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Thursday, May 30, 2013

Pathology


Pathology



A renal cell carcinoma (chromophobe type) viewed on auhematoxylin & eosin stained slide


Pathology is the scientific study of the nature, causes, processes, development, and consequences of the diseases.

Pathology addresses four components of disease:

  • cause/etiology
  • mechanisms of development (pathogenesis)
  • structural alterations of cells (morphologic changes)
  • the consequences of changes (clinical manifestations)

Pathology is further separated into divisions, based on either the system being studied (e.g. veterinary pathology and animal disease) or the focus of the examination (e.g. forensic pathology and determining the cause of death).



History of pathology:

The history of pathology can be traced back to antiquity when people began examining bodies. The examination of bodies led to the dissection of bodies in order to justify the cause of death. During that time, the people already began formulating today what we know as inflammation, tumors, boils, and much more.

Pathology began to develop as a subject during the 19th Century through teachers and physicians that studied pathology. They referred to it as “pathological anatomy” or “morbid anatomy.” However, pathology as a field of medicine was not recognized until the late 19th and early 20th centuries. In the 19th century, physicians realized that disease-causing pathogens, germs, created themselves and that symptoms were not the vital characteristics of a disease. Through the new information gathered regarding germ reproduction, physicians began to compare the characteristics of one germ’s symptoms as they developed within an affected individual to another germ’s characteristics and symptoms.

This realization led to the foundational understanding that diseases are able to create themselves, and that they can affect human beings in unique ways. In order to determine causes of diseases, medical experts used the most common and widely accepted assumptions or symptoms of their times. This is true for those in the past and today.

What set pathology apart from other specialties was the ability to determine a symptom with the naked eye. During the 19th century, Rudolf Virchow gave the biggest contribution to the field by introducing the procedure of analyzing tissue and cells through a microscope to pathologists. This greatly affected the discipline because it was another way to analyze objects, and it led to more advanced technological developments.

By the late 1920s to early 1930s pathology was deemed a medical specialty.  During the years following, the decision to split pathology into sub-specialties arose. Today, anatomical, clinical, molecular, plant, forensic, oral, veterinary, dermatopathology, hematopathology, and pathology exist as medical specialties. Today, pathologists are discovering new diseases, examining exotic diseases that enter the country, and working on a solution to cure diseases such as AIDS, HIV, Herpes, cancer, and more. Thus the evolution of pathology is evidence of the real value of science, which lies in its ability to continually research and develop new methods while giving credit to those who originally developed the idea.



Anatomical pathology:



Pathologist instructor and students of anatomical pathology

Anatomical pathology (Commonwealth) or anatomic pathology (United States) is a medical specialty that is concerned with the diagnosis of disease based on the gross, microscopic, chemical, immunologic and molecular examination of organs, tissues, and whole bodies (autopsy).
Anatomical pathology is itself divided in subspecialties, the main ones being surgical pathology, cytopathology, and forensic pathology. To be licensed to practice pathology, one has to complete medical school and secure a license to practice medicine. An approved residency program and certification (in the United States, the American Board of Pathology or the American Osteopathic Board of Pathology) is usually required to obtain employment or hospital privileges.

Anatomical pathology is one of two branches of pathology, the other being clinical pathology, the diagnosis of disease through the laboratory analysis of bodily fluids and tissues. Often, pathologists practice both anatomical and clinical pathology, a combination known as general pathology. The distinction between anatomic and clinical pathology is increasingly blurred by the introduction of technologies that require new expertise and the need to provide patients and referring physicians with integrated diagnostic reports. Similar specialties exist in veterinary pathology.



Clinical pathology:




Clinical chemistry: an automated blood chemistry analyzer

Clinical pathology is a medical specialty that is concerned with the diagnosis of disease based on the laboratory analysis of bodily fluids such as blood and urine, and tissues using the tools of chemistry, microbiology, hematology and molecular pathology. Clinical pathologists work in close collaboration with medical technologists, hospital administrations, and referring physicians to ensure the accuracy and optimal utilization of laboratory testing.

Clinical pathology is one of the two major divisions of pathology, the other being anatomical pathology. Often, pathologists practice both anatomical and clinical pathology, a combination sometimes known as general pathology.



Dermatopathology:

Dermatopathology is a subspecialty of anatomic pathology that focuses on the skin as an organ. It is unique in that there are two routes which a physician can use to obtain this specialization. All general pathologists and general dermatologists are trained in the pathology of the skin; however, the dermatopathologist is a specialist in this organ. In the USA, either a general pathologist or a dermatologist can undergo a 1 to 2 year fellowship in the field of dermatopathology. The completion of this fellowship allows one to take a subspecialty board examination, and becomes a board certified dermatopathologist.



Hematopathology:



Hematopathology: A Wright's stained bone marrow aspirate smear of patient with precursor B-cell acute lymphoblastic leukemia

Hematopathology is the study of diseases of blood cells (White blood cells, red blood cells, platelets) and cells/tissues/organs comprising the hematopoietic system. The term hematopoietic system refers to tissues and organs that produce and/or primarily host hematopoietic cells and include bone marrow, lymph node, thymus, spleen, and other lymphoid tissues. In the United States, hematopathology is a board certified subspecialty (American Board of Pathology) practiced by those physicians who have completed general pathology residency (anatomic, clinical, or combined) and an additional year of fellowship training in hematology. The hematopathologist reviews biopsies of lymph nodes, bone marrows and other tissues involved by an infiltrate of cells of the hematopoietic system. In addition, the hematopathologist may be in charge of flow cytometric and/or molecular hematopathology studies. After the hematopathologist makes the diagnosis, the hematologist or hemato-oncologist can make a decision about the best course of action.



Renal pathology:

Membranous glomerulonephritis
Classification and external resources



Micrograph of membranous nephropathy showing prominent glomerular basement membrane spikes. MPAS stain

Renal pathology is the study of medial diseases (non-tumor) of the kidney. In the United States, renal pathology is practiced by physicians who have completed general pathology residency training (anatomic or combined anatomic/clinical) and an additional year of fellowship training in renal pathology. A renal pathologist reviews biopsies of the kidney and integrates findings from multiple methodologies including light microscopy, immunofluorescence microscopy, and electron microscopy. Renal pathologists work closely with nephrologists and carefully integrate the clinical history/laboratory studies in the evaluation of renal biopsy specimens. Renal pathologists require a detailed understanding of immunology as it is often critical in interpreting specimens (particularly from renal transplants) as well as conceptualizing pathogenesis of many renal diseases. Once a morphologic diagnosis is made by a renal pathologist, the diagnosis is communicated to the clinical physician (nephrologist) who can then formulate a plan of care/treatment.



Oral and Maxillofacial Pathology:

Oral and Maxillofacial Pathology is one of nine dental specialties recognized by the American Dental Association. Oral Pathologists must complete three years of post doctoral training in an accredited program and subsequently obtain Diplomate status from the American Board of Oral and Maxillofacial Pathology. The specialty focuses on the diagnosis, clinical management and investigation of diseases that affect the oral cavity and surrounding maxillofacial structures including but not limited to odontogenic, infectious, epithelial, salivary gland, bone and soft tissue pathologies.



Forensic pathology:

Forensic pathology is a branch of pathology concerned with determining the cause of death by examination of a cadaver. The autopsy is performed by the pathologist at the request of a coroner usually during the investigation of criminal law cases and civil law cases in some jurisdictions. Forensic pathologists are also frequently asked to confirm the identity of a cadaver.
The word forensics is derived from the Latin forēnsis meaning forum.



Veterinary pathology:

Veterinary pathologists are doctors of veterinary medicine who specialize in the diagnosis of diseases through the examination of animal tissue and body fluids. As with medical pathology, veterinary pathology is divided in two branches, anatomical pathology and clinical pathology.

Veterinary pathologists are also critical participants in the drug discovery and development. Drug discovery is most often accomplished by testing for efficacy in animal models of disease such as arthritis. Drug discovery involves modification of chemical molecules to improve their biological characteristics of absorption, distribution, metabolism and elimination (ADME) where veterinary toxicologic pathologists evaluate new candidate drugs for toxic effects in animals before they are tested on humans.



Plant pathology:




Powdery mildew, a biotrophic fungus

Plant pathology (also phytopathology) is the scientific study of plant diseases caused by pathogens (infectious diseases) and environmental conditions (physiological factors). Organisms that cause infectious disease include fungi, oomycetes, bacteria, viruses, viroids, virus-like organisms, phytoplasmas, protozoa, nematodes and parasitic plants. Not included are insects, mites, vertebrate or other pests that affect plant health by consumption of plant tissues. Plant pathology also involves the study of pathogen identification, disease etiology, disease cycles, economic impact, plant disease epidemiology, plant disease resistance, how plant diseases affect humans and animals, pathosystem genetics, and management of plant diseases.

