Monday, June 30, 2014

What's Wrong with Tumor Case Reports?


The Case Report (also known as Case Study) is a poorly utilized resource. Every healthcare worker is familiar with case reports; medical journals sometimes contain a section devoted to them. Case reports typically begin with a comment regarding the extreme rarity of the featured disease. You can expect to see phrases such as "fewer than a dozen have been reported in the literature" or "the authors have encountered no other cases of this lesion," or such and such a finding makes this lesion particularly uncommon and difficult to diagnose; and so on. The point that the authors are trying to convey is that the case report is worthy of publication specifically because it is rare. After describing the clinical and pathologic features of the case, there is usually some obligatory paragraph explaining how the disease can be distinguished from more common diseases, with which it may have overlapping clinical or pathological features. Sometimes the case report will contain an end-paragraph that undermines the accuracy of the start-paragraph, suggesting that the lesion is more common than one might think; implying here that under-diagnosis is the root cause of the lesion's apparent rarity. Always, the case report serves as a cautionary exercise, intended to ward against misdiagnosis.

The "beware this lesion" approach to case reporting can easily miss the most important aspect of this type of publication. Science, and most aspects of human understanding, involve generalizing from the specific. When Isaac Newton saw an apple falling, he was not thinking that he could write a case report about how he once saw an apple drop, thus warning others not to stand under apple trees lest a rare apple might thump them upon the head. Newton generalized from the apple to all objects, and questioned the basic nature of gravity, to produce mathematically-described laws by which gravity interacts with matter.

Every case report of a rare disease or of a rare presentation of a common disease should serve as a special instance of a general phenomenon. In natural systems, there are no outliers. Every event, no matter how rare, is produced as the consequence of general laws of nature. The case report gives us an opportunity to clarify the general way things work, by isolating one specific and rarely observed factor.

Much of what we know about common tumors has come from studying familial cases, and then testing to see if the same gene that caused the familial cases is also present in the sporadic cases. Here are a few examples, taken from my recently published book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases.
- Germline mutations of the p53 tumor suppressor gene are present in the rare Li–Fraumeni syndrome. A somatic p53 mutation is present in about half of all human cancers [28].

- Families with germline mutations of the KIT gene develop gastrointestinal stromal tumors (GISTs). Somatic mutations of KIT occur in the majority of sporadic GIST tumors.

- Germline RET gene mutations occur in familial medullary carcinoma of thyroid, and in most cases of sporadic medullary carcinoma of thyroid [29,30].

- Germline RB1 gene mutations occur in familial retinoblastoma syndrome and in sporadic cases of retinoblastoma [31].

- Germline patched (ptc) gene mutations occur in basal cell nevus syndrome and in sporadically occurring basal cell carcinomas [32].

- Germline PTEN mutations occur in Cowden syndrome and Bannayan– Riley–Ruvalcaba syndrome, two inherited disorders associated with a high rate of endometrial carcinomas. PTEN mutations are found in 93% of sporadically occurring endometrial carcinomas [15].

In tumor after tumor, the genetic lesion present in sporadically occurring cancers would not have been found without prior knowledge of the syndromic gene (the gene responsible for the rare inherited condition). It would have been a terrible oversight if Li-Fraumeni syndrome, GISTs, medullary carcinoma of the thyroid, retinoblastoma, basal cell nevus syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba syndrome had merely served as rare case reports for the literature. Every rare disease should be accepted as an opportunity to find a cure for rare diseases and common diseases.

The process by which observations on rare diseases can be applied generally to all diseases, is discussed in detail in my recently published book, which builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.



I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: case report, case study, rare diseases, orphan diseases, orphan drugs, case studies, Li-Fraumeni syndrome, GISTs, medullary carcinoma of the thyroid, retinoblastoma, basal cell nevussyndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome

Thursday, June 26, 2014

Orphanet Blog on my Rare Diseases Book

Orphanet has just posted a blog spot featuring my new book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases



There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: rare disease, rare disease research, rare diseases, orphan diseases, orphan drugs, blog post, orphanet

Wednesday, June 25, 2014

Animal Models for Common Diseases (including cancer)

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.



Here is a short excerpt from Chapter 14.

“The proper study of Mankind is Man.”
—Alexander Pope in “An Essay on Man,” 1734.

Common diseases are complex, as is the response of humans to treatments for the common diseases. Are we likely to find adequate animal models for common diseases?

