Warren Pearlson Attending Partnerships in Clinical Trials Meeting


Warren Pearlson, Target’s Director of Business Development is attending the 2014 Partnerships in Clinical Trials event, April 1-2, 2014, in Las Vegas, and would welcome the opportunity to meet with you, learn about your organization and explore how we can work together. Our business model includes partnering with other CROs to either supplement their services (e.g. data management, stat or medical writing) or to provide to software solutions to broaden the technology (and cost) options they can offer their clients. Our software is being used by CROs in Europe, Korea, Israel and the U.S. and we are working on several studies with our global partners.


Applied Clinical Trials Direct in an email blast, has highlighted our paper entitled Time to Change the Clinical Trial Monitoring Paradigm Results from a Multicenter Clinical Trial Using a Quality by Design Methodology, Risk-Based Monitoring and Real-Time Direct Data EntryA copy of the paper is also on our website.


ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (CRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchelor Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Chief Editor of On Target

Jules Mitchel, Editor

NIH Urges Older Americans to Protect Their Kidneys


Human kidneys viewed from behind with spine removed from this graphic


In recognition of World Kidney Day 2014 this past March 13, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute on Aging (NIA) at the National Institutes of Health remind older Americans about the importance of protecting their kidneys and urge them to better understand the decline of kidney function as people age.


The kidneys are bean shaped organs that serve several essential regulatory roles. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid-base balance, and regulation of blood pressure (via maintaining salt and water balance). They serve the body as a natural filter of the blood, and remove wastes, which are diverted to the urinary 1) ___. In producing urine, the kidneys excrete wastes such as urea and ammonium, and they are also responsible for the reabsorption of water, glucose, and amino acids. The kidneys also produce hormones including calcitriol, erythropoietin, and the enzyme renin. Located at the rear of the abdominal cavity in the retroperitoneum, the kidneys receive blood from the paired renal arteries, and drain into the paired renal veins. Each kidney excretes urine into a ureter, itself a paired structure that empties into the urinary bladder.


Renal physiology is the study of kidney function, while nephrology is the medical specialty concerned with kidney diseases. Diseases of the kidney are diverse, but individuals with kidney 2) ___ frequently display characteristic clinical features. Common clinical conditions involving the kidney include the nephritic and nephrotic syndromes, renal cysts, acute kidney injury, chronic kidney disease, urinary tract infection, nephrolithiasis, and urinary tract obstruction. Various cancers of the kidney exist; the most common adult renal cancer is renal cell carcinoma. Cancers, cysts, and some other renal conditions can be managed with removal of the kidney, or nephrectomy. Renal function, is measured by the glomerular filtration rate.


In humans the kidneys are located in the abdominal cavity, one on each side of the 3) ___. The asymmetry within the abdominal cavity caused by the liver typically results in the right kidney being slightly lower than the left, and left kidney being located slightly more medial than the right. Resting on top of each kidney is an adrenal gland. The kidney has a 4) ___ -shaped structure. The superior border of the right kidney is adjacent to the liver; and the spleen, for the left kidney; therefore, both move down on inhalation. The substance, or parenchyma, of the kidney is divided into two major structures: superficial is the renal cortex and deep is the renal medulla. Nephrons, the urine-producing functional structures of the kidney, span the cortex and medulla.


The kidneys receive blood from the renal arteries, left and right, which branch directly from the abdominal aorta. Despite their relatively small size, the kidneys receive approximately 20% of the cardiac output. The kidney participates in whole-body homeostasis, regulating acid-base balance, electrolyte concentrations, extracellular fluid volume, and regulation of blood 5) ___. The kidney Various endocrine hormones coordinate these endocrine functions; these include renin, angiotensin II, aldosterone, antidiuretic hormone, and atrial natriuretic peptide, among others. Many of the kidney’s functions are accomplished by relatively simple mechanisms of filtration, reabsorption, and secretion, which take place in the nephron. The kidney generates 180 liters of filtrate a day, while reabsorbing a large percentage, allowing for the generation of only approximately 2 liters of 6) ___. Reabsorption is the transport of molecules from this ultrafiltrate and into the blood. Secretion is the reverse process, in which molecules are transported in the opposite direction, from the blood into the urine. The kidneys excrete a variety of waste products produced by metabolism.


Two organ systems, the kidneys and lungs, maintain acid-base homeostasis, which is the maintenance of pH around a relatively stable value. The lungs contribute to acid-base homeostasis by regulating carbon dioxide (CO2) concentration. The kidneys have two very important roles in maintaining the acid-base balance: to reabsorb bicarbonate from urine, and to excrete hydrogen ions into urine, accomplishes these homeostatic functions both independently and in concert with other organs, particularly those of the endocrine system. Any significant rise in plasma osmolality is detected by the hypothalamus, which communicates directly with the posterior pituitary gland. An increase in osmolality causes the gland to secrete antidiuretic hormone (ADH), resulting in water reabsorption by the kidney and an increase in urine concentration. The two factors work together to return the plasma osmolality to its normal levels.


