absolute insulin deficiency) A. Immune-mediated B. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance) III. Other specific types of diabetes A. Genetic defects of Beta-cell function characterized by mutations in: 1. Hepatocyte nuclear transcription factor (HNF) 4 alfa (MODY 1) (MODY-Maturity Onset Diabetes of Young) 2. Glucokinase (MODY 2) 3. HNF-1 alfa (MODY 3) 4. Insulin promoter factor-1 (IPF-1; MODY 4) 5. HNF-1 beta (MODY 5) 6. NeuroD1 (MODY 6) 7. Mitochondrial DNA 8. Subunits of ATP-sensitive potassium channel 9. Proinsulin or insulin conversion B. Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson-Mendenhall syndrome 4. Lipodystrophy syndromes C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl ester lipase D. Endocrinopathies—acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma E. Drug- or chemical-induced—Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, beta-adrenergic agonists, thiazides, phenytoin, alfa-interferon, protease inhibitors, clozapine F. Infections—congenital rubella, cytomegalovirus, coxsackie G. Uncommon forms of immune-mediated diabetes—"stiff-person" syndrome, anti-insulin receptor antibodies H. Other genetic syndromes sometimes associated with diabetes—Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome IV. Gestational diabetes mellitus (GDM)

Two features of the current classification of DM diverge from previous classifications.

First, the terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are obsolete. Since many individuals with type 2 DM eventually require insulin treatment for control of glycemia, the use of the term NIDDM generated considerable confusion.

A second difference is that age is not a criterion in the classification system. Although type 1 DM most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM. Likewise, type 2 DM more typically develops with increasing age but is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.

Other Types of DM

Other etiologies for DM include specific genetic defects in insulin secretion or action, metabolic abnormalities that impair insulin secretion, mitochondrial abnormalities, and a host of conditions that impair glucose tolerance (Table 338-1).

Maturity onset diabetes of the young (MODY) is a subtype of DM characterized by autosomal dominant inheritance, early onset of hyperglycemia (usually <25 years), and impairment in insulin secretion (discussed below).

Mutations in the insulin receptor cause a group of rare disorders characterized by severe insulin resistance.

DM can result from pancreatic exocrine disease when the majority of pancreatic islets are destroyed.

Hormones that antagonize insulin action can also lead to DM. Thus, DM is often a feature of endocrinopathies such as acromegaly and Cushing's disease.

Viral infections have been implicated in pancreatic islet destruction but are an extremely rare cause of DM. A form of acute onset of type 1 diabetes, termed fulminant diabetes, has been noted in Japan and may be related to viral infection of islets.

Gestational Diabetes Mellitus (GDM)

Glucose intolerance may develop during pregnancy. Insulin resistance is related to the metabolic changes of late pregnancy, and the increased insulin requirements may lead to IGT. GDM occurs in ~4% of pregnancies in the United States; most women revert to normal glucose tolerance post-partum but have a substantial risk (30–60%) of developing DM later in life.

Accelerated idioventricular rhythm

Accelerated idioventricular rhythm (AIVR) was first described by Thomas Lewis in 1910.1 AIVR is currently defined as an enhanced ectopic ventricular rhythm with at least 3 consecutive ventricular beats, which is faster than normal intrinsic ventricular escape rhythm (≤40 bpm), but slower than ventricular tachycardia (at least 100-120 bpm).1 Importantly, there is rate overlap between AIVR and some slow ventricular tachycardia. AIVR should not be diagnosed solely based on ventricular rate. Other characteristics of AIVR are helpful for its correct diagnosis (see Differentials).

AIVR is generally a transient rhythm, rarely causing hemodynamic instability and rarely requiring treatment. However, misdiagnosis of AIVR as slow ventricular tachycardia or complete heart block can lead to inappropriate therapies with potential complications. AIVR is often a clue to certain underlying conditions, like myocardial ischemia -reperfusion, digoxin toxicity, and cardiomyopathies.2,3,4

Pathophysiology
In most cases, the mechanism of AIVR appears to be related to the enhanced automaticity in His-Purkinje fibers and/or myocardium5 , sometimes accompanied with vagal excess and decreased sympathetic activity.6 Ischemia, reperfusion, hypoxia, drugs, and electrolyte abnormalities can all accelerate the phase 4 action potential depolarization rates in His-Purkinje fiber and myocardium, leading to faster spontaneous cell depolarization (enhanced automaticity).7 When the enhanced automaticity in His-Purkinje fiber or myocardium surpasses that of sinus node, AIVR manifests as the dominant rhythm of the heart. Sinus bradycardia may facilitate the appearance of AIVR.

Under certain conditions such as acute ischemia and digoxin toxicity, triggered activity has been suggested as the mechanism for AIVR.8
Most AIVRs originate from a single focus. Occasionally, in patients with acute myocardial ischemia and myocarditis, AIVR can originate from multiple foci.9,10 The ventricular rate of AIVR is generally between 40 to 100-120 bpm.

Usually, AIVR is hemodynamically well tolerated due to its slow ventricular rate. It is self-limited and resolves as sinus rate surpasses the rate of AIVR. Rarely, AIVR can degenerate into ventricular tachycardia or ventricular fibrillation. In patients with severe myocardial dysfunction, AIVR may lead to hemodynamic instability due to the loss of AV synchrony or relatively rapid ventricular rate.



AIVR in accute myocardial infarction

Clinically, AIVR has been best studied in patients with acute ST-elevation myocardial infarction (STEMI). In the thrombolysis era, AIVR was noted to be a marker of reperfusion.11 However, not all patients with reopened coronary artery have AIVR. In patients with acute myocardial infarction treated with primary percutaneous coronary intervention, the reported incidence of AIVR varied significantly, raging from 15-50%, depending on methods of monitoring.7,12

Recently, studies in patients with STEMI treated with primary percutaneous coronary intervention support that AIVR is a marker of occluded coronary artery reopening, but is not necessarily a marker for complete reperfusion. In fact, AIVR seems to be associated with more extensive myocardial damage and delayed microvascular reperfusion12 , although the mortality rates are similar in patients with and without AIVR.


Frequency
United States
The true prevalence of AIVR is unknown.

International
The true prevalence of AIVR is unknown.

Mortality/Morbidity
In general, AIVR does not significantly affect the patients’ mortality and morbidity.
In a very small retrospective observation study, AIVR was found to be associated with lower 7 days survival in postresuscitation patients.13


Race
No racial preponderance exists.

Sex
Men and women are equally affected.

Age
No age predilection exists.

Clinical
History
History is helpful for identifying the underlying etiology for AIVR. The presence of the following conditions supports a potential diagnosis of AIVR.



•Most patients with AIVR have chest pain or shortness of breath, symptoms related to myocardial ischemia. They often have recent history of myocardial reperfusion with drugs or coronary artery interventions.
•Some patients with AIVR have chest discomfort, shortness of breath, peripheral edema, cyanosis, clubbing, symptoms related to cardiomyopathy, myocarditis, and congenital heart diseases.
•Occasionally, patients with AIVR have history of using digoxin, some anesthetic agents, or illicit drugs such as cocaine.
•Rarely, AIVR can occur in people without apparent heart disease and no identifiable triggers.

Physical
There are no specific physical findings for AIVR. The following physical signs may be present.



