The Summary of Japanese Grammar

May 16, 2018 Japanese, Uncategorized No comments ,

I wrote this thread because I want to intense the study and memorization of Japanese grammar, simply keeping me learning. This thread keeps updating. Hopefully what has been written here could help other Japanese learners.

Grammar Lesson 1

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The function of this grammar structure is to mean “It is”, “I am”, “He is”, etc. The Y is what after the predicate, and the X next to the は is the subject.

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じゅうにじはんです (It) is half past twelve.

がくせいです (I) am a student.

にほんごです (My major) is the Japanese language.

山下先生は桜大学の学生でした Mr. Yamashita was a student at Sakura University.

あれは日本の映画じゃなかったです That was not a Japanese movie.

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By adding か after the predicate です, the sentence is transformed to a “yes / no” question form. In addition, by expanding the predicate into the structure of なんxxxですか , the meaning of the sentence become “what is”.


りゅうがくせいですか (Are you) an international student?

せんこうはなんですか What is your major?

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の is a particle that connects two nouns. The noun after の expressed the main idea and the one before is the specific characteristic of the main idea.

Grammar Lesson 3

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There are generally three types of verbs and Japanese verbs exist in three forms, including: 1) dictionary forms, 2) the present tense affirmative forms, and 3) the present tense negative forms.

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There are three subtypes of dictionary forms, the “ru-verbs”, the “u-verbs”, and the irregular verbs.

The past tense forms of verbs look like the following.

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メアリーさんは九時ごろうさに帰りました Mary returned home at about nine.

私は昨日日本語を勉強しませんでした I did not study Japanese yesterday.

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Nouns used in sentences generally be followed by particles, which indicate the relations that the nouns bear to the verbs.

 The particle を indicates “direct objects,” the kind of things that are directly involved in, or affected by, the event. Note that this particle is pronounced “o”.


コーヒーを飲みます I drink coffee.

音楽を聴きます I listen to music.

テレビをます I watch TV.

 The paticle で indicates where the event described by the verb takes place.


図書館で本を読みます I will read books in the library.

うちでテレビを見ます I will watch TV at home.

 The particle に has many meanings, but there here we focus on two: 1) the goal toward which things move (location), and 2) the time at which an event takes place.


私は今日学校に行きません I will not go to school today.

私はうちに帰ります I will return home.

日曜日に京都に行きます I will go to Kyoto on Sunday.

十一時に寝ます I will go to bed at eleven.

十一時ごろ(に)寝ます I will go to bed at about eleven.

私は今日学校へ行きません I will not go to school today.

私はうちへ帰ります I will return home.

You do not use the particle に with 1) time expressions defined relative to the present moment, such as “today,” and “tomorrow,” 2) expressions describing regular intervals, such as “every day,” and 3) the word for “when.”


明日きます I will come tomorrow.

毎晩テレビを見ます I watch TV every evening.

いつ行きますか When will you go?

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You can use ませんか (= the present tense negative verb, plus the question particle) to extend an invitation. It should be noted that its affirmative counterpart, ますか, cannot be so used.

昼ご飯を食べませんか What do you say to having lunch with me?

テニスをしませんか Will you play tennis with me?

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Japanese sentences are fairly flexible in the arrangement of elements that appear in them. Generally, sentences are made up of several noun-particle sequences followed by a verb or an adjective, which in turn is often followed by a sentence-final particle such as か, ね, orよ. Among the noun-particle sequences, their relative orders are to a large extent free. A typical sentence, therefore, looks like the following, but several other arrangements of non-particle sequences are also possible.

私は今日図書館で日本語を勉強します I will study Japanese in the library today.

私はよく七時ごろうちへ帰ります I often go back home at around seven.

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You can add a frequency adverb such as 毎日, よく, ときどき to a sentence to describe how often you do something.


私はときどき喫茶店に行きます I sometimes go to a coffee shop.

私はぜんぜんテレビを観ません I do not watch TV at all.

たけしさんはあまり勉強しません Takeshi does not study much.

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The particle は presents the topic of one’s utterance. It puts forward the item that you want to talk about and comment on. A topic phrase, however, need not be the subject of a sentence. We see three sentences in the dialogue of this lesson where non subject phrases are made topics with the help of the particle は.

メアリーさん、週末はたいて何をしますか Mary, what do you usually do on the weekend?

今日は京都に行きます I’m going to Kyoto today.

In the above two examples, は promotes time expressions as the topic of each sentence. Its effects can be paraphrased like this: “Let’s talk about weekends; what do you do on weekends?” “Let me say what I will do today; I will go to Kyoto.”

Grammar Lesson 4

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Xがあります means “there is/are X (nonliving thing).” The particle が introduces, or presents, the item X. There are some rules for this verb. First, it calls for the particle に for the place description. Second, place description usually comes at the beginning of the sentence. Third, the thing description is usually followed by the particle が.

You can also use あります to say that you have or own something. Besides, you can use あります when you want to say that an event will take place.


時間があります (I) have time.

時間がありますか (Do you) have time?

時間がありません (I don’t) have time.

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The Japanese version of “X is in front of Y” looks like



あのデパートの前です It’s in front of that department store.

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銀行は図書館のとなりです The bank is next to the library.

かさはテーブルの下です The umbrella is under the table.

レストランはデパート病院の間です The restaurant is between the department store and the hospital.

One can use any of the above location words together with a verb to describe an event that occur in the place.

私はモスバーガーの前でメアリーさんを待ちました I waited for Mary in front of the Mom Burger place.

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The duration of an activity is expressed with a bare noun, like 一時間. Such a noun stands alone (that is, not followed by an particle).


メアリーさんはそこでたけしさんを一時間待ちました Mary waited for Takeshi there for an hour.