Although the kidney cannot directly sense blood, long-term regulation of 7) ___ pressure predominantly depends upon the kidney. This primarily occurs through maintenance of the extracellular fluid compartment, the size of which depends on the plasma sodium concentration. Renin is the first in a series of important chemical messengers that make up the renin-angiotensin system. Changes in renin ultimately alter the output of this system, principally the hormone angiotensin II and aldosterone. Each hormone acts via multiple mechanisms, but both increase the kidney’s absorption of sodium chloride, thereby expanding the extracellular fluid compartment and raising blood pressure. When renin levels are elevated, the concentrations of angiotensin II and aldosterone increase, leading to increased sodium chloride reabsorption, expansion of the extracellular fluid compartment, and an increase in blood pressure. Conversely, when renin levels are low, angiotensin II and aldosterone levels decrease, contracting the extracellular fluid compartment, and decreasing blood pressure.


The kidneys secrete a variety of hormones, including erythropoietin, and the enzyme renin. Erythropoietin is released in response to hypoxia (low levels of 8) ___ at tissue level) in the renal circulation. It stimulates erythropoiesis (production of red blood cells) in the bone marrow. Calcitriol, the activated form of vitamin D, promotes intestinal absorption of calcium and the renal reabsorption of phosphate. Part of the renin-angiotensin-aldosterone system, renin is an enzyme involved in the regulation of aldosterone levels. The CDC estimates that more than 10% of adults in the United States — more than 20 million people — may have chronic kidney disease or CKD. Diabetes and high blood pressure are the leading causes of kidney disease; and kidney failure. Together, diabetes and high blood pressure accounted for 72% of new kidney failure cases in 2011.


Age is a major risk factor for kidney disease. With advancing years, kidney function generally declines, resulting in increased vulnerability of the older kidney to acute injury and CKD. As the kidney 9) ___, filtering capacity decreases, the overall amount of kidney tissue may decrease, and the blood vessels that supply the kidney may narrow, further reducing the capacity of the kidneys to filter blood. This decline in kidney function, with age is nearly universal, but occurs at different rates in different people. Conditions such as high blood pressure, smoking and diabetes can accelerate these changes. Because healthy people have significant reserve kidney function, most age-related decline in kidney function does not make an older person feel or function any differently. If kidney function appears to be declining at a rate faster than expected, reversible or treatable causes might be identified to slow the process and preserve kidney function. Regardless of whether the cause is aging, disease, or both, complications from certain medications increase as kidney function declines. The level of some medicines in the blood may increase because impaired kidneys are less able to eliminate them. The kidneys may also become more sensitive to certain medications. For example, non-steroidal anti-inflammatory drugs such as ibuprofen, some antibiotics, and x-ray contrast agents may be more likely to cause acute kidney injury. The next time you pick up a prescription or buy an over-the-counter medicine or supplement, ask your 10) ___ how the product may affect your kidneys.


The main risk factors for developing kidney disease are


1. diabetes

2. high blood pressure

3. cardiovascular (heart and blood vessel) disease

4. family history of kidney failure.



1. Renal pyramid;  2. Interlobular artery;  3. Renal artery;  4. Renal vein 5. Renal hilum;  6. Renal pelvis; 7. Ureter;  8. Minor calyx;  9. Renal capsule;  10. Inferior renal capsule;  11. Superior renal capsule;  12. Interlobular vein; 13. Nephron;  14. Minor calyx;  15. Major calyx;  16. Renal papilla;  17. Renal column


Each kidney contains about one million tiny filtering units made up of blood vessels. These filters are called glomeruli. Diabetes and high blood pressure damage these blood vessels, so the kidneys are not able to 11) ___ the blood as well as they used to. Usually this damage happens slowly, over many years. This is called chronic kidney disease. As more and more filtering units are damaged, the kidneys eventually are unable to maintain health. Early kidney disease usually has no symptoms, which means you can’t feel if you have it. Blood and urine tests are the only way to check for kidney damage or measure kidney function. If you have diabetes, high blood pressure, heart disease, or a family history of kidney failure, you should be tested for kidney disease. Kidney disease can get worse over time, and may lead to kidney failure. Kidney failure means very advanced kidney damage with less than 15% normal function. End-stage renal disease (ESRD) is kidney failure treated by dialysis or kidney transplant. If the kidneys fail, treatment options such as dialysis or a 12) ___kidney transplant can help replace kidney function; the patient decides whether or not to use these treatment options.




ANSWERS: 1) bladder; 2) disease; 3) spine; 4) bean; 5) pressure; 6) urine; 7) blood; 8) oxygen; 9) ages; 10) pharmacist; 11) filter; 12) kidney

Hippocrates of Cos (460 BC – 370 BC), Father of Medicine Including Nephrology


Hippokrates of Kos c. 460 – c. 370 BC),


Hippocrates and Nephrology


Hippocrates and the medical school of Kos were mainly concerned with the common elements of various diseases and the accurate description of symptoms and signs, as well as their prognostic implications. In contrast, the medical school of Knidos (in neighboring Asia Minor) and its chief member Euryphon were interested in the systematic classification of diseases according to the systems involved. Galen mentions that Knidian physicians were familiar with four renal diseases, probably the same described in the book About Inner Sufferings, whose author is not known with certainty; most investigators attribute it to the Knidian school (5th century BC), while others consider it to be a Hippocratic work. Both theories are logical and possible, since Hippocrates himself was familiar with the work of the Knidian school and a rival of Euryphon. The first renal disease described in the book is nephrolithiasis with renal colic. Its description is considered a classic one and it is well known for its accuracy and clarity. The second disease corresponds to renal tuberculosis, while the remaining two are somewhat unclear, the third resembles either renal vein thrombosis or bilateral papillary necrosis. The fourth disease, described in the greatest detail of all, corresponds to a chronic suppurative renal infection or a sexually transmitted urethritis, complicated by renal involvement. Some statements concerning treatment follow; they consist of diet modification, physical exercise, ingestion of herbal extracts and surgery, as a last resort. It is therefore evident that Hippocrates is the father of clinical nephrology and that Hippocratic medicine lies at the root of the development of clinical nephrology. NIH.gov