14.3.1 Rule—For the common diseases of humans, there are no adequate animal models.
Brief Rationale—The common diseases are complex, the end result of many genetic and environmental factors. There is no reason to expect that a complex set of factors interacting in humans could be replicated in an animal.


Rodents, especially mice and rats, are often used in disease research. Historically, the drug development process employs mouse models to identify candidate drugs for clinical trials in humans [20]. Few such mouse-inspired trials have shown success [21–24]. In a review of human clinical trials based on research data collected from mouse models, every one of 150 clinical trials of inflammatory responses in humans was a failure [20]. In the vascular field, there are animal models for stroke. Based on animal models, about 500 candidate drugs were proposed as neuroprotective agents in human stroke. Of the 500 candidate drugs, only two were shown to be of value for humans [23].

In the field of cancer research, carcinogens induce cancers in rodents, and the cancers that occur in rodents and humans share a set of fundamental properties: continuous growth, autonomous growth, invasiveness, metastasis (see Glossary item, Autonomous growth). Beyond these features, most animals models deviate from their human counterparts. Here just are a few examples:

- Rodent tumors develop over a very short period of time, limited by the short life expectancy of the mouse or rat. A strong carcinogen can produce palpable mouse tumors in mere weeks. The commonly occurring tumors in humans require years to develop.

- In most strains of rodent, tumors lack molecular markers commonly found in human tumors (e.g., p53). The cytogenetic markers for rodent tumors are different from the cytogenetic markers for human tumors. In fact, the karyotype, physical mappings of genes, causal genes, and gene polymorphisms of rodent tumors are all quite different from human tumors (see Glossary items, Synteny, Haplotype).

- Animals metabolize drugs differently compared to humans.

- Viruses, bacteria, and other organisms that cause human cancer are different from the organisms causing cancer in animals.

- The diet of animals is different from the diet of humans.

- The host factors of animals, including immune status, are different from those of humans.


I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: rare disease, animal models, carcinogenicity, cancer models, tumor models, drug development, drug trials, new drugs under development, rare disease research, rare diseases, orphan diseases, orphan drugs

Monday, June 23, 2014

Recent Posts on Rare Cancers and other Rare Diseases

This past week, I've been busy writing blogs on the topic of Rare Diseases. I'm hoping to generate some interest for my newly published book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases.

Here is the list of my rare disease posts, with links to blog sites:

Developing Diagnostic Tests for Common Diseases: Role of the Rare Diseases

Rare Diseases Account for Subsets of Common Diseases

Improving Clinical Trials by Focusing on Rare Diseases

Rare Diseases of Unknown Origin

Rare Diseases are Sentinels for the Common Diseases

Biological Differences between Rare Cancers and Common Cancers

Rare Diseases are Biologically Different from Common Diseases

Rare Cancers are Biologically Different from Common Cancers

Rare Cancers

Clinical Trials and Rare Diseases

Rules for the Rare Diseases

The Rationale for Funding Rare Disease Research

New Book Explains the Importance of Rare Disease Research

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: rare cancers, rare neoplasms, rare diseases, orphan drugs, funding justification, funding for rare diseases, funding for orphan drugs, rare disease organizations

Thursday, June 19, 2014

Clinical Trials and Rare Diseases

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases, including cancer, will come after we have developed cures for rare diseases.



Here is a book excerpt, from Chapter 14, Section 2:

It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical, and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial [12]. Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials [12].

Overall, about 95% of drugs that move through the clinical trial gauntlet will fail [13]. Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error [14–16]. Like any human endeavor, clinical trials need to be validated in clinical practice [10]. It may take years or decades to determine whether a treatment that demonstrated a small but statistically significant effect in a clinical trial will have equivalent value in everyday practice.

Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed toadvance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.

14.2.2 Rule—Clinical trials for common diseases have limited value if the test population is heterogeneous; as is often the case.

Brief Rationale—Abundant evidence suggests that most common diseases are heterogeneous, composed of genotypically and phenotypically distinct disease populations, with each population responding differently with the clinical trial.

The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail [13].

14.2.3 Rule—Clinical trials for the rare diseases are less expensive, can be performed with less money, and provide more definitive results than clinical trials on common diseases.