私は昨日日本語を三時間くらい勉強しました I studies Japanese for about three hours yesterday.

昨日7時間半寝ました (I) slept for seven and a half hours last night.

Pharmacokinetics – Distribution Series

November 11, 2017 Pharmacodynamics, Pharmacokinetics, Uncategorized No comments , , , , , , , , ,

As a result of either direct systemic administration or absorption from an extravascular route, drug reaches the systemic circulation, where it very rapidly distributes throughout the entire volume of plasma water and is delivered to tissues around the body. Two aspects of drug distribution need to be considered: how radidly, and to what extent, the drug in the plasma gets taken up by the tissues. A lot of information on the rate of drug disribution can be obtained by observing the pattern of the changes in the plasma concentrations in the early period following drug administration. Information about the extent of drug distribution can be obtained by considering the value of the plasma concentration once distribution is complete. Thus, the plasma concentration constitutes a "window" for obtaining information on the distribution of the bulk of the drug in the body and how it changes over time.

Extent of Drug Distribution

A drug must reach its site of action to produce an effect. Generally, this involves only a very small amount of the overall drug in the body, and access to the site of action is generally a problem only if the site is located in a specialized area or space. The second important aspect of the extent of drug distribution is the relative distribution of a drug between plasma and the rest of the body. This affects the plasma concentration of the drug and is important because: 1) as discussed above, the plasma concentration is the "window" through which we are able to "see" the drug in the body. It is important to know how a measured plasma concentration is related to the total amount of drug in the body; 2) Drug is delivered to the organs of elimination via the blood. If a drug distributes extensively from the plasma to the tissues, the drug in the plasma will constitute only a small fraction of the drug in the body. Little drug will be delivered to the organs of elimination, and this will hamper elimination. Conversely, it a drug is very limited in its ability to distribute beyond the plasma, a greater fraction of the drug in the body will be physically located in the plasma. The organs of elimination will be well supplied with drug, and this will enhance the elimination processes.

Drug distribution to the tissues is driven primarily by the passive diffusion of free, unbound drug along its concentration gradient. Consider the administration of a single intravenous dose of a drug. In the early period after administration, the concentration of drug in the plasma is much higher than that in the tissues, and there is a net movement of drug from the plasma to the tissues; this period is known as the distribution phase. Eventually, a type of equilibrium is established between the tissues and plasma, at which point the ratio of the tissue to plasma concentration remains constant. At this time the distribution phase is complete and the tissue and plasma concentrations rise and fall in parallel; this period is known as the postdistribution phase. It should be noted that after a single dose, true equilibrium between the tissues and the plasma is not achieved in the postdistribution phase because the plasma concentration falls constinuously as drug is eliminated from the body. This breaks the equilibrium between the two and results in the redistribution of drug from the tissues to the plasma. Uptake and efflux transporters in certain tissues may also be involved in the distribution process and may enhance or limit a drug's distribution to specific tissues.

Physiologic Volumes

Three important physiological volumes – plasma water, extracellular fluid, and total body water, are shown in Figure 4.2. In the systemic circulation, drugs distribute throughout the volume of plasma water (about 3 L). Where a drug goes beyond this, including distribution to the cellular elements of the blood, depends on the physicochemical properties of the drug and the permeability characteristics of individual membranes.

The membranes of the capillary epithelial cells are generally very loose in nature and permit the paracellular passage of even polar and/or large drug molecules. Thus, most drugs are able to distribute throughout the volume of extracellular fluid, a volume of about 15 L. However, the capillary membranes of certain tissues, notably delicate tissues such as the central nervous system, the placenta, and the testes, have much more tightly knit membranes, which may limit the access of certain drugs, particularly large and/or polar drugs.

Once in the extracellular fluid, drugs are exposed to the individual cells of tissues. The ability of drugs to penetrate the membrane of these cells is dependent on a drug's physicochemical properties. Polar drugs and large molecular mass drugs will be unable to pass cell membranes by passive diffusion. However, polar drugs may enter cells if they are substrates for specialized uptake transporters. On the other hand, efflux transporters will restrict the distribution of their substrates. Small lipophilic drugs that can easily penetrate cell membranes can potentially distribute throughout the total body water, which is around 40 L.

In summary, drugs are able to pass through most of the capillary membranes in the body and distribute into a volume approximately equal to that of the extracellular fluid (about 15 L). The ability of a drug to distribute beyond this depends primarily on its physicochemical characteristics. Small, lipophilic drug molecules should penetrate biological membranes with ease and distribute throughout the total body water (about 40 L). A drug's distribution to specific tissues may be enhanced by uptake transporters. Conversely, efflux transporters will restrict the tissue distribution of their substrates. Total body water, about 40 L, represents the maximum volume into which a drug can distribute.

Tissue Binding and Plasma Protein Binding

Given that drug distribution is driven primarily by passive diffusion, it would be reasonable to assume that once distribution has occurred, the concentration of drug would be the same throughout its distribution volume. This is rarely the case because of tissue and plasma protein binding. Drugs frequently bind in a reversible manner to sites on proteins and other macromolecules in the plasma and tissues. At this time it is important to appreciate that bound drug cannot participate in the concentration gradient that drives the distribution process. The bound drug can be considered to be secreted away or hidden in tissue or plasma. Binding has a very important influence on a drug's distribution pattern. Consider a drug that binds extensively (90%) to the plasma proteins but does not bind to tissue macromolecules. In the plasma, 90% of the drug is bound and only 10% is free and able to diffuse to the tissues. At equilibrium, the unbound concentrations in the plasma and tissue will be the same, but the total concentration of drug in the plasma will be much higher than that in the tissues.