The "disease triangle" is a central concept of plant pathology. It is based on the principle that infectious diseases develop, or do not develop, based on three-way interactions between the host, the pathogen, and environmental conditions. Pathology is the medical specialty concerned with the study of the nature and causes of diseases. It underpins every aspect of medicine, from diagnostic testing and monitoring of chronic diseases to cutting-edge genetic research and blood transfusion technologies. Pathology is integral to the diagnosis of every cancer.

Pathology plays a vital role across all facets of medicine throughout our lives, from pre-conception to post mortem. In fact it has been said that “Medicine IS Pathology”.

Due to the popularity of many television programs, the word ‘pathology’ conjures images of dead bodies and people in lab coats investigating the cause of suspicious deaths for the police. That’s certainly a side of pathology, but in fact it’s far more likely that pathologists are busy in a hospital clinic or laboratory helping living people.

Pathologists are specialist medical practitioners who study the cause of disease and the ways in which diseases affect our bodies by examining changes in the tissues and in blood and other body fluids. Some of these changes show the potential to develop a disease, while others show its presence, cause or severity or monitor its progress or the effects of treatment.

The doctors you see in surgery or at a clinic all depend on the knowledge, diagnostic skills and advice of pathologists. Whether it’s a GP arranging a blood test or a surgeon wanting to know the nature of the lump removed at operation, the definitive answer is usually provided by a pathologist. Some pathologists also see patients and are involved directly in the day-to-day delivery of patient care.

Currently pathology has nine major areas of activity. These relate to either the methods used or the types of disease which they investigate. For further information on each discipline please click on one of the following:
Anatomical Pathology Chemical Pathology Clinical Pathology Forensic Pathology General Pathology Genetic Pathology Haematology Immunopathology Microbiology



Molecular pathology:

Molecular pathology is an emerging discipline within pathology, and focuses in the study and diagnosis of disease through the examination of molecules within organs, tissues or bodily fluids. Molecular pathology shares some aspects of practice with both anatomic pathology and clinical pathology, molecular biology, biochemistry, proteomics and genetics, and is sometimes considered a "crossover" discipline. It is multi-disciplinary in nature and focuses mainly on the sub-microscopic aspects of disease and unknown illnesses with strange causes.

It is a scientific discipline that encompasses the development of molecular and genetic approaches to the diagnosis and classification of human tumors, the design and validation of predictive biomarkers for treatment response and disease progression, the susceptibility of individuals of different genetic constitution to develop cancer, and the environmental and lifestyle factors implicated in carcinogenesis.



General pathology:

General pathology is a broad and complex scientific field which covers all of the areas of more specialist pathologies. General pathologists seek to understand the mechanisms of injury to cells and tissues, as well as the body's means of responding to and repairing injury. Areas of study include cellular adaptation to injury, necrosis, inflammation, wound healing and neoplasia. The term "general pathology" is also used to describe the practice of both anatomical and clinical pathology.



Pathology as a medical specialty:


Pathologist
Occupation
NamesDoctor, Medical Specialist
Activity sectorsMedicine

Description
Education requiredDoctor of Medicine, Doctor of Osteopathic Medicine

Pathologists are doctors who diagnose and characterize disease in living patients by examining biopsies or bodily fluids. In addition, pathologists interpret medical laboratory tests to help prevent illness or monitor a chronic condition.

The vast majority of cancer diagnoses are made by pathologists. Pathologists examine tissue biopsies to determine if they are benign or cancerous. Some pathologists specialize in genetic testing that can, for example, determine the most appropriate treatment for particular types of cancer. In addition, a pathologist analyzes blood samples from a patient's annual physical and alerts their primary care physician to any changes in their health early, when successful treatment is most likely. Pathologists also review results of tests ordered or performed by specialists, such as blood tests ordered by a cardiologist, a biopsy of a skin lesion removed by a dermatologist, or a Pap test performed by a gynecologist, to detect abnormalities.


This mastectomy specimen contains an infiltrating ductal carcinoma of the breast. A pathologist will use immunohistochemistry and fluorescent in-situ hybridization to detect markers which determine the optimal chemotherapy regimen for this patient.

Pathologists work with other doctors, medical specialty societies, medical laboratory professionals, and health care consumer organizations to set guidelines and standards for medical laboratory testing that help improve a patient's medical care and guide treatment, as well as ensure the quality and safety of domestic and international medical laboratories.

Pathologists may also conduct autopsies to investigate causes of death. Autopsy results can aid living patients by revealing a hereditary disease unknown to a patient's family.

Pathology is a core discipline of medical school and many pathologists are also teachers. As managers of medical laboratories (which include chemistry, microbiology, cytology, the blood bank, etc.), pathologists play an important role in the development of laboratory information systems. Although the medical practice of pathology grew out of the tradition of investigative pathology, most modern pathologists do not perform original research.

Pathology is a unique medical specialty. Pathology touches all of medicine, as diagnosis is the foundation of all patient care. In fact, more than 70 percent of all decisions about diagnosis and treatment, hospital admission, and discharge rest on medical test results.

Pathologists play a critical role on the patient care team, working with other doctors to treat patients and guide care. To be licensed, candidates must complete medical training, an approved residency program, and be certified by an appropriate body. In the US, certification is by the American Board of Pathology or the American Osteopathic Board of Pathology. The organization of subspecialties within pathology varies between nations, but usually includes anatomic pathology and clinical pathology.




REFERENCE:
https://en.wikipedia.org/wiki/Pathology

Drug design


Drug design


Drug design is the process of how the active ingredients been manufacturing through finding new medications based on the knowledge of a biological target. Mostly, the drug is commonly an organic small molecule that inhibits or activates the function of a biomolecule such as a protein, resulting in a therapeutic benefit to the patient through reaching its target. Basically, drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques.This type of modeling is often referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design.

The phrase "drug design" is to some extent a misnomer. What is really meant by drug design is ligand design (i.e., design of a small molecule that will bind tightly to its target). Although modeling techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as bioavailability, metabolic half-life, lack of side effects, etc., that first must be optimized before a ligand can become a safe and efficacious drug. These other characteristics are often difficult to optimize using rational drug design techniques.



Background on Drug design:

Typically a drug target is a key molecule involved in a particular metabolic or signaling pathway that is specific to a disease condition or pathology or to the infectivity or survival of a microbial pathogen. Some approaches attempt to inhibit the functioning of the pathway in the diseased state by causing a key molecule to stop functioning. Drugs may be designed that bind to the active region and inhibit this key molecule. Another approach may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state. In addition, these drugs should also be designed so as not to affect any other important "off-target" molecules or antitargets that may be similar in appearance to the target molecule, since drug interactions with off-target molecules may lead to undesirable side effects. Sequence homology is often used to identify such risks.

Most commonly, drugs are organic small molecules produced through chemical synthesis, but biopolymer-based drugs (also known as biologics) produced through biological processes are becoming increasingly more common. In addition, mRNA-based gene silencing technologies may have therapeutic applications.



Types of Drug design:




Flow charts of two strategies of structure-based drug design

There are two major types of drug design. The first is referred to as ligand-based drug design and the second, structure-based drug design.

1)     Ligand-based:

Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target. In other words, a model of the biological target may be built based on the knowledge of what binds to it, and this model in turn may be used to design new molecular entities that interact with the target. Alternatively, a quantitative structure-activity relationship (QSAR), in which a correlation between calculated properties of molecules and their experimentally determined biological activity, may be derived. These QSAR relationships in turn may be used to predict the activity of new analogs.


2)     Structure-based:

Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy. If an experimental structure of a target is not available, it may be possible to create a homology model of the target based on the experimental structure of a related protein. Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. Alternatively various automated computational procedures may be used to suggest new drug candidates.

As experimental methods such as X-ray crystallography and NMR develop, the amount of information concerning 3D structures of biomolecular targets has increased dramatically. In parallel, information about the structural dynamics and electronic properties about ligands has also increased. This has encouraged the rapid development of the structure-based drug design. Current methods for structure-based drug design can be divided roughly into two categories. The first category is about “finding” ligands for a given receptor, which is usually referred as database searching. In this case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This method is usually referred as ligand-based drug design. The key advantage of database searching is that it saves synthetic effort to obtain new lead compounds. Another category of structure-based drug design methods is about “building” ligands, which is usually referred as receptor-based drug design. In this case, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. These pieces can be either individual atoms or molecular fragments. The key advantage of such a method is that novel structures, not contained in any database, can be suggested.