Brief Rationale—Common diseases are heterogeneous and produce a mixed set of results on subpopulations. This in turn dilutes the effect of a treatment and enlarges the required number of trial participants. Rare diseases are much more homogeneous than the common diseases, thus producing a uniform effect in the trial population, and thus lowering the number of trial participants required to produce a statistically convincing result.


Rare diseases often have a single genetic aberration, driving a single metabolic pathway that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are consistent, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease [13].

It is wrong to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminate the hit-or-miss accrual activities that characterize clinical trials for common diseases.

- Jules J. Berman, Ph.D., M.D.

tags: clinical trials, orphan drugs, drug trials, rare diseases, zebra diseases, rare disease organizations, rare disease advocates, cancer trials, diabetes trials, clinical trials for common diseases, clinical trials for rare diseases, rare diseases and orphan drugs

Tuesday, June 17, 2014

Rare Cancers are Biologically Different from Common Cancers

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. Chapter 8 covers the topic of rare cancers. This chapter builds the argument that our best chance of curing the common cancers will come after we have developed cures for rare cancers.


The chapter begins with a list of biological properties that distinguish the rare cancers from the common cancers:
1. Just a few types of common cancers account for the majority of occurrences of cancer.

2. Most of the different types of cancers are rare cancers. Specifically, there are several thousand different types of rare cancers, while there are only a few dozen types of common cancers.

3. Virtually every common cancer is composed of cells derived from the ectodermal or the endodermal layers of the embryo (see Glossary items, Ectoderm, Endoderm). Rare cancers derive from all three germ layers, but the majority of rare cancers derive from the mesoderm.

4. All of the childhood cancers are rare cancers.

5. All the advanced stage cancers that we can currently cure are rare cancers, and most of the curable rare cancers are cancers that occur in children.

6. Inherited syndromes that cause rare cancers are often associated with increased risk for developing common cancers; hence, the causes of rare cancers are related to the causes of common cancers.

7. Rare cancers are genetically simpler than common cancers (i.e., have fewer mutations). In many cases, we know the underlying mutation that leads to the development of rare cancers. We do not know the underlying mutation(s) that leads to common cancers.

8. Common cancers are genetically heterogeneous and may contain one or more rare types of cancer having the same clinical phenotype as the common cancer.

9. Most of what we know about the pathogenesis of cancer has come from observations on rare cancers.

10. The rare cancers serve as sentinels for environmental agents that can cause various types of cancer; either rare or common. Common cancers cannot serve as sentinels.

11. Treatments developed for the rare cancers will almost certainly apply to the common cancers.

- Jules Berman, Ph.D., M.D.

Friday, June 6, 2014

Rare Cancers

This week, my latest book entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Academic Press, an imprint of Elsevier.

The book develops a set of biological principles that apply to rare diseases and which distinguish the rare diseases from the common diseases on something other than a numeric basis (i.e., not just by their rarity).

Chapter 8 discusses the rare cancers, and their relationships to the common cancers. The chapter is sprinkled with general rules that are discussed in depth within the text. Here, the term “rule” means observations that are generally true. In many cases, counter-examples and constraints are also provided in the chapter. The rules are intended to encourage readers to think critically about the subject matter. Readers will find that the disease descriptions in the chapters will have greater meaning if the disease can be associated with a biological rule.

Here are the "rules" of rare cancers.

8.2.1 Rule—Most common cancers are caused by environmental agents.

Brief Rationale—The vast majority of cancers occur at body sites that are directly exposed to chemical, physical, or biological agents delivered by food, water, and air. The tissues that receive the highest levels of exposure are the same tissues that yield the highest number of tumors. Tissues of the body that are not directly exposed to outside agents (e.g., muscle, connective tissues) are not sites at which common cancers develop.

8.2.2 Rule—In adults, diseases of cells derived from ectoderm or from endoderm typically have an environmental cause.

Brief Rationale—Tissues deriving from ectoderm and endoderm are exposed to toxins at higher levels than are the tissues that derive from mesoderm. When a disease targets ectodermal- or endodermal-derived cells in adults, it is likely to have a toxic etiology. Cells of mesodermal origin (i.e., the inside cells) are typically spared, because they are less exposed to the environment.

8.2.3 Rule—Most of the metabolism of foreign compounds entering the human body is handled by cells derived from endoderm or ectoderm.

Brief Rationale—It stands to reason that the cells that receive the brunt of environmental toxins will be the cells that are adapted to detoxify exogenous chemicals.