Plasma protein binding has the effect of limiting distribution and concentrating drug in the plasma. On the other hand, consider a drug that binds extensively to macromolecules in the tissues but does not bind to the plasma proteins. Assume that overall 90% of the drug in the tissue is bound and only 10% is free. As the distribution process occurs, a large fraction of the drug in the tissues will bind and be removed from participation in the diffusion gradient. As a result, more and more drug will distribute to the tissues. When distribution is complete, the unbound concentrations in the plasma and tissues wil be the same, but the total (bound plus free) average tissue concentration will be much larger than the plasma concentration. Tissue binding essentially draws drug from the plasma and concentrates it in the tissues. Drugs often bind to both the plasma proteins and tissue macromolecules. In this case the final distribution pattern will be determined by which is the dominant process.

Assessment of the Extent of Drug Distribution

Once distribution has gone to completion, the ratio of the total tissue concentration to the total plasma concentration remains constant. The actual tissue concentration (and the ratio) will vary from tissue to tisue, depending on the relative effects of tissue and plasma protein binding. It is not possible to measure individual tissue concentrations, and it is convenient to consider an overall average tissue concentration (Ct). The ratio of Ct to Cp will vary from drug to drug.

It is important to find a way to express a drug's distribution characteristics using a number or distribution parameter that can easily be estimated clinically. The ratio discussed above (Ct/Cp) expresses distribution but cannot be measured easily. Instead, we use the ratio of amount of drug in the body vs. plasma concentration at the same time to express a drug's distribution, that is, the apparent volume of distribution (Vd).

It is important to appreciate that the (apparent) volume of distribution is simply a ratio that has units of volume. It is not physiological volume and, despite its name, it is not the volume into which a drug distributes. The fact that drug A has a Vd value of 20 L does not mean that it distributes into a volume of 20 L, which is greater than extracellular fluid and less than the total body water.

The value of a drug's volume of distribution can be used to estimate the fraction of the drug in the body that is physically present in either the plasma or the tissues. The drug in the body (Ab) may be partitioned into drug in the plasma (Ap) and drug outside the plasma or in the tissues (At):

Ab = Ap + At

the fraction of the drug in the plasma,

fraction in plasma = Ap / Ab

After some algebra, we get

fraction in plasma = Vp / Vd

In a standard 70-kg adult male, Vp = 3 L:

fraction in plasma = 3 / Vd

The fraction of the drug in the body located in the tissues:

fraction in tissue = 1 – fraction in plasma = 1 – 3 / Vd

With this formula we can estimate the fraction of drug in plasma and in tissues, respectively.

Drug in the body is located in either the plasma or the tissues. The amount of drug in either of these spaces is the product of the concentration of drug and the volume of the space. And because Ab = Ap + At, we get

Cp * Vd = Cp *Vp + Ct * Vt

where Cp is the plasma concentration of the drug, Vd the volume of distribution, and Vp the volume of plasma water, Ct the average tissue concentration of the drug, the Vt the overall volume of tissues that the drug distributes.

And because the unbound (free) drug concentration equals the total drug concentration multiplying fraction of unbound, while the unbound drug concentrations between plasma and tissues (extraceullar space) must be the same after reaching distribution equilibrium, we get,

Cp*fu = Ct * fut

After some algebra, we have

Vd = Vp + Vt * fu / fut

where fu is the fraction of unbound drug in plasma and fut is the fraction of unbound drug in tissues. This final equation shows that a drug's volume of distribution is dependent on both the volume into which a drug distributes and on tissue and plasma protein binding. It also shows that increased tissue binding (fut gets smaller) or decreased plasma protein binding (fu gets larger) will result in an increase in the volume of distribution. Also, if a drug binds to neither the plasma proteins (fu = 1) nor the tissues (fut = 1), its volume of distribution will be equal to that of the volume into which the drug distributes (physiologic volume).


  • Vd is a ratio that reflects a drug's relative distribution between the plasma and the rest of the body.
  • It is dependent on the volume into which a drug distributes and a drug's binding characteristics.
  • It is a constant for a drug under normal conditions.
  • Conditions that alter body volume may affect its value.
  • Altered tissue and/or protein binding may alter its value.
  • It provides information about a drug's distribution pattern. Large values indicate extensive distribution of a drug to the tissues.
  • It can be used to calculate the amount of drug in the body if a drug's plasma concentration is known.

Plasma Protein Binding

A very large number of therapeutic drugs bind to certain sites on the proteins in plasma to form drug-protein complexes. The binding process occurs very rapidly, it is completely reversible, and equilibrium is quickly established between the bound and unbound forms of a drug. If the unbound or free drug concentration falls due to distribution or drug elimination, bound drug dissociates rapidly to restore equilibrium. Clinically, although the total drug concentration is measured routinely, pharmacological and toxicological activity is thought to reside with the free unbound drug (Cpu). It is only this component of the drug that is thought to be able to diffuse across membranes to the drug's site of action and to interact with the receptor. Binding is usually expressed using the parameter fraction unbound (fu), and the unbound pharmacologically active component can be calculated:

Cpu = Cp * fu

The three primary plasma proteins combining drugs include albumin, 𝛼1-acid glycoprotein (AAG), and the lipoproteins. AAG is present in lower concentration than albumin and binds primarily neutral and basic drugs. It is referred to as an acute-phase reactant protein because its concentration increases in response to a variety of unrelated stressful conditions, such as cancer, inflammation, and acute myocardial infarction. Given that the unbound concentration is the clinical important fraction and that it is the total concentration that is routinely measured, it is important to know how and when the unbound fraction may change for a drug.

The binding of drug and plasma protein could be regarded as a drug and "receptor" interaction (occupation). So the pharmacodynamic Emax model could be used to describe this interacton mathematically. After some algebra modifications, we get


where PT is the serum concentration of plasma binding protein, Kd the equilibrium dissociation constant, and the Cpu the plasma concentration of unbound (free) drug.