Thirty-six Hippocratic Aphorisms of Nephrologic Interest


The Hippocratic aphorisms are concise, often pithy, and memorable statements of literal truths and frequently obvious wisdoms. “The finest thoughts in the fewest words.“ The term aphorism itself originally was coined to refer to the aphorisms of Hippocrates that are included in the Corpus Hippocraticum, which is the full collection of Hippocratic writings. The most famous of the Hippocratic aphorisms is the first and remains familiar: “Life is short, and Art [of medicine] long; the crisis fleeting; experience perilous, and decision difficult. The physician must not only be prepared to do what is right himself, but also to make the patient, the attendants and the externals cooperate.“  To best understand the aphorisms, it is important to place them into the context of both the medical knowledge and cultural practices of the times. In the era of Hippocrates, knowledge of anatomy was reasonably thorough, reflecting a lengthy history of battlefield medicine. The Corpus Hippocraticum is composed of some writings by Hippocrates himself, some by students of Hippocrates, and some inserted into the collection at a later date. The Hippocratic aphorisms were probably written circa 400 BCE and contain 400 entries dealing with all aspects of practical medicine. Although authorship of much of the Corpus Hippocratum is debated, the aphorisms are considered one of the few works in the Corpus most likely penned by Hippocrates himself. This belief was held as far back as Galen and the Byzantines and is echoed by more recent writers, including Paul-Emile Littre (1801-1811) in the 19th century, although several scholars still express reservations about their authenticity. The book of aphorisms was very influential because of its clarity and brevity. Numerous writers extensively commented on it; from the Greek-speaking world alone, these included Soranus, Rufus, Galen, Paladius, Stephanus of Athens, Theophilus Protospatharius, Damascius, and Johannes Actuarius.


The aphorisms were translated into Latin at an early stage, facilitating dissemination in Western medical thought. Characteristic of the high esteem the work had in the Renaissance, Theophrastus Paracelsus, on June 24, 1527, surrounded by a crowd of cheering students, publicly burned the works of Avicenna and Galen and showed respect only to the aphorisms of Hippocrates. Rarely are there so many aphorisms referring to a single specialty.


Hippocrates writings are in blue italics


On Uroscopy


4.69: When the urine is thick, grumoss, and scanty in cases not free from fever, a copious discharge of thinner urine proves beneficial. Such a discharge more commonly takes place when the urine has had a sediment from the beginning, or soon after the commencement.  This could very well be a description of oliguric renal failure complicating a febrile disease. The scanty amount of urine that is thick and “grumoss“ (“thrombodea,“ i.e., like a thrombus, dark red, curdled) may very well be the result of an acute tubular necrosis, whereas the large amount of thin urine that follows could represent the lysis of the failure with its polyuric phase.


4.70: When in fevers the urine is turbid, like that of a beast of burden, in such a case there either is or will be headache.  The urine of horses, donkeys, and cattle is turbid, probably because of the high concentration of phosphates that they consume through their vegetative feeding. Ancients had noticed this as a difference compared with human urine, which is clear even when highly concentrated. This observation had been reported initially in Mesopotamian writings, then in ancient Greek writings. The most probable explanation for the turbid urine Hippocrates describes is either pyuria or overexcretion of organic or inorganic salts. Such a condition eventually will lead to an abnormal internal milieu and thus possibly headache. In the case of macroscopic pyuria, one can suggest pyelonephritis; hence, the headaches. In the case of turbid urine caused by proteinuria (“macroscopic“ proteinuria if one can coin such a term), this implies massive nephrotic-range proteinuria. Such a condition will almost certainly be accompanied by activation of the renin-angiotensin system with salt retention, generalized edema, and hypertension. Thus, the “either is or will be headache“ prediction also could be a sign of hypertension.


4.71: In cases which come to a crisis on the seventh day, the urine has a red nubecula on the fourth day, and the other symptoms accordingly.  This is a prognostic aphorism. The hematuria that presents on the fourth day after the outbreak of the disease is a sign of the severity of the disease, and the aphorism predicts that there will follow a crisis on the seventh day. By crisis, it is meant the end of the disease, not worsening. Although it is not unusual for transient hematuria to cease after a few days, we cannot give any significance to the numbers 4 or 7 of the corresponding days. This numbering is a remnant of the pre-Socratic and Pythagorean teachings on the significance of numbers in medicine. It was based on the Mesopotamian and Babylonian line of thought to connect earthly phenomena with the phases of the moon.