8.2.4 Rule—Most chemical carcinogens need to be metabolized before they are converted to an active (i.e., mutagenic) molecular form.

Brief Rationale—Activated carcinogens are highly reactive molecules that can bind to just about any kind of molecule. Naturally active carcinogens would react with, and be neutralized by, non-genetic molecules before they could reach DNA. Highly carcinogenic molecules exist as stable, inactive molecular species that are metabolized within cells to active molecules that react with DNA.

8.3.1 Rule—Virtually all cancers of childhood have a germline genetic component to their pathogenesis.

Brief Rationale—The common cancers have multi-step etiologies, requiring many years to develop, and occurring in adults. Children simply do not have the opportunity to express diseases that involve repeated exposures to commonly occurring environmental agents. Hence, cancers in children develop from inborn mutations. Cancer-causing germline mutations are rare; hence, childhood cancers are rare.

8.3.2 Rule—Rare tumors are much more likely to have a single cause, a single carcinogenic pathway, a single inherited gene, or a single acquired marker, than are any of the common tumors.

Brief Rationale—Many different factors can lead to a common cancer; that is why the cancer is common. Only very specific and highly unlikely factors (e.g., genetic mutation) lead to rare cancers; that is why they are rare. 8.3.3 Rule—In a tumor that can occur as a rare, inherited form, or as a common, sporadic form, we always learn the most by studying the rare, inherited form and later extending our gained knowledge to the common, sporadic form. Brief Rationale—Only the subset of cases arising from an inherited germline mutation can be studied in affected and unaffected relatives.

8.3.4 Rule—If you look hard enough, you can usually find examples of syndromic disorders accounting for what might otherwise be considered to be a sporadic or non-syndromic childhood cancer.

Brief Rationale—A germline mutation having the biological power to cause cancer might be expected to produce some additional phenotypic effects in the organism.

8.3.5 Rule—There is no such thing as a mutation that is necessary and sufficient, by itself, to cause cancer.

Brief Rationale—In the worst of the inherited cancer syndromes, tumors do not occur in every organ, or even in every individual who carries the cancercausing mutation. The empiric absence of a 100% penetrant cancer mutation (i.e., one that always causes cancer) suggests that more than one event or condition must prevail during carcinogenesis.

8.3.6 Rule—In contrast to rare cancers, common cancers are characterized by many different mutations in many different genes, and the affected genes will vary from patient to patient and from tumor sample to tumor sample within the same patient.

Brief Rationale—Common cancers are genetically unstable.

8.4.1 Rule—Carcinogenesis, the pathogenesis of tumors, is a multi-step process.

Brief Rationale—Interventions can stop the process of carcinogenesis at various points in tumor development (e.g., the precancer stage), indicating the presence of multiple biological steps, each with characteristic properties and vulnerabilities.

8.4.2 Rule—Each step in carcinogenesis is a potential target of cancer prevention.

Brief Rationale—The key thing to know about carcinogenesis is that it occurs in steps. Because there are multiple steps in carcinogenesis, there are multiple opportunities for blocking the progression of cancer [6,7].

8.4.3 Rule—Rare cancers and rare cancer syndromes have helped us to dissect the various steps of carcinogenesis.

Brief Rationale—We see rare cancers and rare cancer syndromes that target various cellular processes occurring throughout carcinogenesis. These would include polymorphisms in genes that metabolize carcinogens at the time of initiation, that repair DNA (e.g., xeroderma pigmentosum), that preserve the integrity of DNA replication, that control microsatellite stability (e.g., hereditary non-polyposis colon cancer syndrome), that control apoptosis, that activate tumor suppressor genes (e.g., Li–Fraumeni syndrome) and tumor oncogenes (BCR/ABL fusion gene in chronic myelogenous leukemia), that drive hyper- plasia of particular cell types (e.g., c-KIT gastrointestinal stromal tumors), and so on.

8.4.4 Rule—Rare cancers are easier to cure than common cancers.

Brief Rationale—The malignant phenotypes of rare cancers are often driven by a single genetic alteration or a single cellular pathway. It is feasible to target and inhibit a single pathway with a single drug. Common cancers are driven by hundreds or thousands of aberrant pathways. We currently have no way of inhibiting all of the possible pathways that drive the malignant phenotype in common cancers.