At low concentrations, binding increases in direct proportion to an increase in the free drug (fu remains constant as Cpu increases, where Cpu < Kd). As the free drug concentration increases further, some saturation of the proteins occurs, and proportionally less drug can bind (fu will increase as Cpu increases further). Eventually, at high drug concentrations, all the binding sites on the protein are taken and binding cannot increase further.

The Changes of fu

  • Affinity

The affinity of the drug for the protein is the main determinant of fu. Affinity is expressed by Kd, which is a reciprocal form of affinity. As affinity increases, Kd gets smaller. Drugs with small Kd values bind extensively, whereas those with large Kd values will not bind extensively.

  • Free drug concentration

Because the therapeutic plasma concentrations of most drugs are much less than their Kd values, binding is able to increase in proportion to increases in the total concentration: fu remains constant over therapeutic plasma concentrations. There are, however, a few drugs that have therapeutic plasma concentrations that are around the range of their Kd values. These drugs, which tend to be drugs that have very high therapeutic plasma concentrations, include valproic acid and salicylates, both of which bind to albumin, and disopyramide, which binds to AAG. The binding of these drugs uses a substantial amount of protein, and as a result they display concentration-dependent binding. As the drug concentration increases, some degree of saturation is observed, and the fraction unbound gets larger.

  • Plasma binding protein concentration

As predicted by the law of mass action, changes in the protein concentration will produce changes in the degree of binding. In the case of AAG, increases in the concentration are more common. Physiological stress caused by myocardial infarction, cancer, and surgery can lead to four- to fivefold increases in the AAG concentration. Lipoprotein concentrations vary widely in the population. They can decrease as a result of diet and therapy with HMG-CoA reductase inhibitors (statins), and increase due to alcoholism and diabetes mellitus.

  • Displacement

The binding of one drug may displace a second drug from its binding site. This displacement occurs because two drugs compete for a limited number of binding sites on the protein. Not surprisingly, displacers tend to be those drugs that achieve high concentrations in the plasma, use up a lot of protein, and display concentration-dependent binding.

  • Renal and hepatic disease

The binding of drugs to ablumin is often decreased in patients with severe renal disease. This appears to be the result of both decreased albumin levels and the accumulation of compounds that are normally eliminated, which may alter the affinity of drugs for albumin and/or compete for binding sites. The binding of several acidic drugs, including phenytoin and valproic acid, is reduced in severe renal disease. Plasma protein binding may also be reduced in hepatic disease.

Clinical Consequences of Changes in Plasma Protein Binding

Changes in fu as a result of altered protein concentration or displacement will result in a change in the fraction of the total drug that is unbound. Two issues need to be addressed when considering the clinical consequences of this: the potential changes in the unbound drug concentration at the site of action, and the interpretation and evaluation of the routinely measured total plasma concentrations.

When binding decreases, the pharmacologically active unbound component increases, and in theory, the response or toxicity could increase. However, the clinical consequences of altered plasma protein binding are minimized by two factors: 1) increased elimination and 2) little change in drug concentrations outside the plasma.

In many cases, only the unbound drug is accessible to the organs of elimination. This is known as restrictive elimination because elimination is restricted by protein binding and is limited to the unbound drug. For drugs display restrictive clearance, the increase in the unbound concentration that occurs when binding decreases results in an increase in elimination of the drug. The increase in elimination is usually proportional to the increase in unbound concentration. As a result, the unbound drug concentration in the plasma eventually falls to exactly the same value as that before the change in binding. In other words, the increase in the unbound concentration is canceled out by increased elimination.

The time it takes for the unbound concentration to return to its normal level is determined by the rate of elimination of the drug (the elimination half-life). If the drug is eliminated rapidly, the unbound concentration returns to its original level quickly. If the drug is eliminated slowly, it takes a long time for the unbound concentration to return to its original level. The time it takes to return can be important for drugs that have a narrow therapeutic index.

The plasma comprises a relative small physiological volume (3 L). Even when plasma protein binding is extensive, the fraction of the drug in the body that is located in the plasma is much less than that in the tissues. As a result, when the fraction unbound increases, the extra drug that distributes to the tissue is often very small in comparison to the amount of drug already present. This is particularly the case for drugs that have large volumes of distribution, where the majority of the drug in the body is in the tissues and only a very small fraction resides in the plasma.

Interpreting Cp

In clinical practice, drug therapy may be monitored by ensuring that plasma concentrations lie within the therapeutic range. The therapeutic range of a drug is expressed most conveniently in terms of concentration routinely measured, the total plasma concentration (Cp). But since the unbound concentration is the pharmacologically active component, the therapeutic range should more correctly be expressed in terms of this unbound concentration. Formulas have been developed for some drugs that will convert a measured plasma concentration of a drug to the value that it would be if the protein concentration were normal. We can prove the below formula with algebra modification.

 (when plasma drug concentration << Kd)

The Process of Differential Diagnosis

May 24, 2017 Uncategorized No comments , , , , ,

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Elements of the Differential Diagnosis

Decision-making on the Basis of Diagnosis. The physician endeavors to organize the subjective complaints and the objective findings of a patient in order to receive further indications to proceed. This approach is frequently chosen because a diagnosis in the conventional sense is not always easy to make, as more than one diagnosis can often be possible at the same time. Therefore, an important first step is to create a list of problems with a detail description.