  • Active site identification:

Active site identification is the first step in this program. It analyzes the protein to find the binding pocket, derives key interaction sites within the binding pocket, and then prepares the necessary data for Ligand fragment link. The basic inputs for this step are the 3D structure of the protein and a pre-docked ligand in PDB format, as well as their atomic properties. Both ligand and protein atoms need to be classified and their atomic properties should be defined, basically, into four atomic types:


  • hydrophobic atom: All carbons in hydrocarbon chains or in aromatic groups.
  • H-bond donor: Oxygen and nitrogen atoms bonded to hydrogen atom(s).
  • H-bond acceptor: Oxygen and sp2 or sp hybridized nitrogen atoms with lone electron pair(s).
  • Polar atom: Oxygen and nitrogen atoms that are neither H-bond donor nor H-bond acceptor, sulfur, phosphorus, halogen, metal, and carbon atoms bonded to hetero-atom(s).


The space inside the ligand binding region would be studied with virtual probe atoms of the four types above so the chemical environment of all spots in the ligand binding region can be known. Hence we are clear what kind of chemical fragments can be put into their corresponding spots in the ligand binding region of the receptor.

  • Ligand fragment link:



Flow chart for structure-based drug design

When we want to plant “seeds” into different regions defined by the previous section, we need a fragments database to choose fragments from. The term “fragment” is used here to describe the building blocks used in the construction process. The rationale of this algorithm lies in the fact that organic structures can be decomposed into basic chemical fragments. Although the diversity of organic structures is infinite, the number of basic fragments is rather limited.

Before the first fragment, i.e. the seed, is put into the binding pocket, and other fragments can be added one by one, it is useful to identify potential problems. First, the possibility for the fragment combinations is huge. A small perturbation of the previous fragment conformation would cause great difference in the following construction process. At the same time, in order to find the lowest binding energy on the Potential energy surface (PES) between planted fragments and receptor pocket, the scoring function calculation would be done for every step of conformation change of the fragments derived from every type of possible fragments combination. Since this requires a large amount of computation, using different tricks may use less computing power and let the program work more efficiently.

When a ligand is inserted into the pocket site of a receptor, groups on the ligand that bind tightly with the receptor should have the highest priority in finding their lowest-energy conformation. This allows us to put several seeds into the program at the same time and optimize the conformation of those seeds that form significant interactions with the receptor, and then connect those seeds into a continuous ligand in a manner that make the rest of the ligand have the lowest energy. The pre-placed seeds ensure high binding affinity and their optimal conformation determines the manner in which the ligand will be built, thus determining the overall structure of the final ligand. This strategy efficiently reduces the calculation burden for fragment construction. On the other hand, it reduces the possibility of the combination of fragments, which reduces the number of possible ligands that can be derived from the program. The two strategies above are widely used in most structure-based drug design programs. They are described as “Grow” and “Link”. The two strategies are always combined in order to make the construction result more reliable.

  • Scoring method:

Structure-based drug design attempts to use the structure of proteins as a basis for designing new ligands by applying accepted principles of molecular recognition. The basic assumption underlying structure-based drug design is that a good ligand molecule should bind tightly to its target. Thus, one of the most important principles for designing or obtaining potential new ligands is to predict the binding affinity of a certain ligand to its target and use it as a criterion for selection.

One early method was developed by Böhm to develop a general-purposed empirical scoring function in order to describe the binding energy. The following “Master Equation” was derived:




where:

  1. desolvation – enthalpic penalty for removing the ligand from solvent
  2. motion – entropic penalty for reducing the degrees of freedom when a ligand binds to its receptor
  3. configuration – conformational strain energy required to put the ligand in its "active" conformation
  4. interaction – enthalpic gain for "resolvating" the ligand with its receptor


The basic idea is that the overall binding free energy can be decomposed into independent components that are known to be important for the binding process. Each component reflects a certain kind of free energy alteration during the binding process between a ligand and its target receptor. The Master Equation is the linear combination of these components. According to Gibbs free energy equation, the relation between dissociation equilibrium constant, Kd, and the components of free energy was built.

Various computational methods are used to estimate each of the components of the master equation. For example, the change in polar surface area upon ligand binding can be used to estimate the desolvation energy. The number of rotatable bonds frozen upon ligand binding is proportional to the motion term. The configurational or strain energy can be estimated using molecular mechanics calculations. Finally the interaction energy can be estimated using methods such as the change in non polar surface, statistically derived potentials of mean force, the number of hydrogen bonds formed, etc. In practice, the components of the master equation are fit to experimental data using multiple linear regression. This can be done with a diverse training set including many types of ligands and receptors to produce a less accurate but more general "global" model or a more restricted set of ligands and receptors to produce a more accurate but less general "local" model.



Rational drug discovery:

In contrast to traditional methods of drug discovery, which rely on trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments, rational drug design begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required. The first is evidence that modulation of the target will have therapeutic value. This knowledge may come from, for example, disease linkage studies that show an association between mutations in the biological target and certain disease states. The second is that the target is "drugable". This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule.

Once a suitable target has been identified, the target is normally cloned and expressed. The expressed target is then used to establish a screening assay. In addition, the three-dimensional structure of the target may be determined.

The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. This may be done by using the screening assay (a "wet screen"). In addition, if the structure of the target is available, a virtual screen may be performed of candidate drugs. Ideally the candidate drug compounds should be "drug-like", that is they should possess properties that are predicted to lead to oral bioavailability, adequate chemical and metabolic stability, and minimal toxic effects. Several methods are available to estimate druglikeness such as Lipinski's Rule of Five and a range of scoring methods such as Lipophilic efficiency. Several methods for predicting drug metabolism have been proposed in the scientific literature, and a recent example is SPORCalc. Due to the complexity of the drug design process, two terms of interest are still serendipity and bounded rationality. Those challenges are caused by the large chemical space describing potential new drugs without side-effects.



Computer-aided drug design:

Computer-aided drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. Semi-empirical, ab initio quantum chemistry methods, or density functional theory are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential, polarizability, etc.) of the drug candidate that will influence binding affinity.

Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. Also, knowledge-based scoring function may be used to provide binding affinity estimates. These methods use linear regression, machine learning, neural nets or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target.

Ideally the computational method should be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized. The reality however is that present computational methods are imperfect and provide at best only qualitatively accurate estimates of affinity. Therefore in practice it still takes several iterations of design, synthesis, and testing before an optimal molecule is discovered. On the other hand, computational methods have accelerated discovery by reducing the number of iterations required and in addition have often provided more novel small molecule structures.

Drug design with the help of computers may be used at any of the following stages of drug discovery:

  1. hit identification using virtual screening (structure- or ligand-based design)
  2. hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
  3. lead optimization optimization of other pharmaceutical properties while maintaining affinity




Flowchart of a Usual Clustering Analysis for Structure-Based Drug Design

In order to overcome the insufficient prediction of binding affinity calculated by recent scoring functions, the protein-ligand interaction and compound 3D structure information are used to analysis. For structure-based drug design, several post-screening analysis focusing on protein-ligand interaction has been developed for improving enrichment and effectively mining potential candidates:

  • Consensus scoring


  1. Selecting candidates by voting of multiple scoring functions
  2. May lose the relationship between protein-ligand structural information and scoring criterion


  • Geometric analysis


  1. Comparing protein-ligand interactions by visually inspecting individual structures
  2. Becoming intractable when the number of complexes to be analyzed increasing


  • Cluster analysis


  1. Represent and cluster candidates according to protein-ligand 3D information
  2. Needs meaningful representation of protein-ligand interactions.




Examples:

A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as X-ray crystallography and NMR spectroscopy. Computer-aided drug design in particular becomes much more tractable when there is a high-resolution structure of a target protein bound to a potent ligand. This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide, which was approved in 1995.

Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.