•Slow (<55 bpm) or fast (>100 bpm) pulse rate.
•Variable heart sound intensity and cannon A waves related to atrioventricular dissociation.
•Some irregularity of heart rate/pulse rate due to competing sinus rhythm and AIVR.
•Rarely, hypotension related to either AV asynchrony or relatively rapid ventricular heart rate during AIVR.

Causes
The AIVR can occur in people with and without apparent heart diseases.14 The most common cause of AIVR is myocardial ischemia-reperfusion. Other causes include the following:

•Buerger disease15 •Congenital heart disease16 •Dilated cardimyopathy4 •Myocarditis10 •Drugs: Digoxin toxicity3 , cocaine toxicity17 , and various anesthesia agents18,19 •Electrolyte abnormality
•Postresuscitation13

Blood Test for Emphysema

Endothelial microparticles (EMPs) in plasma may be an early marker for emphysema, according to a study published online March 11 in the American Journal of Respiratory and Critical Care Medicine.

Alveoli enable gas exchange between air and blood through the alveolar epithelium, interstitial connective tissue, and capillary endothelium. The stress of chronic smoking can destroy alveoli, resulting in emphysema. Increasing evidence suggests that apoptosis in alveolar endothelial cells is a key element in the pathogenesis of lung damage.

EMPs are small vesicles that are released from activated or apoptotic endothelial cells, and plasma levels are elevated in vascular disorders. The researchers hypothesized that in smokers, EMP levels in plasma could be used as a marker for emphysema.

Cynthia Gordon, PhD, from the Department of Genetic Medicine, and Ronald C. Crystal, MD, senior author and chief, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York City, and colleagues assessed lung health using pulmonary function tests, including total lung capacity (DLCO) and normal spirometry, as well as chest X-ray. Smoking status was determined by urine nicotine and cotinine. The researchers classified EMP levels (CD42b−CD31+ microparticles) as activated or apoptotic.

The study included an initial cohort of 92 healthy nonsmokers (defined by pulmonary function test), healthy smokers, and smokers with early signs of lung destruction (normal spirometry, low DLCO). The researchers then tested 2 prospective cohorts: One group was similar to the first, and another was HIV1-positive.

Compared with healthy nonsmokers, there was a slight increase in EMP levels in healthy smokers with normal spirometry and normal DLCO, as well as symptomatic smokers (P < 10−4 for both comparisons). The researchers found no differences between healthy smokers and symptomatic smokers (P > .4).

However, EMP levels were significantly higher in healthy smokers with normal spirometry but low DLCO (P < 10−4 compared with healthy nonsmokers; P < 10−3 compared with healthy smokers). EMP levels in healthy nonsmokers were between 0 and 500 EMP/μL. In 50% of healthy smokers, EMP levels were above the normal range seen in healthy nonsmokers. EMP levels were above the range of healthy smokers in 95% of healthy smokers with normal spirometry and low DLCO: 52% were distributed between 500 and 1250 EMP/μL, and 43% had levels higher than1250 EMP/μL.

Ratios of CD62+/CD31+ were reduced (P < 10−4), and CD42b−CD31+ annexin V+ EMPs were elevated (P < 10−4). These results suggest involvement of endothelial apoptosis.

Most elevated EMPs were positive for angiotensin converting enzyme, a sign that they might originate from pulmonary capillaries. The data from the initial cohort were confirmed in both prospective cohorts.

The results suggest that EMP levels could be a useful means of screening for early stages of emphysema without resorting to radiation exposure that is associated with chest high-resolution computed tomography.

"Interestingly, the smokers with the highest plasma EMP levels are healthy smokers with normal spirometry and isolated low DLCO. This suggests that the vascular-based contributions to the pathogenesis of emphysema may contribute to the early development of emphysema, and may identify a point in time where intervention with smoking cessation therapy may prevent the irreversible lung destruction associated with the development of (chronic obstructive pulmonary disease)," the authors write.

The study was supported in part by grant funding from the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Fall of statues on Tank Bund

Statues on tank bund fell. Statues are of the ones, who were stalwarts, who were never petty or parochial nor had any viciousness of Seemandhra leadership. Never should we compare them with the crony capitalists and the Andhra ruling midgets. This destruction, in a way, slights their contribution; but these statues are caught up in the cross-fire between the indolent and intransigent state/central governments and the relentless Telanganites. These are destroyed out of anger against Andhra rulers rather than anger on them per se.

But I must also say that there is another side to it as well; more about flesh, blood and life of struggling Telangana people. A civilised world should be more worried about people than the statues.

The Andhra media is shouting hoarse describing the agitators as lumpen disturbing the order. It is similar to white right winger press crying hoarse when blacks revolted in America and South Africa.

Setting the illegality of the act aside and wishing that it would not happen again, let us look at the ones who installed them on the bund. By reading installers and their minds, we get the social construct and the deeper meaning behind the rise and fall of the statues. Let us look at it as social scientists and not as advocates of one cause or the other.

There is a social agenda in erecting them in Hyderabad. When British came to India they brought English language first. When laissez-faire (free market) enters in the name of reforms, coca cola heralds it. Europeans (Spanish) took their religious icons to subjugate after conquering Latin America.

Similarly, for cultural enslavement, Andhra elite have brought in these icons as cultural weaponry to dismiss our very own identity.

Tank bund was built by Hussain, a Sufi engineer 200 hundred years ago. NTR/TDP changed the very character of the region by wholesale importation of the Andhra culture, cultural and historical icons. Historically important Husain’s tank bund was defaced. This ‘period’ structure was distorted. It is an assault on native Hyderabadi and Telangana culture, as Shilparamam is an onslaught on NUMAISH and telangana cultural ethos. Victorious roman conquerors and British conquerors put their statues on the land of the vanquished in a similar way. Jagan wants to seal his grip on the people by YSR statues, like land mines are planted so that no one moves away from him. It is not about Krishna deveraya in that statue. He was great by himself. But there is also an Andhra social and political order in it. There is thought control in it. There is suzerainty and Andhra cultural hegemony in it. NTR’s carving out of the above statue in his own image tells it all, that it is symbolic of the Andhra ruling elite power over the natives.

By submerging it in Husain-sagar waters Telanganites have symbolically washed themselves of this. It is declaring their cultural independence and with their collective unconscious they have declared that they are a separate state and culture and they have nothing in common culturally with Andhra.

If one is non judgemental, in socio psychological perspective, this is the only explanation. Commoners of Andhra should understand the dynamics of statue installations and see the things through.

August Comte, father of sociology, says that society is an organism by itself and not sum total of individuals. On the day of million march the primal force of Telangana was expressed. It would be a blessing, if the social scientists of India study this phenomenon to understand the nation and guide in its policy and planning, instead of leaving the nation in the hands of blinkered bureaucrats and petty professional self seeking politicians.