Dynamics of Reaching a Diagnosis. The diagnosis is of utmost importance not only for the prognosis but also for the introduction of an appropriate therapy. An established diagnosis always needs to be reassessed. Secondary diseases, complications, and side-effects can supervene. Each diagnosis continues to be a differential diagnosis, since the particular symptoms, even during the course of a disease, have to be continually reevaluated, carefully considered, and differentiated. For a proper evaluation of the symptoms and risk factors, knowledge of their clinical meaning is crucial. Consequently, the purpose of differential diagnosis is to point out what disease can occur, when specific symptoms appear, and what risk factors with the utmost probability accompany specific diseases. In most cases, there are numerous possibilities and additional factors that have to be taken into account. Exclusively listing all the possibilities would not be beneficial.

Practical Procedure for Establishing a Diagnosis

The diagnosis is based on four essential aspects:

  • medical history
  • state of health
  • laboratory and other investigations
  • monitoring

In case of an unsolved disease, the number of possible remaining diagnoses can be reduced drastically via history-taking and clinical examination. The additional morphological, physical, chemical, and biological examinations allow the isolation of the most probable diagnosis. Monitoring is a critical quality control of the previous diagnostic process, as well as the subsequent therapeutic decisions.

Cardinal Symptoms. In differential diagnosis we proceed from a single dominant symptom, or group of symptoms or main symptoms, and try to classify as much as possible on the basis of the current research, in order to obtain a clinical picture. In most cases, a differential diagnosis is considered when a cardinal symptom indicates the direction of further measures. This leading symptom can emerge from the medical history, from clinical findings, as well as from laboratory work results. So-called problem-oriented patient care is practiced in a similar manner.

Correct Evaluation of Evident Findings and the Differential Diagnosis

Process of Clinical Judgement. The correct evaluation of findings is crucial for the diagnosis. Positive and negative predictive values play important roles in this context. Nevertheless, personal intuition with regard to the individual patient remains an important factor.

Pathognomonic symptoms or combinations of symptoms are rare, but must be recognized when present. Except in the most obvious cases, we are subject to continuous uncertainty in everyday clinical life – we must use the available resources to decide on the most probable diagnosis for our individual patients and select the most effective treatment. It is assumed that with additional clinical experience the correct clinical judgement will automatically be made. In this we are supported by studies that critically analyze individual investigative steps and diagnostic processes. Guidelines which critically assess current research and place it in context are often helpful.

Probability-based Decision Analysis. In cases of ambiguous and usually complex situations, the physician can decrease the probability of error when diagnosing or excluding a disease using reasoning based on decision analysis. He or she analyses the probability of a disease diagnosis on the basis of the findings (post-test probability), whereby both the sensitivity and specificity of the test must be given, as well as considering the pretest probability (current probability).

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Diagnostic Process. The path from unspecified disease to definitive diagnosis is only rarely a linear one by which data are first collected and then analyzed according to established criteria. Additional examinations are to be conducted as indicated, whereupon everything is reevaluated in order to make a definite diagnosis. Frequently, only a few minutes into a medical discussion, first working hypotheses are formulated that ultimately direct further history-taking and examination.

Preliminary Diagnosis and Immediate Therapeutic Consequences. The first impression is on the one hand crucial, but on the other hand can be dangerous if not continually challenged by results of ongoing examinations. It is essential to recognize serious disease as early as possible, and to quickly initiate the appropriate measures, which are often vital to the prognosis. During the diagnostic process it is therefore often necessary to introduce therapeutic measures without a firm diagnosis, and independent of the specific etiology. Treatment on the basis of a preliminary diagnosis is often acceptable for most common diseases.

In cases of new symptoms or an “atypical” course of disease, the diagnosis should be challenged. The following possibilities must be considered:

  • The first diagnosis was wrong
  • The diagnosis was correct, a complication supervened
  • The diagnosis was correct, a secondary independent disease supervened
  • The diagnosis was correct, side effects from therapy occurred
  • The diagnosis was correct and the course of the disease is indeed atypical

Factors that Can Influence the Differential Diagnostic Thought Process

Prevalence of Disease

Differential diagnosis is based on the knowledge as to which symptoms and disease are common. According to an American study involving over 300 million cases of consultations in private practices of internists, the most common complaints are: abdominal pain, thoracic pain, back pain, headaches, fatigue, coughing and catarrhal symptoms, as well as leg pain, skin symptoms, and vertigo.

Differential diagnosis also takes into account the frequency of diseases according to the overall situation.


The influence of age must always be considered. Knowledge of age distribution provides valuable clues for the diagnosis.


Some diseases occur more frequently in males than in females, and vice versa. This is especially true for occupational diseases as well as diseases caused by smoking or alcohol. Because on their anatomic configuration, women are susceptible to reoccurring urinary tract infections, pyelonephritis and iron deficiency due to menorrhea.


Lifestyle is very important to people today. Some positive habits are healthy nutrition and fitness; harmful habits include addictive behaviors. The influence of alcohol especially on the liver, blood pressure, and nervous system is well known. Smoking, which is particularly on the rise in adolescents, is responsible for the emergence of vascular diseases as well as pulmonary diseases.

Eating Habits

Eating habits are at least partly responsible for many diseases. To a large extent, obesity is closely associated with disease. Diabetes mellitus type 2, arthrosis, and hypertension are more frequently observed in obese persons. Obesity is one of the risk factors in the development of arteriosclerosis and its consequences. Also the influence of eating habits with regard to malignant tumors is suggested.

Season, Time of Day, and Weather

Certain diseases are clearly dependent on the season:

  • Food-associated infectious diseases in particular, e.g., salmonellosis, occur more frequently in warm seasons.
  • The seasonal emergence of allergic coryza depends on airborne pollens (spring/summer)
  • Respiratory infections occur more frequently during the winter months and cause higher morbidity and mortality in the elderly population, especially in a humid climate and after sudden changes of weather (influenza, respiratory syncytial virus).