Additional examples include:
  • Many of the atypical antipsychotics
  • Cimetidine, the prototypical H2-receptor antagonist from which the later members of the class were developed:
  • Selective COX-2 inhibitor NSAIDs
  • Dorzolamide, a carbonic anhydrase inhibitor used to treat glaucoma
  • Enfuvirtide, a peptide HIV entry inhibitor
  • Nonbenzodiazepines like zolpidem and zopiclone
  • Probenecid
  • SSRIs (selective serotonin reuptake inhibitors), a class of antidepressants
  • Zanamivir, an antiviral drug
  • Isentress, HIV Integrase inhibitor
Case studies:
  • 5-HT3 antagonists
  • Acetylcholine receptor agonists
  • Angiotensin receptor blockers
  • Bcr-Abl tyrosine kinase inhibitors
  • Cannabinoid receptor antagonists
  • CCR5 receptor antagonists
  • Cyclooxygenase 2 inhibitors
  • Dipeptidyl peptidase-4 inhibitors
  • HIV protease inhibitors
  • NK1 receptor antagonists
  • Non-nucleoside reverse transcriptase inhibitors
  • Proton pump inibitors
  • Triptans
  • TRPV1 antagonists
  • Renin inhibitors
  • c-Met inhibitors




REFERENCE:
https://en.wikipedia.org/wiki/Drug_design














Wednesday, May 29, 2013

History of medicine Part 1


History of medicine



Prehistoric medicine:

There is no specific time that we can say when we used the plants for the first time in healing but the use of plants as healing agents is a long-standing practice. Over time through emulation of the behavior of animals, a medicinal knowledge base developed and was passed between generations. As clannish culture specialized specific castes, Shamans and apothecaries performed the 'niche occupation' of healing.




The Hippocratic Corpus, is a collection of early medical works from ancient Greece strongly associated with the ancient Greek physician Hippocrates and his teachings



Antiquity:

  • Egypt




The Edwin Smith Surgical Papyrus, written in the 17th century BCE, contains the earliest recorded reference to the brain

Ancient Egypt developed a large, varied and fruitful medical tradition. Herodotus described the Egyptians as "the healthiest of all men, next to the Libyans", due to the dry climate and the notable public health system that they possessed. According to him, the practice of medicine is so specialized among them that each physician is a healer of one disease and no more." Although Egyptian medicine, to a good extent, dealt with the supernatural, it eventually developed a practical use in the fields of anatomy, public health, and clinical diagnostics.

Medical information in the Edwin Smith Papyrus may date to a time as early as 3000 BCE. The earliest known surgery was performed around 2750 BCE. Imhotep in the 3rd dynasty is sometimes credited with being the founder of ancient Egyptian medicine and with being the original author of the Edwin Smith Papyrus, detailing cures, ailments and anatomical observations. The Edwin Smith Papyrus is regarded as a copy of several earlier works and was written c. 1600 BCE. It is an ancient textbook on surgery almost completely devoid of magical thinking and describes in exquisite detail the examination, diagnosis, treatment, and prognosis of numerous ailments.

The Kahun Gynaecological Papyrus treats women's complaints, including problems with conception. Thirty four cases detailing diagnosis a treatment survive, some of them fragmentarily. Dating to 1800 BCE, it is the oldest surviving medical text of any kind.
Medical institutions, referred to as Houses of Life are known to have been established in ancient Egypt as early as the 1st Dynasty.

The earliest known physician is also credited to ancient Egypt: Hesy-Ra, “Chief of Dentists and Physicians” for King Djoser in the 27th century BCE.Also, the earliest known woman physician, Peseshet, practiced in Ancient Egypt at the time of the 4th dynasty. Her title was “Lady Overseer of the Lady Physicians.” In addition to her supervisory role, Peseshet trained midwives at an ancient Egyptian medical school in Sais.


  • Middle East:

The oldest Babylonian texts on medicine date back to the Old Babylonian period in the first half of the 2nd millennium BCE. The most extensive Babylonian medical text, however, is the Diagnostic Handbook written by the ummânū, or chief scholar, Esagil-kin-apli of Borsippa, during the reign of the Babylonian king Adad-apla-iddina (1069-1046 BCE).
Along with the Egyptians the Babylonians introduced the practice of diagnosis, prognosis, physical examination, and remedies. In addition, the Diagnostic Handbook introduced the methods of therapy and etiology. The text contains a list of medical symptoms and often detailed empirical observations along with logical rules used in combining observed symptoms on the body of a patient with its diagnosis and prognosis.

The Diagnostic Handbook was based on a logical set of axioms and assumptions, including the modern view that through the examination and inspection of the symptoms of a patient, it is possible to determine the patient's disease, its aetiology and future development, and the chances of the patient's recovery. The symptoms and diseases of a patient were treated through therapeutic means such as bandages, herbs and creams.
There was little development after the medieval era. Major European treatises on medicine took 200 years to reach the Middle East, where local rulers might consult Western doctors to get the latest treatments. Medical works in Arabic, Turkish, and Persian as late as 1800 were based on medieval Islamic medicine.


  • India:

The Atharvaveda, a sacred text of Hinduism dating from the Early Iron Age, is the first Indian text dealing with medicine, like the medicine of the Ancient Near East based on concepts of the exorcism of demons and magic. The Atharvaveda also contain prescriptions of herbs for various ailments. The use of herbs to treat ailments would later form a large part of Ayurveda.

In the first millennium BCE, there emerges in post-Vedic India the traditional medicine system known as Ayurveda, meaning the "complete knowledge for long life". Its two most famous texts belong to the schools of Charaka, born c. 600 BCE, and Sushruta, born 600 BCE. While these writings display some limited continuities with the earlier medical ideas known from the Vedas, historians have been able to demonstrate direct historical connections between early Ayurveda and the early literature of the Buddhists and Jains. The earliest foundations of Ayurveda were built on a synthesis of traditional herbal practices together with a massive addition of theoretical conceptualizations, new nosologies and new therapies dating from about 400 BCE onwards, and coming out of the communities of thinkers who included the Buddha and others.

According to the compendium of Charaka, the Charakasamhitā, health and disease are not predetermined and life may be prolonged by human effort. The compendium of Suśruta, the Suśrutasamhitā defines the purpose of medicine to cure the diseases of the sick, protect the healthy, and to prolong life. Both these ancient compendia include details of the examination, diagnosis, treatment, and prognosis of numerous ailments. The Suśrutasamhitā is notable for describing procedures on various forms of surgery, including rhinoplasty, the repair of torn ear lobes, perineal lithotomy, cataract surgery, and several other excisions and other surgical procedures. Most remarkable is Sushruta's penchant for scientific classification: His medical treatise consists of 184 chapters, 1,120 conditions are listed, including injuries and illnesses relating to ageing and mental illness. The Sushruta Samhita describe 125 surgical instrument, 300 surgical procedures and classifies human surgery in 8 categories

The Ayurvedic classics mention eight branches of medicine: kāyācikitsā (internal medicine), śalyacikitsā (surgery including anatomy), śālākyacikitsā (eye, ear, nose, and throat diseases), kaumārabhṛtya (pediatrics), bhūtavidyā (spirit medicine), and agada tantra (toxicology), rasāyana (science of rejuvenation), and vājīkaraṇa (aphrodisiacs, mainly for men). Apart from learning these, the student of Āyurveda was expected to know ten arts that were indispensable in the preparation and application of his medicines: distillation, operative skills, cooking, horticulture, metallurgy, sugar manufacture, pharmacy, analysis and separation of minerals, compounding of metals, and preparation of alkalis. The teaching of various subjects was done during the instruction of relevant clinical subjects. For example, teaching of anatomy was a part of the teaching of surgery, embryology was a part of training in pediatrics and obstetrics, and the knowledge of physiology and pathology was interwoven in the teaching of all the clinical disciplines. The normal length of the student's training appears to have been seven years. But the physician was to continue to learn.
As an alternative form of medicine in India, Unani medicine got deep roots and royal patronage during medieval times. It progressed during Indian sultanate and mughal periods. Unani medicine is very close to Ayurveda. Both are based on theory of the presence of the elements (in Unani, they are considered to be fire, water, earth and air) in the human body. According to followers of Unani medicine, these elements are present in different fluids and their balance leads to health and their imbalance leads to illness.
By the 18th century A.D., Sanskrit medical wisdom still dominated. Muslim rulers built large hospitals in 1595 in Hyderabad, and in Delhi in 1719, and numerous commentaries on ancient texts were written. Some European plants and medicinals were gradually incorporated into the Indian pharmacopeia, but otherwise there was little intellectual exchange with the West.


  • China:

China also developed a large body of traditional medicine. Much of the philosophy of traditional Chinese medicine derived from empirical observations of disease and illness by Taoist physicians and reflects the classical Chinese belief that individual human experiences express causative principles effective in the environment at all scales. These causative principles, whether material, essential, or mystical, correlate as the expression of the natural order of the universe.

The foundational text of Chinese medicine is the Huangdi neijing, or Yellow Emperor's Inner Canon, written 5th century to 3rd century BCE). near the end of the 2nd century AD, during the Han dynasty, Zhang Zhongjing, wrote a Treatise on Cold Damage, which contains the earliest known reference to the Neijing Suwen. The Jin Dynasty practitioner and advocate of acupuncture and moxibustion, Huangfu Mi (215-282), also quotes the Yellow Emperor in his Jiayi jing, c. 265. During the Tang Dynasty, the Suwen was expanded and revised, and is now the best extant representation of the foundational roots of traditional Chinese medicine. Traditional Chinese Medicine that is based on the use of herbal medicine, acupuncture, massage and other forms of therapy has been practiced in China for thousands of years.