PS: For better understanding of statues read Carl Jung’s books on symbolism, Books on semiotics and symbolism and also a classic Book fore worded by jean paul satre “ The colonizer and the colonized” written by Albert Memmi

Images of gaddafi

INR -- INTERNATIONAL NORMALIZED RATIO

The current method for monitoring vitamin K antagonist (AVK) anticoagulant therapy is the international normalized ratio (INR) that provides consistency and standardization for the prothrombin time (PT) assay value. Even after the standardization of the INR, inaccuracies of this value have still been reported. To make the INR even more accurate, better local assessments of INR parameters are becoming available. These new methods use plasmas with certified INR values to locally verify and, if necessary, recalculate the international sensitivity index (ISI) for the local laboratory's reagent and instrument system. This CE Update will discuss the concepts of local verification and calibration to better define the manufacturer's assigned ISI value, thus reporting more accurate INR results.
Introduction

Our understanding of the basic science and clinical issues surrounding hemostasis has skyrocketed within the last 10 to 15 years. These advances have: 1) established better treatment for patients at risk for hemorrhage or thrombosis; 2) identified new hereditary coagulation disorders; and 3) provided mechanism(s) for clinical hemostatic diseases. With this in mind, clinicians have begun to put more demand on the coagulation laboratory. The laboratory has had to keep pace by developing new coagulation tests and better standardizing those tests already in use. The cornerstones of clinical coagulation testing are the prothrombin time and/or international normalized ratio (PT/INR) and the activated partial thromboplastin time (aPTT) for identifying and monitoring clinical coagulation disorders and therapeutics. Manufacturers have varied the sensitivities of these reagents to more easily assess this variety of clinical conditions. It now has become important for each laboratory to evaluate the commercial reagents to determine the most appropriate one for their clinical needs. The criteria for how reagents should be evaluated include: sensitivity for intended use, compatibility with instrumentation, number of assays performed each day, and cost.

In this CE Update, we discuss: 1) how to determine the INR; 2) how to locally verify and calibrate the PT reagent for more accurate INR values; and 3) the clinical use of the INR for monitoring anti-vitamin K anticoagulant therapy.

Oral Anticoagulant Therapy Monitoring Using the PT/INR

Anticoagulant therapy is used to treat and/or prevent both arterial and venous thrombosis.[1] Currently in the United States, IV anticoagulants (heparin and direct thrombin inhibitors [DTI]) are administered to inhibit further clot formation. The oral drug Coumadin (or warfarin) is given for long-term prevention of new thrombus formation; however, it is an indirect acting drug requiring 3 to 5 days to reach therapeutic effectiveness.[1] Warfarin derivatives are the standard therapy worldwide.[3] Annually, there are more than 21 million prescriptions written in the United States.[3] Warfarin derivatives (generally known as vitamin K antagonists [AVK]) act by inhibiting the vitamin K-associated post-translational modifications of the vitamin K-dependent clotting factors.[1] Unfortunately, warfarin has a very narrow therapeutic window and dosing responses vary between individuals of up to 10-fold and 2–3 fold within an individual caused by changes in medications, diet, or health status.[4] Warfarin is the second most common mismanaged therapeutic drug, requiring more than 40,000 emergency room visits per year and about $40 million to $60 million in additional medical costs per year.[4] The therapeutic window for oral anticoagulant drugs is very narrow; therefore the accuracy for monitoring these drugs' INR is essential since inadequate dosing increases thrombotic risk and excessive doses significantly increase the bleeding risk.

Monitoring AVK anticoagulant therapy using the INR is in its final phases of a slow transition in the United States compared with most European countries routinely using the INR value. The INR is a mathematically transformed or calculated value converting the PT in seconds to a standard ratio value.[1,2] The INR theoretically eliminates the differences in sensitivity of various PT reagents. However, within individual coagulation laboratories, the INR may not eliminate all of the variables of the PT assay, requiring local adjustment to make the reagent's INR more accurate with a specific instrument within the local environment.

Sensitivity to AVK anticoagulant therapy using the INR is the most important consideration when choosing a PT reagent.[2] A single plasma sample from an anticoagulated patient may give clinically significant different PT clotting times when tested against a variety of PT reagents; theoretically the INR value should be the same. It is important to pick a reagent with clotting times based on a scientific rationale rather than one with clotting times "familiar" to your clinicians.

Concept of the INR

The differences in PT results are dependent upon the composition of the PT reagent.[2] The reagent is composed of thromboplastin (tissue factor and phospholipid), extracted from a variety of sources (human and rabbit are the most common). Historically, each laboratory extracted thromboplastin from the human brain, but as commercial reagents were made available the major tissue source became rabbit brain. This is still used in a number of commercial reagents today. Now manufacturers are again starting to make reagents using human thromboplastin (placenta and recombinant).[5] The therapeutic responsiveness of the PT reagent is different depending on the source and composition of the thromboplastin.[1]

When the PT assay was first used to monitor AVK therapy, most providers based their therapeutic decisions on PT values in the range of 1.5 to 2.5 times the control value. However, now with the production of different reagent sensitivities with new sources of thromboplastin, the 1.5 to 2.5 range is not an accurate reflection of therapeutic anticoagulation.

In 1983, the World Health Organization (WHO) adopted a method to establish consistency of the PT value for patients on AVK.[6] This mathematical expression of the PT value is termed INR.[2] The INR calculation is based on the international sensitivity index (ISI) value specific to each PT reagent[1] and is valid only for stable AVK anticoagulant therapy and only up to an INR of 4.5.[1,2] An ISI value is determined for each thromboplastin reagent by comparing the responsiveness of the PT reagent with a WHO international reference preparation (IRP).[6,7]

Theoretically, the INR of a patient receiving AVK therapy would be the same regardless of the reagent and instrument used or in which the laboratory the sample was tested.[1,2,6] The specific PT reagent ISI value is determined using a WHO standard protocol comparing both PT reagent and IRP values from 20 normal individuals and 60 stable AVK individuals.[6,7] The slope of the regression calculation (orthogonal) of the 2 values is the ISI value of the unknown reagent.[2,6] Variation in the assigned ISI calculated by the manufacturer can vary +5%. This type of error can contribute to clinically different INR results.[6]

The INR is calculated using the assigned ISI value and the mean normal PT (MNPT) value (Figure 1).[2] The MNPT is determined by the laboratory using 20 to 40 (40 being optimal) healthy individuals reflecting the laboratory's patient base.[2] The mean is calculated using the geometric mean rather than the arithmetic mean.[2,8] The geometric mean assumes a non-normally distributed set of values. Geometric mean calculation transforms the data to log values before determining the mean. The arithmetic mean assumes a normally distributed normal population. The use of the arithmetic mean instead of the geometric mean can lead to a clinically significant difference in the MNPT and INR value.

Accuracy of the Manufacturer-assigned ISI

The ISI value reported in the PT reagent package insert has been determined by the manufacturer using the WHO standard method.[6] However, there are potential sources of error associated with this assigned ISI value (Table 1).[2,9] When these errors are compounded, a significant difference in the reported INR value and the true INR value can be found. These types of errors must be reduced by each laboratory. A manufacturer usually reports 2 ISI values for any PT reagent.[9,10] The first is the "generic ISI" and is determined for instruments using the same end-point detection method but not a specific instrument. This ISI must be used when the reagent of 1 manufacturer is used on an instrument made by a second manufacturer. However, the accuracy of this ISI value for the reagent-instrument system may be of clinical concern. The second reported ISI value is specific to the PT reagent and instrument combination ("instrument-specific ISI"). In several studies, the accuracy of INR results was enhanced when instrument-specific ISI was used instead of the generic ISI.[10,11] The range of discrepancy between the manufacturer-derived ISI and the local validated ISI can vary between +15% and 30%, thus making clinically significant differences in the INR value. Therefore the ISI value should be verified, especially in laboratories using generic ISI values. If the local validated ISI value is significantly different from the reported ISI, then the ISI must be determined locally.
i Initially, the ISI is assigned by the manufacturer based on the WHO ISI IRP. The yellow-shaded area shows the validation of the ISI at the local laboratory level. Every new reagent lot must at least be verified by the local laboratory. For proper local verification, the locally determined ISI must agree within 15% to be acceptable. If greater than 15%, then the ISI must be locally calibrated and re-verified.
Initially, the ISI is assigned by the manufacturer based on the WHO ISI IRP. The yellow-shaded area shows the validation of the ISI at the local laboratory level. Every new reagent lot must at least be verified by the local laboratory. For proper local verification, the locally determined ISI must agree within 15% to be acceptable. If greater than 15%, then the ISI must be locally calibrated and re-verified.