TABLE OF CONTENTS for Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases

PART I. Understanding the Problem

1. What are the Rare Diseases, and Why Do We Care?

1.1 The Definition of Rare Disease

1.2 Remarkable Progress in the Rare Diseases

2. What are the Common Diseases?

2.1 The Common Diseases of Humans, a Short but Terrifying List

2.2 The Recent Decline in Progress against Common Diseases

2.3 Why Medical Scientists have Failed to Eradicate the Common Diseases

3. Six Observations to Ponder While Reading This Book

3.1 Rare Diseases are Biologically Different from Common Diseases

3.2 Common Diseases Typically Occur in Adults; Rare Diseases are Often Diseases of Childhood

3.3 Rare Diseases Usually Occur with a Mendelian Pattern of Inheritance. Common Diseases are Non-Mendelian

3.4 Rare Diseases Often Occur as Syndromes, Involving Several Organs or Physiologic Systems, Often in Surprising Ways. Common Diseases are Typically Non-Syndromic

3.5 Environmental Factors Play a Major Role in the Cause of Common Diseases; Less so in the Inherited Rare Diseases

3.6 The Difference in Rates of Occurrence of the Rare Diseases Compared with the Common Diseases is Profound, Often on the Order of a Thousand-Fold

3.7 There are Many More Rare Diseases than there are Common Diseases

PART II. Rare Lessons for Common Diseases

4. Aging

4.1 Normal Patterns of Aging

4.2 Aging and Immortality

4.3 Premature Aging Disorders

4.4 Aging as a Disease of Non-Renewable Cells

5. Diseases of the Heart and Vessels

5.1 Heart Attacks

5.2 Rare Desmosome-Based Cardiomyopathies

5.3 Sudden Death and Rare Diseases Hidden in Unexplained Clinical Events

5.4 Hypertension and Obesity: Quantitative Traits with Cardiovascular Co-Morbidities

6. Infectious Diseases And Immune Deficiencies

6.1 The Burden of Infectious Diseases in Humans

6.2 Biological Taxonomy: Where Rare Infectious Diseases Mingle with the Common Infectious Diseases

6.3 Biological Properties of the Rare Infectious Diseases

6.4 Rare Diseases of Unknown Etiology

6.5 Fungi as a Model Infectious Organism Causing Rare Diseases

7. Diseases of Immunity

7.1 Immune Status and the Clinical Expression of Infectious Diseases

7.2 Autoimmune Disorders

8. Cancer

8.1 Rare Cancers are Fundamentally Different from Common Cancers

8.2 The Dichotomous Development of Rare Cancers and Common Cancers

8.3 The Genetics of Rare Cancers and Common Cancers

8.4 Using Rare Diseases to Understand Carcinogenesis

PART III. Fundamental Relationships between Rare and Common Diseases

9. Causation And the Limits of Modern Genetics

9.1 The Inadequate Meaning of Biological Causation

9.2 The Complexity of the So-Called Monogenic Rare Diseases

9.3 One Monogenic Disorder, Many Genes

9.4 Gene Variation and the Limits of Pharmacogenetics

9.5 Environmental Phenocopies of Rare Diseases

10. Pathogenesis; Causation's Shadow

10.1 The Mystery of Tissue Specificity

10.2 Cell Regulation and Epigenomics

10.3 Disease Phenotype

10.4 Dissecting Pathways Using Rare Diseases

10.5 Precursor Lesions and Disease Progression

11. Rare Diseases and Common Diseases: Understanding Their Fundamental Differences

11.1 Review of the Fundamentals in Light of the Incidentals

11.2 A Trip to Monte Carlo: How Normal Variants Express a Disease Phenotype

11.3 Associating Genes with Common Diseases

11.4 Mutation Versus Variation

12. Rare Diseases and Common Diseases: Understanding Their Relationships

12.1 Shared Genes

12.2 Shared Phenotypes

13. Shared Benefits

13.1 Shared Prevention

13.2 Shared Diagnostics

13.3 Shared Cures

14. Conclusion

14.1 Progress in the Rare Diseases: Social and Political Issues

14.2 Smarter Clinical Trials

14.3 For the Common Diseases, Animals are Poor Substitutes for Humans

14.4 Hubris

Appendix I List of Genes Causing More Than One Disease

Appendix II Rules, Some of Which are Always True,

and All of Which are Sometimes True

Glossary

Index

-Jules J. Berman, Ph.D., M.D.