In the 18th century, during the Qing dynasty, there was a proliferation of popular books as well as more advanced encyclopedias on traditional medicine. Jesuit missionaries introduced Western science and medicine to the royal court, the Chinese physicians ignored them.
Finally in the 19th century, Western medicine was introduced at the local level by Christian medical missionaries from the London Missionary Society (Britain), the Methodist Church (Britain) and the Presbyterian Church (USA). Benjamin Hobson (1816-1873) in 1839, set up a highly successful Wai Ai Clinic in Guangzhou, China. The Hong Kong College of Medicine for Chinese was founded in 1887 by the London Missionary Society, with its first graduate (in 1892) being Sun Yat-sen, who later led the Chinese Revolution (1911). The Hong Kong College of Medicine for Chinese was the forerunner of the School of Medicine of the University of Hong Kong, which started in 1911.

Due to the social custom that men and women should not be near to one another, the women of China were reluctant to be treated by male doctors. The missionaries sent women doctors such as Dr. Mary H. Fulton (1854-1927). Supported by the Foreign Missions Board of the Presbyterian Church (USA) she in 1902 founded the first medical college for women in China, the Hackett Medical College for Women, in Guangzhou.



Greek and Roman medicine:

  • Homer:

Around 800 BCE Homer in The Iliad gives descriptions of wound treatment by "the two sons of Asklepios, the admirable physicians Podaleirius and Machaon and one acting doctor, Patroclus. Because Machaon is wounded and Podaleirius is in combat Eurypylus asks Patroclus “to cut out this arrow from my thigh, wash off the blood with warm water and spread soothing ointment on the wound." Askelpios like Imhotep becomes god of healing over time. Temples dedicated to the healer-god Asclepius, known as Asclepieia (Ancient Greek: Ἀσκληπιεῖα, sing. Ἀσκληπιεῖον, 'Asclepieion), functioned as centers of medical advice, prognosis, and healing. At these shrines, patients would enter a dream-like state of induced sleep known as enkoimesis (ἐγκοίμησις) not unlike anesthesia, in which they either received guidance from the deity in a dream or were cured by surgery. Asclepeia provided carefully controlled spaces conducive to healing and fulfilled several of the requirements of institutions created for healing. In the Asclepieion of Epidaurus, three large marble boards dated to 350 BCE preserve the names, case histories, complaints, and cures of about 70 patients who came to the temple with a problem and shed it there. Some of the surgical cures listed, such as the opening of an abdominal abscess or the removal of traumatic foreign material, are realistic enough to have taken place, but with the patient in a state of enkoimesis induced with the help of soporific substances such as opium.

The first known Greek medical school opened in Cnidus in 700 BCE. Alcmaeon, author of the first anatomical work, worked at this school, and it was here that the practice of observing patients was established. As was the case elsewhere, the ancient Greeks developed a humoral medicine system where treatment sought to restore the balance of humours within the body.


  • Hippocrates:

A towering figure in the history of medicine was the physician Hippocrates of Kos (c. 460 – c. 370 BCE), considered the "father of modern medicine." The Hippocratic Corpus is a collection of around seventy early medical works from ancient Greece strongly associated with Hippocrates and his students. Most famously, Hippocrates invented the Hippocratic Oath for physicians, which is still relevant and in use today.
Hippocrates and his followers were first to describe many diseases and medical conditions. He is given credit for the first description of clubbing of the fingers, an important diagnostic sign in chronic suppurative lung disease, lung cancer and cyanotic heart disease. For this reason, clubbed fingers are sometimes referred to as "Hippocratic fingers".

Hippocrates was also the first physician to describe Hippocratic face in Prognosis. Shakespeare famously alludes to this description when writing of Falstaff's death in Act II, Scene iii. of Henry V. Hippocrates began to categorize illnesses as acute, chronic, endemic and epidemic, and use terms such as, "exacerbation, relapse, resolution, crisis, paroxysm, peak, and convalescence."

Another of Hippocrates's major contributions may be found in his descriptions of the symptomatology, physical findings, surgical treatment and prognosis of thoracic empyema, i.e. suppuration of the lining of the chest cavity. His teachings remain relevant to present-day students of pulmonary medicine and surgery. Hippocrates was the first documented chest surgeon and his findings are still valid.



View of the Askleipion of Kos, the best preserved instance of an Asklepieion




The Plinthios Brokhos as described by Greek physician Heraklas, a sling for binding a fractured jaw. These writings were preserved in one of Oribasius' collections


  • Celsus and Alexandria:

Two great Alexandrians laid the foundations for the scientific study of anatomy and physiology, Herophilus of Chalcedon and Erasistratus of Ceos. Other Alexandrian surgeons gave us; ligature (hemostasis), lithotomy, hernia operations, ophthalmic surgery, plastic surgery, methods of reduction of dislocations and fractures,tracheotomy, and mandrake as anesthesia. Most of what we know of them comes from Celsus and Galen of Pergamum (Greek: Γαληνός)

Herophilus of Chalcedon, working at the medical school of Alexandria placed intelligence in the brain, and connected the nervous system to motion and sensation. Herophilus also distinguished between veins and arteries, noting that the latter pulse while the former do not. He and his contemporary, Erasistratus of Chios, researched the role of veins and nerves, mapping their courses across the body. Erasistratus connected the increased complexity of the surface of the human brain compared to other animals to its superior intelligence. He sometimes employed experiments to further his research, at one time repeatedly weighing a caged bird, and noting its weight loss between feeding times. In Erasistratus' physiology, air enters the body, is then drawn by the lungs into the heart, where it is transformed into vital spirit, and is then pumped by the arteries throughout the body. Some of this vital spirit reaches the brain, where it is transformed into animal spirit, which is then distributed by the nerves.


  • Galen:

The Greek Galen was one of the greatest surgeons of the ancient world and performed many audacious operations—including brain and eye surgeries— that were not tried again for almost two millennia. Later, in medieval Europe, Galen's writings on anatomy became the mainstay of the medieval physician's university curriculum along; but they suffered greatly from stasis and intellectual stagnation. In the 1530s, however, Belgian anatomist and physician Andreas Vesalius took on a project to translate many of Galen's Greek texts into Latin. Vesalius's most famous work, De humani corporis fabrica, was greatly influenced by Galenic writing and form. The works of Galen were regarded as authoritative until well into the Middle Ages.
The Romans invented numerous surgical instruments, including the first instruments unique to women, as well as the surgical uses of forceps, scalpels, cautery, cross-bladed scissors, the surgical needle, the sound, and speculas. Romans also performed cataract surgery.


  • Islamic Middle Ages 9th-12th:




An Arabic manuscript, dated 1200, titled Anatomy of the Eye, authored by al-Mutadibih


The Islamic civilization rose to primacy in medical science as its physicians contributed significantly to the field of medicine, including anatomy, ophthalmology, pharmacology, pharmacy, physiology, surgery, and the pharmaceutical sciences. The Arabs were influenced by, and further developed Greek, Roman and Byzantine medical practices. Galen & Hippocrates were pre-eminent authorities.The translation of 129 works of ancient Greek physician Galen into Arabic by Hunayn ibn Ishaq and his assistants, and in particular Galen's insistence on a rational systematic approach to medicine, set the template for Islamic medicine, which rapidly spread throughout the Arab Empire. Muslim physicians set up dedicated hospitals.


  • Medieval Europe 400 to 1400 AD:



A miniature depicting the Schola Medica Salernitana

After 400 A.D., most of the medical institutions of the Roman Empire broke down and disappeared. Medical services were provided, especially for the poor, in the thousands of monasteries that sprang up across Europe. Rich nobles gave permanent endowments to the monasteries, in the expectation that these good works would lead to their salvation, and lessen their time in purgatory. Catholic theology held that the sick, especially the poor peasants, would also gain grace and lessen their own time in purgatory, through their suffering. Most of the medical advances of the Roman empire were forgotten, at his medicine relied increasingly on folk remedies.

Wallis identifies a prestige hierarchy with university educated physicians on top, followed by learned surgeons; craft-trained surgeons; barber surgeons; itinernant specialists such as dentist and oculists; empirics; and midwives.