The definition of verification is "the confirmation through the provision of objective evidence that the specified requirements have been fulfilled" (within a pre-established set of criteria).[2,9] Verification is usually a 1-time process completed to confirm test performance before the INR system is used for patient testing. If significant differences in the INR test system are present, then calibration is performed followed by repeating the verification process. Calibration is "a set of operations establishing, under specified conditions, the relationship between true quantitative values indicated by the measuring test system."[9] For the INR test system, if the verification is not different from the reported ISI value, then calibration does not need to be performed. If significant differences (>15%) are found between the ISI values, then calibration of the ISI is required, followed by re-verification to ensure INR accuracy.[9,10]

The local verification and calibration (if necessary) of the ISI is performed with FDA-approved kits that provide all of the certified plasmas, the procedure, and data calculations. This ISI verification can be performed by any technologist or supervisor in all laboratories performing patient PT/INR results. The procedure usually takes 3 days of performing PT/INR testing on the certified plasmas and about 20 to 30 minutes of calculations that can be performed either by the manufacturer of the kit or through the manufacturer's Web-based program. This local verification and calibration procedure should be included in all new reagent and/or instrument contracts, cost per test, and cost per reportable result contracts. International sensitivity index verification and calibration (if necessary) should be performed (as part of the contract) at installation of the instrument, when starting a new reagent, for lot changes, and after instrument repair or internal or external QC issues. The procedure itself is relatively straightforward and has safeguards built in to provide a more accurate local ISI with clinically correct INR values.

Verification of the ISI in the Local Laboratory

The laboratory should not accept the initial ISI value assigned by the manufacturer as the local laboratory's working parameters, and conditions may significantly affect the patient's calculated INR results. With this in mind, it becomes the laboratory's responsibility to verify the validity of the ISI (Table 2).[9]

Two basic methods for local verification of ISI are available.[9] The first is the impractical method of using the WHO standard protocol. It is not feasible since it requires fresh plasma samples, an IRP, and the ability to perform the labor-intensive tilt tube assays. The second, more practical method uses certified plasmas to determine the ISI. These plasmas are purchased from the manufacturer of the reagent system or from an independent vendor especially for the reagent system. The verification kit should be part of the validation process for new installations, new reagents, and changes in reagents lots (Table 2). The procedure for verification per the provided instructions must be followed. The verification kit should be FDA approved following the established guidelines of Clinical and Laboratory Standards Institute (CLSI).[2,9] In brief, the procedure requires a minimum of 3 certified plasmas in the range of 1.5 INR to 4.5 INR. These plasmas can be lyophilized or frozen. The certified plasmas are evaluated exactly as patient samples. The PT and INR values are determined for each plasma tested in duplicate once per day for 3 days. The INR values obtained are compared to the assigned INR of the certified plasma. If these values compare within 15%,[2,9] then the ISI has been verified, and the PT reagent can be used with the assigned ISI value. If the verification procedure fails (INR values >15%), then a local calibration must be performed (see below).[2,9] Table 3 and Table 4 show examples of a passing verification and a failing verification, respectively. In Table 3, the mean INR values are within 15% of the assigned value for all 3 plasmas, the ISI is verified, and the assigned ISI value is correct. In Table 4, the highest INR certified plasma failed verification (>15%), so the assigned ISI cannot be used, and local calibration must be performed to determine a local valid ISI.

Local System Calibration of the ISI for the Local Laboratory

If verification fails, then the laboratory must not report patient results until the correct ISI is determined.[9] The laboratory must establish that: 1) instrument(s) was(were) working properly; 2) reagents were reconstituted correctly; 3) MNPT was determined accurately (geometric mean); and 4) no clerical or mathematical errors were made. If these are correct, then proceed to local calibration of the ISI.

Local calibration can be accurately determined using 2 methods: 1) calculating a local ISI, or 2) generating a PT/INR calibration line on which PT values are read as the INR value.[9] Whichever method is used, the calibration kit must be FDA approved. The certified plasmas must be compatible for the reagents and instruments used in the laboratory.[9] As an example, if the laboratory is using recombinant human thromboplastin, the calibration kit should be certified for use with human thromboplastin. The local ISI calibration procedure is a modification of the WHO protocol.[8,9] The PT values for each of the certified plasmas are determined using the local PT reagent and instrument. The local PT values are plotted against the assigned PT values of the certified plasma and an orthogonal regression line is calculated. The ISI calibration is considered valid if the slope has a CV of <3%.[9] The resulting slope of the line is the correct local ISI.[8,9] The procedure is similar to the verification method. The certified plasmas must be run in duplicate for at least 3 days to account for variation due to random error.

The necessary number of certified plasmas depends on a variety of factors, such as the source of the plasma (immuno-depleted or treated individual), type of plasma (frozen or lyophilized), single donor or multiple donors, and the IRP used for the certification of the plasma.[9] The manufacturer of the calibration kit in consultation with and approval by the FDA has determined the minimum number of certified plasmas needed. Most manufacturers will help the local laboratory determine the ISI value through either the Internet or as a "send-in" service. The manufacturer must provide detailed documentation of these ISI determination calculations for accreditation documentation. Of important note, after local calibration, the ISI must again be re-validated to confirm that the calibration and changed ISI are truly correct.

The second method to determine the local ISI is the direct INR calibration line, which is independent of the ISI value and the MNPT.[9] A disadvantage of this method is that many laboratory information systems and/or instrument systems are not programmed for calculating the INR by this method. Using this protocol, the PT values of certified plasmas are determined using the laboratory's system, also testing for 3 days in duplicate. The PT values determined locally are plotted on the y axis against the assigned certified plasma INR values (x axis). Using orthogonal regression, the best fit line is plotted. For a valid calibration curve, the r2 value of the regression line must be >0.95. The patient's INR is mathematically or graphically determined from this calibration line. Significant changes in the reagent-instrument system, such as lot changes, instrumentation repair, QC validity changes, and proficiency testing problems will all require establishing the INR calibration line and recertification

The INR is an important clinical tool for monitoring AVK therapy. The introduction of the INR has added several orders of magnitude of accuracy to anticoagulant monitoring. Still, more accuracy is needed to further reduce clinical problems associated with anticoagulation. To this end, the development of local reagent accuracy through the use of local ISI verification and ISI calibration adds even greater confidence to the correct reporting of INR values. The methods for ISI verification and the local ISI calibrations are just beginning to be used in the United States. The College of American Pathologists (CAP) Laboratory Accreditation program checklist (HEM.23220) requires documentation that the ISI is validated. The local ISI verification and calibration method fulfills that requirement. The methods may appear complex and the mathematics difficult, but kit manufacturers should assist with these calculations. Local determination of the ISI will significantly increase clinical confidence in oral anticoagulant monitoring.

WORK SMARTER NOT HARDER

1) Aim for effectiveness, not neatness. Neatness as an end in itself can even be risky: Putting things away just to clear off your desk can cause you to lose or forget them.