4.72: When the urine is transparent and white, it is bad; it appears principally in cases of phrenitis  This could describe a patient with advanced renal failure. Transparent white urine could be a description of the isosthenuria of chronic renal failure. Galen and Damascius commented that the “phrenitis“ was caused by retention of toxic substances (yellow bile) that were not properly excreted through urine, instead accumulating in the brain and causing the symptom. We suggest that this aphorism is applicable even today because if we replace “yellow bile“ with “uremic toxins,“ we have a description of neurological signs of severe renal failure, i.e., uremic encephalopathy.


4.76When small fleshy substances like hairs are discharged along with thick urine, these substances come from the kidneys.  This could be one of the earliest descriptions of blood casts. What is most impressive is Hippocrates’ certainty that such substances come from the kidneys. Hippocrates was well aware of the complicated anatomy of the kidneys, although he could not explain their function. He clearly distinguished blood in the urine as a sign of hemorrhage, i.e., a ruptured vessel from the bladder or kidneys, and the “fleshy substances“ as originating from the kidneys.


4.77: In those cases where there are furfuraceous particles discharged along with thick urine, then the bladder has scabies [is “scabious“]Thick urine with “furfuraceous“ particles probably describes cystitis with excretion of squamous cells from the epithelium of the bladder. It could also be a case of cystitis with white blood cell aggregates. The term “scabious“ is descriptive rather than diagnostic.


7.31: When there is a farinaceous sediment in the urine during fever, it indicates a protracted illness.  This is a description of cases of fevers that are complicated by either massive discharge of epithelial cells or pyuria. In either case, the renal involvement, an acute inflammatory condition or pyelonephritis, is indeed a case that would have persisted, considering the Hippocratic means of treatment.


7.32: In those cases in which the urine is thin at first, and the sediments become bilious, an acute disease is indicated.  Galen in his comments, clarified that Hippocrates meant black, not yellow, bile. He then explained that this aphorism refers to time only, not to locum, i.e., the aphorism predicts the course of disease, not the affected organ. Is this a description of acute tubular necrosis or postinfectious glomerulonephritis? If this aphorism is connected to the previous one, i.e., it refers to patients with fever, it probably is an exacerbation of some chronic renal disease. The “thin“ urine could be a description of the isosthenuria of a chronic disease. Although “bilious“ in modern English would mean green, Hippocrates refers to bilious as either yellow or black (i.e., very dark red). If we assume he means black bile, as Galen states, this aphorism describes an acute exacerbation of a chronic condition.


7.33: In those cases in which the urine becomes divided there is great disorder in the body.  This aphorism refers to urine with a large quantity of sediment, making it appear “divided“ into 2 parts, sediment and suspension. The large amount of sediment, whatever the cause may be, predisposes to a very severe condition.


7.34: When bubbles settle on the surface of the urine, they indicate disease of the kidneys, and that the complaint will be protracted. Galen elaborated on this aphorism: “Bubbles are created when the liquids are stretched by air. And usually this happens when the liquid contains something sticky. In which case the bubbles don’t break easily and become permanent. “ This is the most frequently quoted “renal“ Hippocratic aphorism and it could be one of the earliest descriptions of proteinuria. It is the increase in the surface tension of the urine caused by the proteins that produces this phenomenon. Unfortunately, the aphorism does not give any detail concerning the patient’s condition, i.e., edema, weakness, headaches (hypertension), and so on.


7.35: When the scum on the surface is fatty and copious, it indicates acute diseases of the kidneys.  Regarding this aphorism, previous commentators have stated that the presence of gross quantities of fat on the surface of urine indicates decomposition of the fat in the body in acute generalized diseases or the perinephric fat in diseases of the kidneys. They also connected this case with cases of fatty stools as having the same cause. The notion persisted through the 19th century with the term lipurie. Although this aphorism provides inadequate detail to be certain, it could be a description of nephrotic-range nonspecific proteinuria with a variety of proteins excreted, thus the “fatty“ (lipoproteins) and “copious“ (in gross quantity).


7.67: We must look to the urinary evacuations, whether they resemble those of persons in health; if not at all so, they are particularly morbid, but if they are like those of healthy persons, they are not at all morbid.  This aphorism is a reminder to all physicians (and known by all nephrologists): Always look at the patient’s urine. It reminds one of another aphorism by Sir Robert Hutchison at the beginning of the 20th century: “The ghosts of dead patients do not ask why we did not employ the latest fad of clinical investigation; they ask ?why did you not test my urine?’ “ Hippocrates so much believed that examination of urine was fundamental for diagnosis and prognosis that he declared that if the urine of a sick person is normal, the prognosis is favorable.


On Diagnosis


4.75: Blood or pus in the urine indicates ulceration either of the kidneys or of the bladder.  The English translator paid no attention to the grammar of this aphorism, not heeding the distinction between “ureei“ (is urinating), which suggests continuity, and “ourese“ (“urinates“), which implies only an instant. A more precise translation of this aphorism is: “If a patient is urinating blood or pus, this indicates ulceration of the kidneys or the bladder.“ On the basis of the use of a continuous tense, Theophilus argued that the aphorism does not refer to rupture of an abscess from another organ, such as the liver, into the urinary system, in which case the blood and pus urinated would not last long, perhaps 2 or 3 days. Asking rhetorically “And why did he not mention the ureters?“ Theophilus further explains that “by mentioning the two ends he included the middle.“ Damascius added: “Urinating implies many days. For urinating and urinate are not the same.“ It is interesting to notice the detail in which these commentators analyzed this aphorism, and its important message is the chronicity of the disease.