1)     Schools:

The first medical schools were opened, most notably the Schola Medica Salernitana at Salerno in southern Italy. The cosmopolitan influences from Greek, Latin, Arabic, and Hebrew sources gave it an international reputation as the Hippocratic City. Students from wealthy families came for three years of preliminary studies and five of medical studies. Graduates were awarded the degree of "magister" (Latin for doctor); indeed physicians were 1st called "doctor" at Salerno. By the thirteenth century the medical school at Montpellier began to eclipse the Salernitan school. In the 12th century universities were founded in Italy, France and England which soon developed schools of medicine. The University of Montpellier in France and Italy's University of Padua and University of Bologna were leading schools. Nearly all the learning was from lectures and readings in Hippocrates, Galen, Avicenna and Aristotle. There was little clinical work or dissection.

2)     Humours:



13th century illustration showing the veins

The underlying principle of most medieval medicine was Galen's theory of humours. This was derived from the ancient medical works, and dominated all western medicine until the 19th century. The theory stated that within every individual there were four humours, or principal fluids - black bile, yellow bile, phlegm, and blood, these were produced by various organs in the body, and they had to be in balance for a person to remain healthy. Too much phlegm in the body, for example, caused lung problems; and the body tried to cough up the phlegm to restore a balance. The balance of humours in humans could be achieved by diet, medicines, and by blood-letting, using leeches. The four humours were also associated with the four seasons, black bile-autumn, yellow bile-summer, phlegm-winter and blood-spring.

Healing included both physical and spiritual therapeutics, such as the right herbs, a suitable, diet, clean bedding, and the sense that care was always at hand. Other procedures used to help patients included the Mass, prayers, relics of saints, and music used to calm a troubled mind or quickened pulse.



Renaissance to Early Modern period 16th-18th century:

The Renaissance brought an intense focus on scholarship to Christian Europe.  A major effort to translate the Arabic and Greek scientific works into Latin emerged. Europeans gradually became experts not only the ancient writings of the Romans and Greeks, but in the contemporary writings of Islamic scientists. During the later centuries of the Renaissance came an increase in experimental investigation, particularly in the field of dissection and body examination, thus advancing our knowledge of human anatomy.

The development of modern neurology began in the 16th century with Vesalius, who described the anatomy of the brain and other organs; he had little knowledge of the brain's function, thinking that it resided mainly in the ventricles. Over his lifetime he corrected over 200 of Galen's mistakes. Understanding of medical sciences and diagnosis improved, but with little direct benefit to health care. Few effective drugs existed, beyond opium and quinine. Folklore cures and potentially poisonous metal-based compounds were popular treatments. Independently from Ibn al-Nafis, Michael Servetus rediscovered the pulmonary circulation, but this discovery did not reach the public cause it was written down for the first time in the "Manuscript of Paris" in 1546, and later published in the theological work which he paid with his life in 1553. Later this was perfected by Renaldus Columbus and Andrea Cesalpino. Later William Harvey provided a refined and complete description of the circulatory system. The most useful tomes in medicine used both by students and expert physicians were Materia Medica and Pharmacopoeia.


  • Paracelsus:

Paracelsus (1493-1541), was an erratic and abusive innovator who rejected Galen and bookish knowledge, calling for experimental research, with heavy doses of mysticism, alchemy and magic mixed in. The point is that he rejected sacred magic (miracles) under Church auspisces and looked for cures in nature. He preached but he also pioneered the use of chemicals and minerals in medicine. His hermetical views were that sickness and health in the body relied on the harmony of man (microcosm) and Nature (macrocosm). He took an approach different from those before him, using this analogy not in the manner of soul-purification but in the manner that humans must have certain balances of minerals in their bodies, and that certain illnesses of the body had chemical remedies that could cure them. Most of his influence came after his death. Paracelsus is a highly controversial figure in the history of medicine, with most experts hailing him as a Father of Modern Medicine for shaking off religious orthodoxy and inspiring many researchers; others say he was a mystic more than a scientist and downplay his importance.


  • Padua and Bologna:



Vesalius's Fabrica contained many intricately detailed drawings of human dissections, often in allegorical poses


University training of physicians began in the 13th century.

The University of Padua began teaching medicine in 1222. It played a leading role in the identification and treatment of diseases and ailments, specializing in autopsies and the inner workings of the body. Starting in 1595, Padua's famous anatomical theatre drew artists and scientists studying the human body during public dissections. The intensive study of Galen led to critiques of Galen modeled on his own writing, as in the first book of Vesalius's De humani corporis fabrica. Andreas Vesalius held the chair of Surgery and Anatomy (explicator chirurgiae) and in 1543 published his anatomical discoveries in De Humani Corporis Fabrica. He portrayed the human body as an interdependent system of organ groupings. The book triggered great public interest in dissections and caused many other European cities to establish anatomical theatres.

At the University of Bologna the training of physicians began in 1219. The Italian city attracted students from across Europe. Taddeo Alderotti built a tradition of medical education that established the characteristic features of Italian learned medicine and was copied by medical schools elsewhere. Turisanus (d. 1320) was his student. The curriculum was revised and strengthened in 1560-1590. A representative professor was Julius Caesar Aranzi (Arantius) (1530–89). He became Professor of Anatomy and Surgery at the University of Bologna in 1556, where he established anatomy as a major branch of medicine for the first time. Aranzi combined anatomy with a description of pathological processes, based largely on his own research, Galen, and the work of his contemporary Italians. Aranzi discovered the 'Nodules of Aranzio' in the semilunar valves of the heart and wrote the first description of the superior levator palpebral and the coracobrachialis muscles. His books (in Latin) covered surgical techniques for many conditions, including hydrocephalus, nasal polyp, goitre and tumours to phimosis, ascites, haemorrhoids, anal abscess and fistulae.


  • Women:

Catholic women played large roles in health and healing in medieval and early modern Europe. A life as a nun was a prestigious role; wealthy families provided dowries for their daughters, and these funded the convents, while the nuns provided free nursing care for the poor.

The Catholic elites provided hospital services because of their theology of salvation that good works were the route to heaven. The Protestant reformers rejected the notion that rich men could gain God's grace through good works-and thereby escape purgatory-by providing cash endowments to charitable institutions. They also rejected the Catholic idea that the poor patients earned grace and salvation through their suffering. Protestants generally closed all the convents and most of the hospitals, sending women home to become housewives, often against their will. On the other hand, local officials recognized the public value of hospitals, and some were continued in Protestant lands, but without monks or nuns and in the control of local governments.

In London, the crown allowed two hospitals to continue their charitable work, under nonreligious control of city officials.The convents were all shut down but Harkness finds that women-some of them former nuns-were part of a new system that delivered essential medical services to people outside their family. The were employed by parishes and hospitals, as well as by private families, and provided nursing care as well as some medical, pharmaceutical, and surgical services.
Meanwhile, in Catholic lands such as France, rich families continued to fund convents and monasteries, and enrolled their daughters as nuns who provided free health services to the poor. Nursing was a religious role for the nurse, and there was little call for science.


  • Age of Enlightenment:

During the Age of Enlightenment, the 18th-century, science was held in high esteem and physicians upgraded their social status by becoming more scientific. The health field was crowded with self-trained barber-surgeons, apothecaries, midwives, drug peddlers, and charlatans.
Across Europe medical schools relied primarily on lectures and readings. In the final year student would have limited clinical experience by trailing the professor through the wards. Laboratory work was uncommon, and dissections were rarely done because of legal restrictions on cadavers. Most schools were small, and only Edinburgh, Scotland, with 11,000 alumni, produced large numbers of graduates.



  • Britain:


In Britain, there but three small hospitals after 1550. Pelling and Webster estimate that in London in the 1580 to 1600 period, out of a population of nearly 200,000 people, there were about 500 medical practitioners. Nurses and midwives are not included. There were about 50 physicians, 100 licensed surgeons, 100 apothecaries, and 250 additional unlicensed practitioners. In the last category about 25% were women. All across Britain-and indeed all of the world-the vast majority of the people in city, town or countryside depended for medical care on local amateurs with no professional training but with a reputation as wise healers who could diagnose problems and advise sick people what to do—and perhaps set broken bones, pull a tooth, give some traditional herbs or brews or perform a little magic to cure what ailed them.
The London Dispensary opened in 1696, the first clinic in the British Empire to dispense medicines to poor sick people. The innovation was slow to catch on, but new dispensaries were open in the 1770s. In the colonies, small hospitals opened in Philadelphia in 1752, New York in 1771, and Boston (Massachusetts General Hospital) in 1811.




Guy's Hospital 1820

Guy's Hospital, the first great British hospital opened in 1721 in London, with funding from businessman Thomas Guy. In 1821 a bequest of £200,000 by William Hunt in 1829 funded expansion for an additional hundred beds. Samuel Sharp (1709–78), a surgeon at Guy's Hospital, from 1733 to 1757, was internationally famous; his A Treatise on the Operations of Surgery (1st ed., 1739), was the first British study focused exclusively on operative technique.