2) Clutter is rarely caused by insufficient space or time. The culprit is usually indecisiveness. So be selective about what you bring into your office and home. If you know what you value and what your goals are, being selective is not hard.

3) Have a place for everything. Open your mail in the same place everyday so it doesn't get strewn everywhere. Put unpaid bills together, separate from paid bills. Store all office supplies together to prevent duplicate purchases.

4) Do not use your entire desk surface as a giant In-box. Instead, determine your next action on every piece of paper and file accordingly. Tasks to be done soon (phone calls to make, questions to ask business associates) and current projects go into your "Action Files," which should not be mixed with Reference Files. Action Files must be kept close at hand.

5) That maxim, "Handle each piece of paper only once," is too extreme to be realistic. But it contains a grain of truth. Do try to take the next action that's required each time you handle a piece of paper. How about that seminar advertisement you left on your desk, as a reminder to decide whether to sign up -- you know, that paper you've shuffled ten times today already? Either call right now to get the information you need, or make a note in your appointment book to call later. Then you're that much closer to being done with it.

6) Don't save paper that you're not willing to spend time filing. If you don't file it properly, you either will forget you have it, or you won't be able to find it when you need it. It does you no good, and the result is the same as if you'd thrown it out in the first place. If you are set up to scan information into your computer, be selective. If you cannot imagine a specific situation when you'd need to refer to the information again, don't scan it. Most of us save a great deal of paper we'll never use again.

7) Use your day planner to help clear your desk. If you avoid filing things out of fear you'll forget to follow up, jot down a reminder in your appointment book or computer software.

8) Often we are own worst enemies, interrupting ourselves by jumping from one half-finished task to another. Stop doing "the desktop shuffle" - moving papers aimlessly around on your desk. Every time you handle an item, take an action towards completing it.

9) Learn to say "No." You could live to be a hundred and still not have time to do everything you want---that's the curse and blessing of being intelligent and having high expectations of yourself. The good news is you can choose what to focus on. You have far more freedom than you may realize. Aside from obligations like caring for vulnerable family members and paying taxes, very little of what you "have" to do is morally or legally mandatory. Review everything in your life and ask, "What's the worst that can happen if I stopped doing this?" Saying "No" sometimes is the only way you can "Yes" to what you really value.

10) Beware of stuff. The more stuff you have, the more you must find a place to put, and the more you'll have to clean, repair, and eventually replace. Stop buying things you don't really need just because they're on sale. You can always get more stuff, and you can always get more money. But you can never get more time.

11) Do buy more of things you use continually. Frantic last-minute shopping trips can be averted by purchasing things before your supply runs out.

12) Schedule appointments with yourself to get things done. Appointments aren't only for business lunches or seeing your doctor. They're for you, too. Commit to spending time on the things you keep "not getting around to." This works for everything -- from taking the next step on that back-burner project, to making sure you get yourself to the gym twice a week.

13) Beware of perfectionism. Most routine work doesn't need to be done perfectly. Ask yourself -- Is your effort disproportionate to the value of the task? Will other, more important projects be delayed as a result? Can you reduce the frequency or level of detail of this task?

Haiti's Cholera Outbreak

February 11, 2011 (Vienna, Austria) — The cholera epidemic that developed in Haiti became a multifocal event as it spread throughout South America, due to factors such as air travel and immigration that act as "vectors" of infectious disease, a new report suggests.

The findings were reported by Jennifer Malaty, from the Georgetown University Medical Center, in Arlington, Virginia, here at the IMED 2011: International Meeting on Emerging Diseases and Surveillance.

"Cholera's sudden emergence in the Americas and the Caribbean after 100 years of silence was a tragic reminder of how mobile pathogens have become," Ms. Malaty told Medscape Medical News. "The [Haitian] population also had the disadvantage of being immunologically naïve," she said.

According to the researchers, local laboratories confirmed that the form of cholera detected in Haiti is commonly found in South Asia and Africa, and that the outbreak originated from contaminated water near a facility that housed Nepalese troops.

Subsequent to the cholera outbreak in Haiti, the migration of humans led to sporadic clusters of cholera cases in new and previously unaffected regions.

By November 16, 2009, the Dominican Republic detected its first case of cholera in a migrant worker who had returned home from Haiti after the outbreak.

Suspected cases of cholera have since been reported in Bolivia, Brazil, Chile, Colombia, Nicaragua, Panama, Peru, and Venezuela. Confirmed imported cases have been reported in Florida. The CDC has reported 13 suspected imported cases, with 5 confirmed as of December 2010.

Based on models of previous cholera spread, the researchers estimate that up to 200,000 cases could arise in the Caribbean in the next 18 months.

"International bonds, the ease of direct flights, and better medical and professional opportunities abroad [compared with in Haiti] have turned the cholera outbreak into a multifocal disease event," the researchers conclude.

According to Ms. Malaty, the study of emerging outbreaks must have both a microscope and a macroscope. Although there is value in case counts and case fatality ratios, diseases are never bound by national borders, she said.

"Biosurveillance is a multidisciplinary field that is influenced by culture, language, history, economics, and sadly, politics," she added. "Monitoring of diseases must be flexible, both in sources of data and in analysis."

Scott F. Dowell, MD, MPH, from the CDC's Division of Global Disease Detection and Emergency Response, and colleagues from the CDC recently authored a Perspective in the New England Journal of Medicine (2011;364:300-301). According to Dr. Dowell and colleagues, when cholera struck in mid-October, it "moved easily from sewage to drinking water sources and spread within 2 months to all departments (provinces) of the country, sickening more than 170,000 people and killing more than 3,600 by December 31, 2010."

"Cholera spreads easily across international borders, and it is likely that occasional importations to other countries in the region will continue," Dr. Dowell told Medscape Medical News. "Fortunately, it is unlikely to cause epidemic disease in places like Florida, where clean water and improved sanitation systems are in place."

He added that "clinicians in the region should remain aware of the possibility of importation, take careful travel histories, recognize the clinical features of cholera and the potential for rapid and dangerous dehydration, and be prepared to treat individual cases and report them to the local public health authorities."

According to the CDC, rehydration is the cornerstone of treatment for cholera. Oral rehydration salts and, when necessary, intravenous fluids and electrolytes, if administered in a timely manner and in adequate volumes, will reduce fatalities to well below 1%. In addition, antibiotics, indicated in severe cases, reduce fluid requirements and duration of illness.

Haiti's Cholera Outbreak

February 11, 2011 (Vienna, Austria) — The cholera epidemic that developed in Haiti became a multifocal event as it spread throughout South America, due to factors such as air travel and immigration that act as "vectors" of infectious disease, a new report suggests.

The findings were reported by Jennifer Malaty, from the Georgetown University Medical Center, in Arlington, Virginia, here at the IMED 2011: International Meeting on Emerging Diseases and Surveillance.

"Cholera's sudden emergence in the Americas and the Caribbean after 100 years of silence was a tragic reminder of how mobile pathogens have become," Ms. Malaty told Medscape Medical News. "The [Haitian] population also had the disadvantage of being immunologically naïve," she said.

According to the researchers, local laboratories confirmed that the form of cholera detected in Haiti is commonly found in South Asia and Africa, and that the outbreak originated from contaminated water near a facility that housed Nepalese troops.