4.41: A copious sweat after sleep occurring without any manifest cause indicates that the body is using too much food. But if it occurs when one is not taking food, it indicates that evacuation is required.  In this case, the skin is used as an alternative route for fluid elimination in cases of overconsumption of food. However, in cases in which there is profuse sweating without overindulgence, Hippocrates states that it is a sign of excess fluids that need to be eliminated through some kind of treatment. That is, the natural eliminating organs, kidneys and/or gastrointestinal tract, are malfunctioning, unable to offer proper catharsis, and therefore some other kind of provoked catharsis must be applied.


4.74: When there is reason to expect that an abscess will form in joints, the abscess is carried off by a copious discharge of urine, which is thick, and becomes white, like what begins to form in certain cases of [exhaustive] quartan fever. It is also speedily carried off by a hemorrhage from the nose. If a nosebleed also occurs as well, lysis will come very fast. Here, Galen and the Byzantine commentators state that the substance accumulated in the joints can be removed by urine and thus the patient be cured.  What would be the triggering factor “to expect that an abscess will form in joints“? In an adult man, the driver is probably overconsumption of food and wine in cases of hyperuricemia. Hyperuricemia could form tophi, which resemble abscesses (gout), whereas polyuria with urine full of a white material (phosphates or amorphous urate salts, although the latter usually are reddish brown) will gradually lead to the lysis of arthritis. However, the aphorism does not indicate whether the polyuria was spontaneous or was to be achieved by some medical intervention, such as water consumption or some medication.


4.78: In those cases where there is a spontaneous discharge of bloody urine where they are urinating bloody urine, it indicates rupture of a small vein in the kidneys.  The key word in this aphorism is “spontaneous.“ Hippocrates had obviously noticed some cases of hematuria that had no apparent cause. In other aphorisms, he refers to hematuria as the result of some known or at least suspected cause, such as the passing of a stone or trauma, a systemic disease with fever, or cancer. However, he realized that spontaneous hematuria could occur with no apparent cause in an otherwise healthy person, and that is the reason he attributed this condition to a “rupture of a small vein.“


Galen elaborates correctly that “spontaneous“ may mean either without apparent external cause (i.e., trauma) or without preliminary symptoms (eg, bladder ulceration). Theophilus again reminds the reader of the grammar of the aphorism, using the verb “urinating,“ not “urinate,“ implying a long duration of the sign. According to Eknoyan, aphorisms 4.75 to 4.78 probably describe papillary necrosis.


4.79: In those cases where there is a sandy sediment in the urine, there is calculus in the bladderThe “sandy“ sediment in the urine could be calcium or urate salts. In either case, the existence of calculi in the bladder and/or kidneys of such a patient is highly probable.


4.80: If a patient pass blood and clots in his urine, and have strangury, and if a pain seizes the hypogastric region and perineum, the parts about the bladder are affected. 7.39: When a patient passes blood and clots, and is seized with strangury and pain in the perineum and pubes, disease about the bladder is indicated.  These 2 diagnostic aphorisms are almost identical, with aphorism 7.39 probably being added at a later date. The topographic localization and association with anatomic structures gives a good idea of Hippocratic knowledge of anatomy.


4.81: If a patient pass blood, pus, and scales, in the urine, and if it has a heavy smell, ulceration of the bladder is indicated.  Theophilus commented extensively on this aphorism, writing that it “gives three facts, locus, constitution and malignity of the affection. Because by scales, which mean petaloid, indicates bladder affection, by pus and blood, indicates abrasion; for there cannot be pus in the urine without ulcer; And by heavy smell, meaning malodourous, indicates malignity; for the malodorous is a sign of sepsis and sepsis indicates malignity.“ This aphorism probably describes a severe case of unattended infection of the genitourinary system. It also could be tuberculosis or cancer complicated by a common infection. The infection probably is in the bladder because the aphorism refers to “scales,“ which may mean discharge of bladder epithelial cells.


On Prognosis 


4.83: When much urine is passed during the night, it indicates a slight retreat of the disease.  This appears to be a description of heart failure or kidney failure, in which the extravascular fluids are mobilized during the night, reflecting homeostatic changes associated with supine positioning (e.g., mobilization of peripheral edema) and subsequently are eliminated through the kidneys with a deceptive improvement in symptoms. Galen and Damascius suggested that the condition was caused by reduced excretion of the fluids that were supposed to be excreted by the gastrointestinal system during nighttime and thus had to be excreted by the kidneys.


6.6: Diseases about the kidneys and bladder are cured with difficulty in old menGalen states that the reason the elderly are cured with difficulty when they have diseases of the genitourinary tract is because they also have other diseases. In a contemporary medical “aphorism,“ it is acknowledged that in older individuals, there often is more than 1 disease that explains symptoms, whereas younger individuals usually have 1 unifying cause. The original aphorism recognized this and noted that the urogenital system often was affected. Diabetes, hypertension, heart failure, already deteriorated renal function, prostate hypertrophy (in men), and mild immunodeficiency make the cure of renal diseases far more difficult in the elderly than the young. Hence, this aphorism is correct.