English physician Thomas Percival (1740-1804) wrote a comprehensive system of medical conduct, Medical Ethics, or a Code of Institutes and Precepts, Adapted to the Professional Conduct of Physicians and Surgeons (1803) that set the standard for many textbooks.



19th century: Rise of modern medicine:




Anatomy of the heart (1890) by Enrique Simonet

The practice of medicine changed in the face of rapid advances in science, as well as new approaches by physicians. Hospital doctors began much more systematic analysis of patients' symptoms in diagnosis. Among the more powerful new techniques were anaesthesia, and the development of both antiseptic and aseptic operating theatres. Actual cures were developed for certain endemic infectious diseases. However the decline in many of the most lethal diseases was more due to improvements in public health and nutrition than to medicine. It was not until the 20th century that the application of the scientific method to medical research began to produce multiple important developments in medicine, with great advances in pharmacology and surgery.

Medicine was revolutionized in the 19th century and beyond by advances in chemistry and laboratory techniques and equipment, old ideas of infectious disease epidemiology were replaced with bacteriology and virology. Bacteria and microorganisms were first observed with a microscope by Antonie van Leeuwenhoek in 1676, initiating the scientific field microbiology.


  • Germ theory:

In Vienna Ignaz Semmelweis (1818–1865) in 1847 dramatically reduced the death rate of new mothers from childbed fever by the simple expedient of requiring physicians to clean their hands before attending to women in childbirth. His discovery pre-dated the germ theory of disease. However, his discoveries were not appreciated by his contemporaries and came into general use only with discoveries of British surgeon Joseph Lister, who in 1865 proved the principles of antisepsis in the treatment of wound.

Louis Pasteur, by laboratory work that linked microorganisms with disease, brought about a revolution in medicine; he successfully reached out to instruct the educated classes of France in the importance of the germ theory. Pasteur with Claude Bernard (1813–1878) invented the process of pasteurization still in use today. Pasteur, along with Robert Koch founded bacteriology. Koch, who was awarded the Nobel Prize in 1905, became famous for the discovery of the tubercle bacillus (1882) and the cholera bacillus (1883) and for his development of Koch's postulates.

The quality of military medicine differed sharply among nations. A comparison of British and French surgical work on wounded sailors at the Battle of Trafalgar of 1805 shows that Royal Navy surgeons practiced triage, amputated immediately rather than delay the operation, and kept surgical areas clean. They were well trained and practiced up-to-date methods of surgery and hygiene. By contrast, French surgeons tolerated unhygienic facilities and had less training and skill, resulting in much higher mortality rates for their patients.



  • Women:

1)     Women as nurses:

Women had always served in ancillary roles, and as midwives and healers. The professionalization of medicine forced them increasingly to the sidelines. As hospitals multiplied they relied in Europe on orders of Roman Catholic nun-nurses, and German Protestant and Anglican deaconesses in the early 19th century. They were trained in traditional methods of physical care that involved little knowledge of medicine. The breakthrough to professionalization based on knowledge of advanced medicine was led by Florence Nightingale in England.

She resolved to provide more advanced training than she saw on the Continent. At Kaiserswerth, where the first German nursing schools was founded in 1836 by Theodor Fliedner, she said, "The nursing was nil and the hygiene horrible.") Britain's male doctors preferred the old system, but Nightingale won out and her Nightingale Training School opened in 1860 and became a model. The Nightingale solution depended on the patronage of upper class women, and they proved eager to serve. Royalty became involved. In 1902 the wife of the British king took control of the nursing unit of the British army, became its president, and renamed it after herself as the Queen Alexandra's Royal Army Nursing Corps; when she died the next queen became president.

Today its Colonel In Chief is the daughter-in-law of Queen Elizabeth. In the United States, upper middle class women who already supported hospitals promoted nursing. The new profession proved highly attractive to women of all backgrounds, and schools of nursing opened in the late 19th century. They soon a function of large hospitals, where they provided a steady stream of low-paid idealistic workers. The International Red Cross began operations in numerous countries in the late 19th century, promoting nursing as an ideal profession for middle class women.

The Nightingale model was widely copied. Linda Richards (1841 – 1930) studied in London and became the professionally trained American nurse. She established nursing training programs in the United States and Japan, and created the first system for keeping individual medical records for hospitalized patients. The Russian Orthodox Church sponsored seven orders of nursing sisters in the late 19th century. They ran hospitals, clinics, almshouses, pharmacies, and shelters as well as training schools for nurses. In the Soviet era (1917-1991), with the aristocratic sponsors gone, nursing became a low-prestige occupation based in poorly maintained hospitals.

2)     Women as doctors:

It was very difficult for women to become doctors before the 1970s. Elizabeth Blackwell (1821–1910) became the first woman to formally study and practice medicine in the United States. She was a leader in women's medical education. While Blackwell viewed medicine as a means for social and moral reform, her student Mary Putnam Jacobi (1842-1906) focused on curing disease. At a deeper level of disagreement, Blackwell felt that women would succeed in medicine because of their humane female values, but Jacobi believed that women should participate as the equals of men in all medical specialties using identical methods, values and insights.


  • Paris:

Paris and Vienna were the two leading medical centers on the Continent in the era 1750-1914.
In 1770s-1850s Paris became a world center of medical research and teaching. The "Paris School" emphasized that teaching and research should be based in large hospitals and promoted the professionalization of the medical profession and the emphasis on sanitation and public health. A major reformer was Jean-Antoine Chaptal (1756-1832), a physician who was Minister of Internal Affairs. He created the Paris Hospital, health councils, and other bodies.

Louis Pasteur (1822-1895) was one of the most important founders of medical microbiology. He is remembered for his remarkable breakthroughs in the causes and preventions of diseases. His discoveries reduced mortality from puerperal fever, and he created the first vaccines for rabies and anthrax. His experiments supported the germ theory of disease. He was best known to the general public for inventing a method to treat milk and wine in order to prevent it from causing sickness, a process that came to be called pasteurization. He is regarded as one of the three main founders of microbiology, together with Ferdinand Cohn and Robert Koch. He worked chiefly in Paris and in 1887 founded the Pasteur Institute there to perpetuate his commitment to basic research and its practical applications. As soon as his institute was created, Pasteur brought together scientists with various specialties.

The first five departments were directed by Emile Duclaux (general microbiology research) and Charles Chamberland (microbe research applied to hygiene), as well as a biologist, Ilya Ilyich Mechnikov (morphological microbe research) and two physicians, Jacques-Joseph Grancher (rabies) and Emile Roux (technical microbe research). One year after the inauguration of the Institut Pasteur, Roux set up the first course of microbiology ever taught in the world, then entitled Cours de Microbie Technique (Course of microbe research techniques). It became the model for numeous research centers around the world named "Pasteur Institutes."


  • Vienna:

The First Viennese School of Medicine, 1750-1800, was led by the Dutchman Gerard van Swieten (1700-1772), who aimed to put medicine on new scientific foundations - promoting unprejudiced clinical observation, botanical and chemical research, and introducing simple but powerful remedies. When the Vienna General Hospital opened in 1784, it at once became the world's largest hospital and physicians acquired a facility that gradually developed into the most important research centre. Progress ended with the Napoleonic wars and the government shutdown in 1819 of all liberal journals and schools; this caused a general return to traditionalism and eclecticism in medicine.

Vienna was the capital of a diverse empire and attracted not just Germans but Czechs, Hungarians, Jews, Poles and others to its world-class medical facilities. After 1820 the Second Viennese School of Medicine emerged with the contributions of physicians such as Carl Freiherr von Rokitansky, Josef Škoda, Ferdinand Ritter von Hebra, and Ignaz Philipp Semmelweis. Basic medical science expanded and specialization advanced. Furthermore, the first dermatology, eye, as well as ear, nose, and throat clinics in the world were founded in Vienna. The textbook of ophthalmologist Georg Joseph Beer (1763-1821) Lehre von den Augenkrankheiten combined practical research and philosophical speculations, and became the standard reference work for decades.


  • Berlin:

After 1871 Berlin, the capital of the new German Empire, became a leading center for medical research. Robert Koch (1843-1910) was a representative leader. He became famous for isolating Bacillus anthracis (1877), the Tuberculosis bacillus (1882) and Vibrio cholerae (1883) and for his development of Koch's postulates. He was awarded the Nobel Prize in Physiology or Medicine in 1905 for his tuberculosis findings. Koch is one of the founders of microbiology, inspiring such major figures as Paul Ehrlich and Gerhard Domagk.