Subsequent to the cholera outbreak in Haiti, the migration of humans led to sporadic clusters of cholera cases in new and previously unaffected regions.

By November 16, 2009, the Dominican Republic detected its first case of cholera in a migrant worker who had returned home from Haiti after the outbreak.

Suspected cases of cholera have since been reported in Bolivia, Brazil, Chile, Colombia, Nicaragua, Panama, Peru, and Venezuela. Confirmed imported cases have been reported in Florida. The CDC has reported 13 suspected imported cases, with 5 confirmed as of December 2010.

Based on models of previous cholera spread, the researchers estimate that up to 200,000 cases could arise in the Caribbean in the next 18 months.

"International bonds, the ease of direct flights, and better medical and professional opportunities abroad [compared with in Haiti] have turned the cholera outbreak into a multifocal disease event," the researchers conclude.

According to Ms. Malaty, the study of emerging outbreaks must have both a microscope and a macroscope. Although there is value in case counts and case fatality ratios, diseases are never bound by national borders, she said.

"Biosurveillance is a multidisciplinary field that is influenced by culture, language, history, economics, and sadly, politics," she added. "Monitoring of diseases must be flexible, both in sources of data and in analysis."

Scott F. Dowell, MD, MPH, from the CDC's Division of Global Disease Detection and Emergency Response, and colleagues from the CDC recently authored a Perspective in the New England Journal of Medicine (2011;364:300-301). According to Dr. Dowell and colleagues, when cholera struck in mid-October, it "moved easily from sewage to drinking water sources and spread within 2 months to all departments (provinces) of the country, sickening more than 170,000 people and killing more than 3,600 by December 31, 2010."

"Cholera spreads easily across international borders, and it is likely that occasional importations to other countries in the region will continue," Dr. Dowell told Medscape Medical News. "Fortunately, it is unlikely to cause epidemic disease in places like Florida, where clean water and improved sanitation systems are in place."

He added that "clinicians in the region should remain aware of the possibility of importation, take careful travel histories, recognize the clinical features of cholera and the potential for rapid and dangerous dehydration, and be prepared to treat individual cases and report them to the local public health authorities."

According to the CDC, rehydration is the cornerstone of treatment for cholera. Oral rehydration salts and, when necessary, intravenous fluids and electrolytes, if administered in a timely manner and in adequate volumes, will reduce fatalities to well below 1%. In addition, antibiotics, indicated in severe cases, reduce fluid requirements and duration of illness.

Reason for Egypt Revolution

Egypt’s internet is severe pain a critical disruption, as a grass-roots critique mutation prepares for infamous rallies captious the ouster of President Hosni Mubarak after perceptibly thirty years in power.

a infamous operate provider for Egypt, Italy-based Seabone, reported early Friday that there was no internet traffic going into or out of the commonwealth after 12.30am inner time.

Associated Press reporters in Cairo were also experiencing outages. Messages abounded on Facebook as good as Twitter from users outside of the country.

Egypt has been besieged by its biggest protests in years this week as the shred sees incentive in transport protests that degraded the organisation in Tunisia.

Social networking sites have been infamous to pulling the protests.

The country’s largest discord movement, the Muslim Brotherhood, said it would knowledge in Friday’s protests, in a skip from the watchful ensue it took towards the protests that started on Tuesday.

at smallest twenty members of the Muslim Brotherhood were arrested overnight Friday, its warn Abdelmoneim Abdel Maqsoud told AFP.

Among those arrested at their homes were five former members of legislature as good as five members of the done during home bureau, whose best known leaders are Essam El-Eriane as good as Mohammed Moursi.

The country’s streamer dissident, Nobel Laureate Mohamed ElBaradei, also said he would take prejudiced in the protests after impending from a revisit to Vienna.

“It is a infamous time in the reason up of Egypt. you have come to knowledge with the Egyptian people,” ElBaradei, a outspoken bury of Mubarak, said before to withdrawal Cairo airport.

Earlier, in Vienna, he told reporters he was ready to “lead the transition” in Egypt if asked.

Fuelled by madness over financial deprivation, the reeling roiling Egypt threatens to criticize the country’s trading enlargement as good as further mangle the government.

Egypt’s routine has warned that it will take “decisive measures” against anti-government protesters who plan further demonstrations.

The third loyal day of protests sent the collection marketplace plummeting Thursday, rattled investors as good as clouding what the organisation has portrayed as its crowing legacy: receiving moody GDP as good as a surging in siege section led by a structure the total crash as good as vibrant, obviously recession-proof banks.

Many say the fruits of enlargement in this formerly insubordinate control to buy have been funnelled almost entirely to a politically successive elite, withdrawal normal Egyptians surrounding by unattainable black of resources such as oppulance housing as good as price elections as they assault to find jobs, recompense each day bills as good as find affordable housing.

The 10.5 percent bearing in the marketplace left the market’s year-to-date balderdash at over twenty percent as good as traders warned that trading repairs could distend if vast protests manifest Friday, as in danger by the opposition.

“Tomorrow will be a trigger,” said Mostafa Abdel-Aziz, a profession with the Cairo-based investment bank, Beltone Financial. “If things pass quietly, there should be a technical rebound” when the marketplace reopens on Sunday.

“But you do not think the exactly perspective will be reversed,” he said.

Egypt’s government jubilee said it was ready for a sermon with the open yet charity no concessions to chateau last for a restraint to prevalent wretchedness as good as done during home shift listened in the country’s largest anti-government protests in years.

Safwat El-Sherif, the cupboard partial of entire of the National Democratic Party as good as a longtime playmate of Mubarak, was dismissive of the protesters at the primary headlines contention by a more aged government jubilee figure since the protests began.

“We are positive of our capacity to listen. The NDP is ready for a sermon with the public, lady as good as certified parties,” he said. `”But democracy has its manners as good as process. The minority does not force its will on the majority.”

The 82-year-old Mubarak has not been seen in open or listened from since the protests began Tuesday with tens of thousands marching in Cairo as good as a twine of other cities.

Mubarak has not said yet possibly he will mountain for an one more six-year reign as trainer in elections this year. he has never allocated a intermediary as good as is theory to be showering his son Gamal to achieve him in spite of popular opposition. according to leaked U.S. memos, paternal duration also does not confront with the defeat of the comprehensive military.

The sustainability of most of the government’s pass unknown income sources – tourism, the Suez Canal, as good as unknown investment – hinges on investors’ notice of restraint in this commonwealth of 80 million, the Arab world’s most populous.

It’s an design the organisation has smoothly attempted to gift for years, looking to founder a insubordinate leave characterised by inefficiency, a judicial bureaucracy as good as waste, as good as fanciful moves toward a free-market control to buy in the early 1980s.

The budding dispense as good as the financial dispense “have undertaken outrageous reforms, yet they’re confusing to mislay some-more than 50 years of trading damage,” said Angus Blair, Beltone’s control of research, said.

following a promissory note difficulty in the late 1990s, the organisation enacted umbrella changes destined at softened determining the financial section as good as boosting in siege section development. It set up a credit bureau, a debt law was inspected as good as unstinting housing communities sprang up around the background of brisk Cairo.

The enlargement rate shot up from almost 4.1 percent in 2004 to almost 7.2 percent in 2008 before to the person from earth financial meltdown sent the star control to buy crashing.

even then, Egypt fared well. While many of the West was in a recession, Egypt’s gross done during home product came in at 4.7 percent in 2009 as good as 5.15 percent in 2010. Relying on buyers’ lay payments instead of uncertain credit, the real-estate section was the singular of the few in the star that transitory the person from earth difficulty often unscathed.