6.11: Hemorrhoids appearing in melancholic [those with increased “black bile“] and nephritic affections are favorable.  This is another aphorism that highlights the Hippocratic belief that some diseases require a kind of catharsis to be cured. The appearance of hemorrhoids with probable rupture and bleeding would provide some means of spontaneous catharsis. Needless to say, it would also decrease blood pressure.


6.28: Eunuchs do not take the gout, nor become bald.

6.29: A woman does not take the gout, unless her menses be stopped.

6.30: A young man [boy] does not take the gout until he indulges in coition.  Aphorisms 6.28, 6.29, and 6.30 deal with the same subject: the relationship between sexual hormones and gout. We now know that testosterone levels increase the likelihood of both gout (and baldness) and that estrogens decrease the risk. The male-female ratio of gout in premenopausal women and similar-age-group men varies from 7:1 to 9:1 and becomes 3:1 in those older than 65 years. Even more impressive are Galen’s comments. Galen added that not only the absence, but also the irregularity, of menses was connected with gout in women and even reported the rarity of cases of gout in women with normal cycles, in accordance with modern statistics. These 3 aphorisms are indeed the triumph of personal experience. They succeeded in correctly connecting signs reflecting sex hormone levels with gout.


7.36: Whenever the aforementioned symptoms occur in nephritic diseases, and along with them acute pains about the muscles of the back, provided these be seated about the external parts, you may expect that there will be an abscess; but if the pains be rather about the internal parts, you may also rather expect that the abscess will be seated internally.  Unfortunately, the aphorism does not mention which exactly are the “aforementioned symptoms.“ However, it is probable that it refers to an abscess that causes pain radiating either internally or externally, in accordance to its location.


7.47: If a dropsical patient be seized with hiccup [cough] the case is hopeless.  For an unknown reason, the English translator Adams translated the word “cough“ as “hiccup.“ It is not impossible that the text Adams had in his hands had the word “lygx,“ not “vyx,“ i.e., hiccups, not cough. Support for use of “cough“ in this aphorism comes from comments by Galen, as well as in Littre’s translation of the aphorisms, in which a word for “cough“ is used. If the aphorism refers to hiccups, it may be a case of end-stage renal failure or more probably describes cases of chronic or tension ascites that cause pressure on the phrenic nerve. In such cases of noncompensating nonretractable ascites, either from heart or liver failure, the emergence of hiccups could be a grave sign.


7.81: In the discharges by the bladder, the belly, and the flesh [the skin?] if the body has departed slightly from its natural condition, the disease is slight; if much, it is great; if very much, it is mortal.  This simple aphorism connects the severity of the sign with the course of the disease. The abnormal urine, feces, and sweat become prognostic tools when compared with the normal excrements. The more the aberration from the normal, the worse the prognosis.


On Therapy 


6.36: Venesection cures dysuria; open the internal veins of the arm.  This aphorism is based on the ancient belief that certain veins correspond to certain organs. By cutting a certain vein, the corresponding organ would be relieved by the excretion of extra or toxic fluids that had accumulated in it. This theory was erroneous and had led to horrific cases of bloodletting, especially during the Middle Ages. However, we must not forget that until the middle of the 20th century, bloodletting with leeches and bloodletting with cupping over the lumbar region were common therapeutic interventions. It is still used in some parts of the world. The correct principle behind this erroneous practice was the elimination of inflammatory toxins from the blood. In Hippocrates’ time, this was sought through bloodletting, whereas nowadays, it is attempted through dialysis.


7.29: When strong diarrhea supervenes in a case of leucophlegmatia, it removes the diseaseBy the term “leucophlegmatia,“ Hippocrates states the overabundance of white phlegm, 1 of the 4 humors. In contemporary English, this could be interpreted as water overload and generalized edema. The term was coined because of the white color of the skin in such patients. The strong diarrhea removes the excess water, thus providing lysis of the disease. In this case, the gut becomes the apparatus of clearance.


7.48: Strangury and dysuria are cured by drinking pure wine [drunkenness], and venesection; open the vein on the inside.  The drinking of pure wine probably has a slight analgesic, diuretic, and antidepressant effect (the original Greek text uses the word “drunkenness“). As for bloodletting, that has to be done from a specific vein.


4.82: When tubercles form in the urethra, if these suppurate and burst, there is relief.  The “tubercles“ are probably tuberculous granulomata from genitourinary tuberculosis or any other chronic infection. Their location inside the urethra would cause pain, dysuria, and difficulties voiding. Undoubtedly their evacuation relieves the patient.


Of General Interest


2.10: Bodies not properly cleansed, the more you feed them the more you injure.  This aphorism may well apply to renal failure, as well as to the failure of other organs, such as the liver or heart. In the case of renal failure, a low-protein diet is the most beneficial and it is interesting to note that the diets described for patients with chronic diseases in the Hippocratic writings were low-protein diets. Consequently, if the patient in renal failure is not “cleansed“ of its uremic toxins, the more we nourish them the more we injure them.


4.2: In purging we should bring away such matters from the body as it would be advantageous had they come away spontaneously; but those of an opposite character should be stopped.  We believe that this aphorism is similar to the theoretical basis of dialysis. Perfect dialysis will remove substances that would have been removed had the kidneys not been damaged and prevent the loss of substances that the kidneys would have spared.