Circadian rhythms also plays a role. Chronic polyarthritis is a disease with an explicit circadian rhythm and reaches maximum activity in the early morning and a minimum of activity in the afternoon. Accordingly, a correlation with the circadian cortisone output and neutrophil count has been identified.

Geographic Distribution

The geographic distribution of diseases must often be considered. It is especially obvious in infectious diseases (tropical diseases), where climatic and hygienic conditions exert influence. The physician is obliged to consider “exotic” diseases in the differential diagnosis of patients with a history of travel (tourism). In addition, even similar clinical pictures (e.g., malaria) result in a different disease course depending on the country of infection (differences in resistance).

Ethnic Groups

The patient’s ethnic background can be of importance for the diagnosis. Thalassemia occurs primarily in populations bordering the Mediterranean. Sickle cell anemia is present nearly exclusively in black populations.

Profession and Leisure

The profession of a patient can provide diagnostic clues. Occupational diseases are defined by a clear correlation between occupational activity and disease.

Besides occupational diseases, leisure pursuits are to be considered. Diseases are often observed due to sporting activities.

Precluding or Promoting Diseases

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From medical experience, certain diseases rarely occur simultaneously, whereas others are associated with each other. Patients with chronic alcohol abuse seldom develop liver cirrhosis and chronic pancreatitis at the same time. Similarly, there are practically no incidences of malaria in patients with sickle cell anemia. Diseases of one organ can be the initial manifestation of an overall dysfunctional organism or a systemic disease that endangers practically all organs. Thus upon emergence of symptoms, other possible manifestations and locations should be carefully considered.

Differential Diagnosis by Groups of Diseases

When differentiating a clinical picture, very often it is initially impossible to identify the real diagnosis, namely the nosological entity. Until relevant findings are present, one has to be content with the classification into one of the groups of diseases. In all unclear cases, consideration is almost always given to this at the beginning of the differential diagnostic process.

  • Degenerative conditions
  • Infectious disease
  • Immune mediated diseases
  • Tumors
  • Metabolic diseases
  • Dysfunction of the endocrine system
  • Mental disorders
  • Hereditary diseases
  • Allergies
  • Intoxications

Conceiving the Research Question and Developing the Study Plan

May 13, 2017 Clinical Research, Clinical Trials, Uncategorized No comments , ,

The research question is the uncertainty that the investigator wants to resolve by performing his/her study. There is no shortage of good research questions, and even as we succeed in answering some questions, we remain surrounded by others. Clinical trials, for example, established that treatments that block the synthesis of estradiol (aromatase inhibitors) reduce the risk of breast cancer in women who have had early stage cancer. But this led to new questions: How long should treatment be continued; does this treatment prevent breast cancer in patients with BRCA 1 and BRCA 2 mutations; and what is the best way to prevent the osteoporosis that is an adverse effect of these drugs? Beyond that are primary prevention questions: Are these treatments effective and safe for preventing breast cancer in healthy women?

Origins of A Research Question

For an established investigator the best research questions usually emerge from the findings and problems she has observed in her own prior studies and in those of other workers in the field. A new investigator has not yet developed this base of experience. Although a fresh perspective is sometimes useful by allowing a creative person to conceive new approaches to old problems, lack of experience is largely an impediment.

A good way to begin is to clarify the difference between a research question and a research interest. Consider this research question:

  • Dose participation in group counseling sessions reduce the likelihood of domestic violence among women who have recently immigrated from Central America?

This might be asked by someone whose research interest involves the efficacy of group counseling, or the prevention of domestic violence, or improving health in recent immigrants. The distinction between research questions and research interests matters because it may turn out that the specific research question cannot be transformed into a viable study plan, but the investigator can still address research interest by asking a different question.

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Of course, it’s impossible to formulate a research question if you are not even sure about your research interest (beyond knowing that you’re supposed to have one). If you find yourself in this boat, you’re not alone: Many new investigators have not yet discovered a topic that interests them and is susceptible to a study plan they can design. You can begin by considering what sorts of research studies have piqued your interest when you’ve seen them in a journal. Or perhaps you were bothered by a specific patient whose treatment seemed inadequate or inappropriate: What could have been done differently that might have improved her outcome? Or one of your attending physicians told you that hypokalemia always caused profound thirst, and another said the opposite, just as dogmatically.

Mastering the Literature

It is important to master the published literature in an area of study: Scholarship is a necessary precursor to good research. A new investigator should conduct a thorough search of published literature in the areas pertinent to the research question and critically read important original papers. Carrying out a systematic review is a great next step for developing and establishing expertise in a research area, and the underlying literature review can serve as background for grant proposals and research reports. Recent advances may be known to active investigators in a particular field long before they are published. Thus, mastery of a subject entails participating in meetings and building relationships with experts in the field.

Being Alert to New Ideas and Techniques

In addition to the medical literature as a source of ideas for research questions, it is helpful to attend conferences in which new work is presented. At least as important as the formal presentations are the opportunities for informal conversations with other scientists at posters and during the breaks. A new investigator who overcomes her shyness and engages a speaker at the coffee break may find the experience richly rewarding, and occasionally she will have a new senior colleague. Even better, for a speaker known in advance to be especially relevant, it may be worthwhile to look up her recent publications and contact her in advance to arrange a meeting during the conference.

A skeptical attitude about prevailing beliefs can stimulate good research questions. For example, it was widely believed that lacerations which extend through the dermis required sutures to assure rapid healing and a satisfactory cosmetic outcome. However, Quinn et al. noted personal experience and case series evidence that wounds of moderate size repair themselves regardless of whether wound edges are approximated. They carried out a randomized trial in which all patients with hand lacerations less than 2 cm in length received tap water irrigation and a 48-hour antibiotic dressing. One group was randomly assigned to have their wounds sutured, and the other group did not receive sutures. The suture group had a more painful and time-consuming treatment in the emergency room, but blinded assessment revealed similar time to healing and similar cosmetic results. This has now become a standard approach used in clinical practice.