But critics remonstrate the gains were little some-more than window dressing. Roughly 40 percent of Egyptians assault along at the World Bank-set wretchedness spin of under $2 per day.

Food prices have customarily augmenting over the past 3 years, healthful their soaring levels even as person from earth commodity prices fell. Beef, which solitary at 40 Egyptian pounds per kilogram ($3.20 per pound) a few months ago, right divided hovers at 65 pounds per kilo ($5.13 per pound) – making it a oppulance many atmosphere once a month or less.

“Food price as good as increase in speed is a material begin in Egypt,” said Ann Wyman, control of taking flight markets at Nomura. “Egypt ranks, for us, as the singular of the most unprotected countries for high food prices. It’s something you’re observant in the popular response.”

Analysts theory that food price increase in speed is right away at an unsustainable seventeen percent yearly.

Clashes in January 1977 over an increase in the price of bread – known in internal Egyptian Arabic as Aish, or reason up – ended with several killed.

Housing stays an one more pass adhering point. While villas in ultimate communities with names identical to Beverly Hills as good as Allegria is free-flowing for the abounding or the tip core class, the rest of the competition struggles even to find one-bedroom apartments.

The begin came to a control late last year when Talaat Mustafa Group, the biggest publicly businessman developer, was sued by a bureau workman over a outline under which it accumulative millions of acres of dusty land to set up its unstinting Madinaty project.

The box in danger to cut the country’s genuine estate section apart on deposit that the organisation overlooked the law in awarding the land through a no-bid process. The begin was resolved when the organisation set up an individualist cupboard – the singular which included in the mailing members of the same housing government that illegally presumed the land – as good as decided to re-award the land to TMG under often the same terms.

“We saw the crime in Madinaty,” said Ahmed Sayed El-Naggar, an researcher with state-sponsored Al-Ahram Center for Political as good as Strategic Studies. “This was land that should have left to the people yet went to people in (the government National Democratic Party).”

TMG was headed at the time by Talaat Mustafa, a nobleman who was convicted of plotting to attempted attempted murder his Lebanese diva girlfriend. Mustafa was, identical to several other blurb operation moguls, a partial of of the parliament.

The organisation aced an descending trading dispute even before to the protests. Subsidies are coming to assimilate about 100 billion pounds ($17.4 billion) of the country’s check this year, as good as any attempts at rupturing these benefits are dangerous.

The censure becomes some-more baleful if the tensions continue or shift to Red Sea coastal hotspots where tens of thousands of tourists organisation to evade wintry winters.

So far, tourism appears to be often unaffected, with operators across Europe saying cancellations have yet to really surface. Only side-trips trips to Cairo as good as Luxor have been cut, while resorts identical to Sharm el-Sheikh are still on the itinerary.

Atopic Dermatitis

Atopic dermatitis (AD) is a pruritic disease of unknown origin that usually starts in early infancy (an adult-onset variant is recognized); it is characterized by pruritus, eczematous lesions, xerosis (dry skin), and lichenification (thickening of the skin and an increase in skin markings). Atopic dermatitis may be associated with other atopic (immunoglobulin E [IgE]) diseases (eg, asthma, allergic rhinitis, urticaria, acute allergic reactions to foods).1 Atopic dermatitis has enormous morbidity, and the incidence and prevalence appear to be increasing. Other conditions with different etiologies and prognoses are often grouped under the umbrella of a diagnosis of atopic dermatitis.
Pathophysiology

Good evidence indicates that genetic factors are important in the development of atopic dermatitis, but the pathophysiology is still poorly understood. Two main hypotheses have been proposed regarding the development of the inflammatory lesions. The first suggests an immune dysfunction resulting in IgE sensitization and a secondary epithelial-barrier disturbance. The second proposes a defect in epithelial cells leading to the defective barrier problem, with the immunological aspects being epiphenomena.

In healthy individuals, balance exists between 2 important subdivisions of T cells (ie, TH 1, TH 2). The immune hypothesis invokes an imbalance in the T lymphocytes, with TH 2 cells predominating; this results in cytokine production of interleukins 4, 5, 12, and 13 and granulocyte macrophage colony-stimulating factor, causing an increase in IgE and lowered interferon gamma levels. Later, in persons with chronic atopic dermatitis, the TH 1-type cells predominate. Other cell types are also involved in the process, including eosinophils, Langerhans cells, keratinocytes, and B cells.2

The second hypothesis involves defective barrier function in the stratum corneum of Atopic dermatitis patients, leading to the entry of antigens that result in the production of inflammatory cytokines. Some authors question whether the antigens can also be absorbed from the gut (eg, from food) and the lungs (eg, from house dust mites). Xerosis is known to be an associated sign in many atopic dermatitis patients. Evidence has shown multiple loss-of-function mutations in the filaggrin gene (FLG) on band 1q21.3 in patients with atopic dermatitis in Europe and other filaggrin mutations in Japanese patients. This gene is mutated in persons with ichthyosis vulgaris; it is associated with early-onset atopic dermatitis and with airway disease in the setting of atopic dermatitis. These changes are only found in 30% of European patients, begging the question of whether other genetic variants may also be responsiblefor some of the findings in the pathogenesis of atopic dermatitis.

In atopic dermatitis, transepidermal water loss is increased. Defective lamellar bodies may be caused by abnormalities of ceramide production. Whether the inflammation causes primary or secondary epidermal barrier breakdown is not known, but with the knowledge that filaggrin is involved in epithelial disruption, it is now thought that this finding leads to increased transepidermal penetration of environmental allergens, increasing inflammation and sensitivity.3,4
Frequency
United States

The prevalence rate for atopic dermatitis is 10-12% in children and 0.9% in adults. More recent information examining physician visits for atopic dermatitis in the United States from 1997-2004 estimates a large increase in office visits for atopic dermatitis occurred. In addition, blacks and Asians visit more frequently for atopic dermatitis than whites. Note that this increase involves all disease under the umbrella of atopic dermatitis and it has not been possible to allocate which type has increased so rapidly.5
International

The prevalence rate of atopic dermatitis is rising, and atopic dermatitis affects 15-30% of children and 2-10% of adults. This figure estimates the prevalence in developed countries. In China and Iran, the prevalence rate is approximately 2-3%. The frequency is increased in patients who immigrate to developed countries from underdeveloped countries.6
Mortality/Morbidity

Incessant itch and work loss in adult life is a great financial burden. A number of studies have reported that the financial burden to families and government is similar to that of asthma, arthritis, and diabetes mellitus. In children, the disease causes enormous psychological burden to families and loss of school days. Mortality due to atopic dermatitis is unusual.