4.3: If the matters which are purged be such as should be purged, it is beneficial and well done; but if the contrary, with difficulty.  In this statement, which follows the previous aphorism described, Hippocrates judges the necessity of the cure by its result. If we removed unnecessary substances, the patient will improve and be comfortable with the treatment, but if we removed the necessary ones, the patient would hardly tolerate it.


These 3 aphorisms on purgation as a means for eliminating metabolic toxins may not be as alien to modern nephrology as they look. We still try to excrete some toxins in renal failure through the gut. Current examples include the use of cation-exchange resins in patients with hyperkalemia or the use of phosphate binders in patients with hyperphosphatemia.




Having reviewed the major Hippocratic aphorisms applicable to nephrology, we are left with the impression that these are fine examples of the power of empiricism at its best. The knowledge displayed reflects the personal opinion formed by astute observation of a competent physician. Because of that, Hippocrates has been rightly referred to by some as the “Father of Clinical Nephrology.“


Sources: http://www.ncbi.nlm.nih.gov/pubmed/9189236;



Prevalence of Allergies the Same, Regardless of Where You Live


According to a study published online (9 February 2014) in the Journal of Allergy and Clinical Immunology, in the largest and most comprehensive nationwide study to examine the prevalence of allergies from early childhood to old age. The results were based on blood serum data compiled from approximately 10,000 Americans in the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Although the study found that the overall prevalence of allergies did not differ between regions, the study discovered that one group of participants did exhibit a regional response to allergens. Among children aged 1-5, those from the southern U.S. displayed a higher prevalence of allergies than their peers living in other U.S. regions. These southern states included Texas, Oklahoma, Louisiana, Arkansas, Tennessee, Kentucky, Mississippi, Alabama, Georgia, West Virginia, Virginia, North Carolina, South Carolina, and Florida.


The NHANES 2005-2006 not only tested a greater number of allergens across a wider age range than prior NHANES studies, but also provided quantitative information on the extent of allergic sensitization. The survey analyzed serum for nine different antibodies in children aged 1-5, and nineteen different antibodies in subjects 6 years and older. Previous NHANES studies used skin prick tests to test for allergies. The study determined risk factors that made a person more likely to be allergic. The study found that in the 6 years and older group, males, non-Hispanic blacks, and those who avoided pets had an increased chance of having allergen-specific IgE antibodies, the common hallmark of allergies. Socioeconomic status (SES) did not predict allergies, but people in higher SES groups were more commonly allergic to dogs and cats, whereas those in lower SES groups were more commonly allergic to shrimp and cockroaches.


By generating a more complete picture of U.S. allergen sensitivity, the team uncovered regional differences in the prevalence of specific types of allergies. Sensitization to indoor allergens was more prevalent in the South, while sensitivity to outdoor allergens was more common in the West. Food allergies among those 6 years and older were also highest in the South.


The authors stated that they anticipate using more NHANES 2005-2006 data to examine questions allergists have been asking for decades. For example, using dust samples obtained from subjects’ homes, the group plans to examine the link between allergen exposure and disease outcomes in a large representative sample of the U.S. population.

High Plasticizer Levels in Males Linked to Delayed Pregnancy for Female Partners


Phthalates, sometimes known as plasticizers, are used in the manufacture of plastics, to make them more flexible. According to the U.S. Centers for Disease Control and Prevention, pthalates are used in hundreds of products, such as fragrances, shampoos, nail polish, plastic film and sheets. For the most part, people are exposed to phthalates by eating and drinking foods that have been in contact with containers and products containing the compounds. Bisphenol A (BPA) is used to make some types of plastic containers, in the protective lining of food cans, and other products.


According to an article published online in Fertility and Sterility (5 March 2014), women whose male partners have high concentrations of three common forms of phthalates, chemicals found in a wide range of consumer products, take longer to become pregnant than women in couples in which the male does not have high concentrations of the chemicals. The study assessed the concentrations of phthalates and BPA in couples trying to achieve pregnancy. For the study, urine concentrations of BPA and 14 phthalate compounds were measured in couples trying to achieve pregnancy. The study authors explained that many phthalates are often broken down and chemically changed before they are excreted from the body.


Results showed that pregnancy took the most time to achieve in couples in which the males had high concentrations of monomethyl phthalate, mono-butyl phthalate, and monobenzyl phthalate. Neither male nor female exposure to BPA was associated with pregnancy rates. Because the study examined only the time it took to achieve pregnancy, the study could not determine precisely how the compounds might affect fertility. Future studies, the authors wrote, would be needed to determine if the compounds affected particular aspects of reproductive health, such as hormone levels.


The authors cited previous studies which found high concentrations of BPA and other phthalates among couples seeking treatment for infertility. One study found that men with a high BPA level had decreased testosterone levels. Another found that men with a high BPA concentration had a reversal in the ratio of testosterone to estradiol, an estrogen-related hormone. Numerous studies found that, compared to infertility patients without high BPA levels, women seeking treatment for infertility had lower estradiol levels, fewer egg cells, lower rates for the implantation of the fertilized egg, and lower pregnancy rates. Similarly, the authors wrote, studies in lab animals suggest that BPA and other phthalates can hinder the maturation of egg cells, impair the production of reproductive hormones, and alter the development of reproductive organs.