The application of new technologies often generates new insights and questions about familiar clinical problems, which in turn can generate new paradigms. Advances in imaging and in molecular and genetic technologies, for example, have spawned translational research studies that have led to new treatments and tests that have changed clinical medicine. Similarly, taking a new concept, technology, or finding from one field and applying it to a problem in a different field can lead to good research questions. Low bone density, for example, is a risk factor for fractures. Investigators applied this technology to other outcomes and found that women with low bone density have higher rates of cognitive decline, stimulating research for factors, such as low endogenous levels of estrogen, that could lead to loss of both bone and memory.

Keeping the Imagination Roaming

Careful observation of patients has led to many descriptive studies and is fruitful source of research questions. Teaching is also an excellent source of inspiration; ideas for studies often occur while preparing presentations or during discussions with inquisitive students. Because there is usually not enough time to develop these ideas on the spot, it is useful to keep them in a computer file or notebook for future reference.

There is a major role for creativity in the process of conceiving research questions, imagining new methods to address old questions, and playing with ideas. Some creative ideas come to mind during informal conversations with colleagues over lunch; others arise from discussing recent research or your own ideas in small groups. Many inspirations are solo affairs that strike while preparing a lecture, showering, perusing the Internet, or just sitting and thinking. Fear of criticism or seeming unusual can prematurely quash new ideas. The trick is to put an unresolved problem clearly in view and allow the mind to run freely around it. There is also a need for tenacity, returning to a troublesome problem repeatedly until a resolution is reached.

Choosing and Working with a Mentor

Nothing substitutes for experience in guiding the many judgements involved in conceiving a research question and fleshing out a study plan. Therefore an essential strategy for a new investigator is to apprentice herself to an experienced mentor who has the time and interest to work with her regularly.

A good mentor will be available for regular meetings and informal discussions, encourage creative ideas, provide wisdom that comes from experience, help ensure protected time for research, open doors to networking and funding opportunities, encourage the development of independent work, and put the new investigator’s name first on grants and publications whenever appropriate. Sometimes it is desirable to have more than one mentor, representing different disciplines. Good relationships of this sort can also lead to tangible resources that are needed – office space, access to clinical populations, data sets and specimen banks, specialized laboratories, financial resources, and a research team.

Characteristics of A Good Research Question

  • Feasible

It is best to know the practical limits and problems of studying a question early on, before wasting much time and effort along unworkable lines.

Number of subjects. Many studies do not achieve their intended purposes because they can not enroll enough subjects. A preliminary calculation of the sample size requirements of the study early on can be quite helpful, together with an estimate of the number of subjects likely to be available for the study, the number who would be excluded or refuse to participate, and the number who would be lost to follow up. Even careful planning often produces estimates that are overly optimistic, and the investigator should assume that there are enough eligible and willing subjects. It is sometimes necessary to carry out a pilot survey or chart review to be sure. If the number of subjects appears insufficient, the investigator can consider several strategies: expanding the inclusion criteria, eliminating unnecessary exclusion criteria, lengthening the time frame for enrolling subjects, acquiring additional sources of subjects, developing more precise measurement approaches, inviting colleagues to join in a multi center study, and using a different study design.

Technical expertise. The investigators must have skills, equipment, and experience needed for designing the study, recruiting the subjects, measuring the variables, and managing and analyzing the data. Consultants can help to shore up technical aspects that are unfamiliar to the investigators, but for major areas of the study it is better to have an experienced colleague steadily involved as a coinvestigator; for example, it is wise to include a statistician as a member of the research team from the beginning of the planning process. It is best to use familiar and established approaches, because the process of developing new methods and skills is time-consuming and uncertain. When a new approach is needed, such as measurement of a new biomarker, expertise in how to accomplish the innovation should be sought.

Cost in time and money. It is important to estimate the costs of each component of the project, bearing in mind that the time and money needed will generally exceed the amounts projected at the outset. If the projected costs exceed the available funds, the only options are to consider a less expensive design or to develop additional sources of funding. Early recognition of a study that is too expensive or time-consuming can lead to modification or abandonment of the plan before expending a great deal of effort.

Scope. Problems often arise when an investigator attempts to accomplish too much, marking many measurements at repeated contacts with a large group of subjects in an effort to answer too many research questions. The solution is to narrow the scope of the study and focus only on the most important goals. Many scientists find it difficult to give up the opportunity to answer interesting side questions, but the reward may be a better answer to the main question at hand.

Fundability. Few investigators have the personal or institutional resources to fund their own research projects, particularly if subjects need to be enrolled and followed, or expensive measurements must be made. The most elegantly designed research proposal will not be feasible if no one will pay for it.

  • Interesting

An investigator may have many motivations for pursuing a particular research question: because it will provide financial support, because it is a logical or important next step in building a career, or because getting at the truth of the matter is interesting. We like this last reason; it is one that grows as it is exercised and that provides the intensity of effort needed for overcoming the many hurdles and frustrations of the research process. However, it is wise to confirm that you are not the only one who finds a question interesting. Speak with mentors, outside experts, and representatives of potential funders such as NIH project officers before devoting substantial energy to develop a research plan or grant proposal that peers and funding agencies may consider dull.