  • U.S. Civil War:

In the American Civil War (1861–65), as was typical of the 19th century, more soldiers died of disease than in battle, and even larger numbers were temporarily incapacitated by wounds, disease and accidents. Conditions were poor in the Confederacy, where doctors and medical supplies were in short supply.The war had a dramatic long-term impact on American medicine, from surgerical technique to hospitals to nursing and to research facilities.

The hygiene of the training and field camps was poor, especially at the beginning of the war when men who had seldom been far from home were brought together for training with thousands of strangers. First came epidemics of the childhood diseases of chicken pox, mumps, whooping cough, and, especially, measles. Operations in the South meant a dangerous and new disease environment, bringing diarrhea, dysentery, typhoid fever, and malaria. There were no antibiotics, so the surgeons prescribed coffee, whiskey, and quinine. Harsh weather, bad water, inadequate shelter in winter quarters, poor policing of camps, and dirty camp hospitals took their toll.

This was a common scenario in wars from time immemorial, and conditions faced by the Confederate army were even worse. The Union responded by building army hospitals in every state. What was different in the Union was the emergence of skilled, well-funded medical organizers who took proactive action, especially in the much enlarged United States Army Medical Department, and the United States Sanitary Commission, a new private agency. Numerous other new agencies also targeted the medical and morale needs of soldiers, including the United States Christian Commission as well as smaller private agencies.
The U.S. Army learned many lessons and in 1886, it established the Hospital Corps.


  • Statistical methods:




"Diagram of the causes of mortality in the army in the East" by Florence Nightingale

A major breakthrough in epidemiology came with the introduction of statistical maps and graphs. They allowed careful analysis of seasonality issues in disease incidents, and the maps allowed public health officials to identifical critical loci for the dissemination of disease. John Snow in London developed the methods. English nurse Florence Nightingale pioneered analysis of large amounts of statistical data, using graphs and tables, regarding the condition of thousands of patients in the Crimean War to evaluate the efficacy of hospital services. Her methods proved convincing and led to reforms in military and civilian hospitals, usually with the full support of the government.

By the late 19th and early 20th century English statisticians led by Francis Galton, Karl Pearson and Ronald Fisher developed the mathematical tools such as correlations and hypothesis tests that made possible much more sophisticated analysis of statistical data.

During the U.S. Civil War the Sanitary Commission collected enormous amounts of statistical data, and opened up the problems of storing information for fast access and mechanically searching for data patterns. The pioneer was John Shaw Billings (1838-1913). A senior surgeon in the war, Billings built the Library of the Surgeon General's Office (now the National Library of Medicine, the centerpiece of modern medical information systems. Billings figured out how to mechanically analyze medical and demographic data by turning facts into numbers and punching the numbers onto cardboard cards that could be sorted and counted by machine. The applications were developed by his assistant Herman Hollerith; Hollerith invented the punch card and counter-sorter system that dominated statistical data manipulation until the 1970s. Hollerith's company became International Business Machines (IBM) in 1911.


  • Worldwide dissemination:


Japan:

European ideas of modern medicine were spread widely through the world by medical missionaries, and the dissemination of textbooks. Japanese elites enthusiastically embraced Western medicine after the Meiji Restoration of the 1860s. However they had been prepared by their knowledge of the Dutch and German medicine, for they had some contact with Europe through the Dutch. Highly influential was the 1765 edition of Hendrik van Deventer's pioneer work Nieuw Ligt ("A New Light") on Japanese obstetrics, especially on Katakura Kakuryo's publication in 1799 of Sanka Hatsumo ("Enlightenment of Obstetrics").

 A cadre of Japanese physicians began to interact with Dutch doctors, who introduced smallpox vaccinations. By 1820 Japanese ranpô medical practitioners not only translated Dutch medical texts, they integrated their readings with clinical diagnoses. These men became leaders of the modernization of medicine in their country. They broke from Japanese traditions of closed medical fraternities and adopted the European approach of an open community of collaboration based on expertise in the latest scientific methods.

Kitasato Shibasaburō (1853-1931) studied bacteriology in Germany under Robert Koch. In 1891 he founded the Institute of Infectious Diseases in Tokyo, which introduced the study of bacteriology to Japan. He and French researcher Alexandre Yersin went to Hong Kong in 1894, where; Kitasato confirmed Yersin's discovery that the bacterium Yersinia pestis is the agent of the plague. In 1897 he isolates and described the organism that caused dysentery. He became the first dean of medicine at Keio University, and the first president of the Japan Medical Association.

Japanese physicians immediately recognized the values of X-Rays. They were able to purchase the equipment locally from the Shimadzu Company, which developed, manufactured, marketed, and distributed X-Ray machines after 1900. Japan not only adopted German methods of public health in the home islands, but implemented them in its colonies, especially Korea and Taiwan, and after 1931 in Manchuria. A heavy investment in sanitation resulted in a dramatic increase of life life expectancy.

  • Psychiatry:



The Quaker-run York Retreat, founded in 1796, gained international prominence as a centre for moral treatment and a model of asylum reform following the publication of Samuel Tuke's Description of the Retreat (1813)

Until the nineteenth century, the care of the insane was largely a communal and family responsibility rather than a medical one. The vast majority of the mentally ill were treated in domestic contexts with only the most unmanageable or burdensome likely to be institutionally confined. This situation was transformed radically from the late eighteenth century as, amid changing cultural conceptions of madness, a new-found optimism in the curability of insanity within the asylum setting emerged. Increasingly, lunacy was perceived less as a physiological condition than as a mental and moral one to which the correct response was persuasion, aimed at inculcating internal restraint, rather than external coercion. This new therapeutic sensibility, referred to as moral treatment, was epitomised in French physician Philippe Pinel's quasi-mythological unchaining of the lunatics of the Bicêtre Hospital in Paris and realised in an institutional setting with the foundation in 1796 of the Quaker-run York Retreat in England.




Patient, Surrey County Lunatic Asylum, c. 185058. The asylum population in England and Wales rose from 1,027 in 1827 to 74,004 in 1900

From the early nineteenth century, as lay-led lunacy reform movements gained in influence, ever more state governments in the West extended their authority and responsibility over the mentally ill. Small-scale asylums, conceived as instruments to reshape both the mind and behaviour of the disturbed, proliferated across these regions. By the 1830s, moral treatment, together with the asylum itself, became increasingly medicalised and asylum doctors began to establish a distinct medical identity with the establishment in the 1840s of associations for their members in France, Germany, the United Kingdom and America, together with the founding of medico-psychological journals.

Medical optimism in the capacity of the asylum to cure insanity soured by the close of the nineteenth century as the growth of the asylum population far outstripped that of the general population.[a] Processes of long-term institutional segregation, allowing for the psychiatric conceptualisation of the natural course of mental illness, supported the perspective that the insane were a distinct population, subject to mental pathologies stemming from specific medical causes. As degeneration theory grew in influence from the mid-nineteenth century, heredity was seen as the central causal element in chronic mental illness, and, with national asylum systems overcrowded and insanity apparently undergoing an inexorable rise, the focus of psychiatric therapeutics shifted from a concern with treating the individual to maintaining the racial and biological health of national populations.

Emil Kraepelin (1856–1926) introduced new medical categories of mental illness, which eventually came into psychiatric usage despite their basis in behavior rather than pathology or etiology. Shell shock among frontline soldiers exposed to heavy artillery bombardment was first diagnosed by British Army doctors in 1915. By 1916, similar symptoms were also noted in soldiers not exposed to explosive shocks, leading to questions as to whether the disorder was physical or psychiatric.In the 1920s surrealist opposition to psychiatry was expressed in a number of surrealist publications. In the 1930s several controversial medical practices were introduced including inducing seizures (by electroshock, insulin or other drugs) or cutting parts of the brain apart (leucotomy or lobotomy). Both came into widespread use by psychiatry, but there were grave concerns and much opposition on grounds of basic morality, harmful effects, or misuse.

In the 1950s new psychiatric drugs, notably the antipsychotic chlorpromazine, were designed in laboratories and slowly came into preferred use. Although often accepted as an advance in some ways, there was some opposition, due to serious adverse effects such as tardive dyskinesia. Patients often opposed psychiatry and refused or stopped taking the drugs when not subject to psychiatric control. There was also increasing opposition to the use of psychiatric hospitals, and attempts to move people back into the community on a collaborative user-led group approach ("therapeutic communities") not controlled by psychiatry. Campaigns against masturbation were done in the Victorian era and elsewhere. Lobotomy was used until the 1970s to treat schizophrenia. This was denounced by the anti-psychiatric movement in the 1960s and later.






REFERENCE:
http://en.wikipedia.org/wiki/History_of_medicine