* Kaposi varicelliform eruption (eczema herpeticum) is a well-recognized complication of atopic dermatitis.
o It usually occurs with a primary herpes simplex infection, but it may also be seen with recurrent infection. Vesicular lesions usually begin in areas of eczema and spread rapidly to involve all eczematous areas and healthy skin. Lesions may become secondarily infected. Timely treatment with acyclovir ensures a relative lack of severe morbidity or mortality.
o Another cause of Kaposi varicelliform eruption is vaccination with vaccinia for the prevention of small pox, but because this is no longer mandatory, patients with atopic dermatitis do not develop the sequelae of eczema vaccinatum that has been seen in the past. It was usually contracted by the patient from the vaccination of themselves or their close relatives. This condition had a high mortality rate (up to 25%). In the current climate of threats of bioterrorism, vaccination may once again become necessary, and physicians should be aware of eczema vaccinatum in this setting.
o Note that chickenpox vaccine does not carry the same risk as herpes simplex and vaccinia.
* Bacterial infection with Staphylococcus aureus or Streptococcus pyogenesis is not infrequent in the setting of atopic dermatitis . The skin of patients with atopic dermatitis is colonized by S aureus. Colonization does not imply clinical infection, and physicians should only treat patients with clinical infection. The emergence of methicillin-resistant S aureus (MRSA) may prove to be a problem in the future in these patients. Eczematous and bullous lesions on the palms and soles are often infected with beta-hemolytic group A Streptococcus.
* Urticaria and acute anaphylactic reactions to food occur with increased frequency in patients with atopic dermatitis. The food groups most commonly implicated include peanuts, eggs, milk, soya, fish, and seafood. In studies in peanut-allergic children, the vast majority were atopic.
* Latex allergy is more common in patients with atopic dermatitis than in the general population.
* Of atopic dermatitis patients, 30% develop asthma and 35% have nasal allergies.

Race

* Atopic dermatitis affects persons of all races. Immigrants from developing countries living in developed countries have a higher incidence of atopic dermatitis than the indigenous population, and the incidence is rapidly rising in developed countries

Sex

* The male-to-female ratio for atopic dermatitis is 1:1.4.

Age

* In 85% of cases, atopic dermatitis occurs in the first year of life; in 95% of cases, it occurs before age 5 years. The incidence of atopic dermatitis is highest in early infancy and childhood. The disease may have periods of complete remission, particularly in adolescence, and may then recur in early adult life.
* In the adult population, the rate of atopic dermatitis frequency is 0.9%, but onset may be delayed until adulthood.

Clinical
History

Incessant pruritus is the only symptom of atopic dermatitis, children often scratch themselves uncontrollably. Although pruritus may be present in the first few weeks of life, parents become more aware of the itch as the itch-scratch cycle matures when the patient is aged approximately 3 months. The disease typically has an intermittent course with flares and remissions occurring, often for unexplained reasons.
Physical

Primary findings of atopic dermatitis include xerosis, lichenification, and eczematous lesions. Excoriations and crusting are common. The eczematous changes and its morphology are seen in different locations depending on the age of the patient.

* Infancy
o Atopic dermatitis is usually noticed soon after birth. Xerosis occurs early and often involves the whole body; the diaper area is usually spared.
o The earliest lesions affect the creases (antecubital and popliteal fossae), with erythema and exudation. Over the following few weeks, lesions usually localize to the cheeks, the forehead and scalp, and the extensors of the lower legs; however, they may occur in any location on the body, usually sparing the diaper area. Lesions are ill-defined, erythematous, scaly, and crusted (eczematous) patches and plaques.
o Lichenification is seldom seen in infancy. A typical presentation is shown in the image below.
o

Typical atopic dermatitis on the face of an infan...
Typical atopic dermatitis on the face of an infant.

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Typical atopic dermatitis on the face of an infan...

Typical atopic dermatitis on the face of an infant.
* Childhood
o Xerosis is often generalized. The skin is flaky and rough.
o Lichenification is characteristic of childhood atopic dermatitis. It signifies repeated rubbing of the skin and is seen mostly over the folds, bony protuberances, and forehead.
o Lesions are eczematous and exudative. Pallor of the face is common; erythema and scaling occur around the eyes. Dennie-Morgan folds (ie, increased folds below the eye) are often seen. Flexural creases, particularly the antecubital and popliteal fossae, and buttock-thigh creases are often affected. See the image below.
o

Flexural involvement in childhood atopic dermatit...
Flexural involvement in childhood atopic dermatitis.

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Flexural involvement in childhood atopic dermatit...

Flexural involvement in childhood atopic dermatitis.
o Excoriations and crusting are common. The crusting with atopic dermatitis should not be confused with infection because both may manifest oozing and crusting.
* Adulthood
o Lesions become more diffuse with an underlying background of erythema. The face is commonly involved and is dry and scaly.
o Xerosis is prominent.
o Lichenification may be present.
o A brown macular ring around the neck is typical but not always present. It represents localized deposition of amyloid. See the image below.
o

Dirty neck sign in chronic atopic dermatitis.
Dirty neck sign in chronic atopic dermatitis.

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Dirty neck sign in chronic atopic dermatitis.

Dirty neck sign in chronic atopic dermatitis.

Until Hanifin and Rajka7 developed diagnostic criteria for the diagnosis of atopic dermatitis in 1980, no standardized methods were available to make the diagnosis. Since then, numerous other experts have developed different criteria suitable for their own environment, and varying with age. The original criteria of Hanifin and Rajka have been modified many times. Efforts to develop practical clinical criteria have not been successful, and those available are not suitable for all geographic areas and age groups. The lack of a good chemical marker for diagnosing the disease is an enormous obstacle to the study of atopic dermatitis.
The following is a constellation of criteria commonly used for the diagnosis of atopic dermatitis:

* Pruritus
* Eczematous changes that vary with age
* Chronic and relapsing course
* Early age of onset
* Atopy (IgE reactivity)
* Xerosis
* Personal history of asthma or hay fever or a history of atopic diseases in a first-degree relative in patients younger than 4 years
* Onset younger than age 2 years (not used if child is aged <4 y)

A firm diagnosis of atopic dermatitis depends on excluding conditions such as scabies, allergic contact dermatitis, seborrheic dermatitis (SD), cutaneous lymphoma, ichthyosis, psoriasis, immunodeficiency, and other primary disease entities.
Causes

* Genetics8,9 : A family history of atopic dermatitis is common. Genome-wide scans have highlighted several atopic dermatitis–related loci on 3q21, 1q21, 16q, 17q25, 20p, and 3p26. Several candidate genes have been identified (5q31-33); they all encode cytokines involved in the regulation of IgE synthesis.
* Infection: The skin of patients with atopic dermatitis is colonized by S aureus. Clinical infection with S aureus often causes a flare of atopic dermatitis, and S aureus has been proposed as a cause of atopic dermatitis by acting as a superantigen.
* Hygiene: The hygiene hypothesis is touted as a cause for the increase in atopic dermatitis. This attributes the rise in atopic dermatitis to reduced exposure to various childhood infections and bacterial endotoxins.10,11
* Climate: Atopic dermatitis flares occur in extremes of climate. Heat is poorly tolerated, as is extreme cold. A dry atmosphere increases xerosis. Sun exposure improves lesions, but sweating increases pruritus. These external factors act as irritants or allergens, ultimately setting up an inflammatory cascade.
* Food antigens: The role of food antigens in the pathogenesis of atopic dermatitis is controversial, both in the prevention of atopic dermatitis and by the withdrawal of foods in persons with established atopic dermatitis. Most reported studies have methodologic flaws. Because of the controversy regarding the role of food in atopic dermatitis, most physicians do not withdraw food from the diet. Nevertheless, acute food reactions (urticaria and anaphylaxis) are commonly encountered in children with atopic dermatitis.
* Probiotics12 : The role of probiotics in the diet of patients with atopic dermatitis remains controversial
* Aeroallergens: A role for aeroallergens and house dust mites has been proposed, but this awaits further corroboration.