  • Novel
Good clinical research contributes new information. A study that merely reiterates what is already established is not worth the effort and cost and is unlikely to receive funding. The novelty of a proposed study can be determined by thoroughly reviewing the literature, consulting with experts who are familiar with unpublished ongoing research, and searching for abstracts of projects in your area of interest that have been funded using the NIH Research Portfolio Online Reporting Tools (RePORT) website. Reviews of studies submitted to NIH give considerable weight to whether a proposed study is innovative such that a successful result could shift paradigms of research or clinical practice through the use of new concepts, methods, or interventions. Although novelty is an important criterion, a research question need not be totally original – it can be worthwhile to ask whether a previous observation can be replicated, whether the findings in one population also apply to others, or whether a new measurement method can clarify the relationship between known risk factors and a disease. A confirmatory study is particularly useful if it avoids the weaknesses of previous studies or if the result to be confirmed was unexpected.
  • Ethical
A good research question must be ethical. If the study poses unacceptable physical risks or invasion of privacy, the investigator must seek other ways to answer the question. If there is uncertainty about whether the study is ethical, it is helpful to discuss it at an early stage with a representative of the institutional review board (IRB).
  • Relevant
A good way to decide about relevance is to imagine the various outcomes that are likely to occur and consider how each possibility might advance scientific knowledge, influence practice guidelines and health policy, or guide further research. NIH reviewers emphasize the significance of a proposed study: the importance of the problem, how the project will improve scientific knowledge, and how the result will change concepts, methods, or clinical services.
Developing the Research Question and Study Plan
It helps a great deal to write down the research question and a brief (one-page) outline of the study plan at an early stage (detail here http://www.tomhsiung.com/wordpress/2017/05/outline-of-a-study/). This requires some self-discipline, but it forces investigator to clarify her ideas about the plan and to discover specific problems that need attention. The outline also provides a basis for specific suggestions from colleagues.

Methods for Assessment of Liver Injury and Liver Function

March 23, 2017 Uncategorized No comments , , , , , , ,

Saving Private Ryan

Blood tests remain a mainstay for the diagnosis of a patient with suspected liver disease or to stage patients with known liver disease. In general, the goal of such tests is to detect the release of products that are characteristic of the liver into the bloodstream, thereby indicating liver cell injury. Similarly, accumulation of molecules normally excreted via the biliary system is indicative of a failure in liver function, although further tests are necessary to assess the site at which the defect is occurring.

Two enzymes referred to as transaminases are easily measured in the serum, and are sensitive markers of liver cell injury. Alanine aminotransferease (ALT) is produced by hepatocytes, and when these cells are injured, its circulating levels are increased. Aspartate aminotransferase (AST) is similarly increased in the setting of hepatocellular injury, although it is less specific for liver disease because it is also produced by other tissues. For example, AST levels are increased following cardiac injury, such as a myocardial infarction. Nevertheless, measurement of AST remains useful in the setting of clinical symptoms consistent with liver disease, particularly because it appears to be disproportionately elevated in patients whose liver injury is related to alcohol abuse. Measurements of ALT and AST over time are also used to assess the progress of established liver disease. It is important to remember, however, that elevations in transaminases can only occur if these is ongoing hepatocellular death. In cirrhosis, where large portions of the liver may be replaced by fibrous tissue, little new cell injury may be occurring and thus ALT and AST levels may not be elevated.

Two other enzymes are useful markers of injury to the biliary system. Alkaline phosphatase, while not specific to the liver (being produced also by bone, the intestine and placenta), is expressed as a membrane protein in the canaliculus. In the setting of localized obstruction to the biliary tree, alkaline phosphatase levels in the serum are increased. Similarly, gamma glutamyltranspeptidase (GGT) is localized predominantly to the apical membrane of cholangiocytes, although some is also expressed in the bile canaliculi. Serum elevations in GGT are therefore largely reflective of cholangiocyte injury.

The foregoing tests, while often referred to as “liver function” tests, are not strictly measures of actual hepatic function. To assess whether liver function is impaired, other tests are needed. One such test that is very important clinically is the measurement of bilirubin. Accumulation of bilirubin in the circulation indicates cholestasis, which can result from injury to either hepatocytes or cholangiocytes, or obstruction within the biliary system. Based on the discussion of the synthetic functions of the liver, it should be easy to understand that liver function can also be assessed by measuring levels of its various products in the circulation. The most useful tests are to measure serum albumin, and a blood clotting parameter, the prothrombin time. Tests of coagulation are not specific for liver disease and thus must be interpreted in the context of other findings. Patients with suspected liver disease are also often evaluated for serum glucose and ammonia levels, since hypoglycemia and hyperammonemia are major problems in the setting of liver failure.

Biopsies and imaging tests also play a major role in the evaluation of liver disease. Liver biopsies, which are usually obtained by inserting a needle into the liver percutaneously, can be used to evaluate the extent of liver fibrosis, or to search for evidence of rejection in a previously transplanted liver. A widely applied imaging technique is referred to as ERCP, which stands for endoscopic retrograde cholangiopancreatography. In this procedure, a special endoscope is introduced into the duodenum via the mouth, and used to insert a small tube through the sphincter of Oddi, through which contrast medium is injected. Subsequent X-rays can then visualize the drainage routes from the biliary system and pancreas, which permits the diagnosis of obstructions or strictures. Other imaging modalities, such as magnetic resonance imaging, are also assuming an increasing role in assessing liver disease and the architecture of the biliary system.

The prognosis of end-stage liver disease, and by extension the urgency of transplantation, has commonly been assessed by calculating the so-called Child-Pugh score, which takes into account 5 measures of hepatic function. The Child-Pugh score was originally designed as a predictor of surgical mortality in liver disease patients. More recently, the Child-Pugh score has been supplemented by the Model for End-Stage Liver Disease (MELD) score, which weights serum bilirubin, creatinine, and prothrombin time to predict survival. Patients awaiting liver transplantation in the United States are now prioritized on the basis of their MELD score, which results in the allocation of organs first to those who are sickest. This has reduced waiting-list mortality without impairing post-transplant outcomes.