The study enrolled 501 couples from four counties in Michigan and 12 counties in Texas from 2005 to 2009. These couples were not being treated for infertility, but were trying to conceive a child. The couples were part of the Longitudinal Investigation of Fertility and the Environment (LIFE) study, established to examine the relationship between fertility and exposure to environmental chemicals and lifestyle. Previous analyses from the LIFE study found that high levels of PCBs as well as of lead and cadmium also were linked to pregnancy delay.


The women taking part in the study ranged from 18 to 44 years of age, and the men were over 18. Couples provided urine samples that were analyzed for BPA and the 14 other phthalate compounds. Women kept journals to record their monthly menstrual cycles, intercourse and the results of home pregnancy tests. The couples were followed until pregnancy or for up to one year of trying. The endpoint of the study was the probability that a couple would achieve pregnancy by using a statistical measure called the fecundability odds ratio (FOR). The measure estimates couples’ probability of pregnancy each cycle, based on their urinary concentration of the compounds. A ratio less than one suggests a longer time to pregnancy, while a ratio greater than one suggests a shorter time to pregnancy.


Results showed that BPA concentrations were not associated with a longer time to pregnancy However, male urinary concentrations of the three metabolites of phthalates were associated with approximately a 20% increase in the time it took for the couples to achieve pregnancy. Female urinary concentrations of these three metabolites were not associated with a delay in pregnancy.


According to the CDC, monomethyl pthalate is excreted in the urine of people exposed to dimethyl phthalate, which is used in manufacturing rocket propellant and consumer products such as insect repellents and plastics. Mono-n-butyl phthalate, excreted in the urine of people exposed to the dibutyl phthalates, is used as additives to personal care products such as nail products and cosmetics, and in printing inks, pharmaceutical coatings, and insecticides. Mono-n-benzyl phthalate, excreted in the urine of people exposed to benzylbutyl phthalate, is used in products such as adhesives, vinyl tile, sealants, car care products, and some personal care products.  People exposed to benzylbutyl phthalate also excrete small amounts of mono-n-butyl phthalatein their urine.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.


First Medical Device to Prevent Migraine Headaches


Migraine headaches are characterized by intense pulsing or throbbing pain in one area of the head, accompanied by nausea or vomiting and sensitivity to light and sound. A migraine can last from four to 72 hours when left untreated. According to the National Institutes of Health, these debilitating headaches affect approximately 10% of people worldwide and are three times more common in women than men.


The FDA has cleared for marketing the first device as a preventative treatment for migraine headaches. This is also the first transcutaneous electrical nerve stimulation (TENS) device specifically authorized for use prior to the onset of pain.


Cefaly is a small, portable, battery-powered, prescription device that resembles a plastic headband worn across the forehead and atop the ears. The user positions the device in the center of the forehead, just above the eyes, using a self-adhesive electrode. The device applies an electric current to the skin and underlying body tissues to stimulate branches of the trigeminal nerve, which has been associated with migraine headaches. The user may feel a tingling or massaging sensation where the electrode is applied. Cefaly is indicated for patients 18 years of age and older and should only be used once per day for 20 minutes.


The FDA reviewed the data for Cefaly through the de novo premarket review pathway, a regulatory pathway for generally low- to moderate-risk medical devices that are not substantially equivalent to an already legally marketed device. The agency evaluated the safety and effectiveness of the device based on data from a clinical study conducted in Belgium involving 67 individuals who experienced more than two migraine headache attacks a month and who had not taken any medications to prevent migraines for three months prior to using Cefaly, as well as a patient satisfaction study of 2,313 Cefaly users in France and Belgium. 


The 67-person study showed that those who used Cefaly experienced significantly fewer days with migraines per month and used less migraine attack medication than those who used a placebo device. The device did not completely prevent migraines and did not reduce the intensity of migraines that did occur. The patient satisfaction study showed that a little more than 53% of patients were satisfied with Cefaly treatment and willing to buy the device for continued use. The most commonly reported complaints were dislike of the feeling and not wanting to continue using the device, sleepiness during the treatment session, and headache after the treatment session. No serious adverse events occurred during either study.


According to FDA, Cefaly provides an alternative to medication for migraine prevention and may help patients who cannot tolerate current migraine medications for preventing migraines or treating attacks.


Cefaly is manufactured by STX-Med in Herstal, Liege, Belgium.

Fruit Chewy Delight


Just out of the oven Friday afternoon  –  ©Joyce Hays, Target Health Inc.



By Sunday afternoon  –  ©Joyce Hays, Target Health Inc.



  • 3 mashed bananas (ripe)
  • 1/3 cup apple sauce (I used Mott’s sugar-free, natural applesauce)
  • 2 cups oats
  • 1/4 cup almond milk
  • 1/2 cup raisins
  • 1 teaspoon vanilla
  • 1 teaspoon cinnamon



Bake at 350 for 15-20 minutes


I chose the Fruit Chews recipe for this week’s focus, because it was given to me by a friend, colleague and my favorite nephrologist, Charlie Nuttall;  And because it’s tasty, healthy and low calorie, I adapted it slightly.


When you have a sweet tooth and want to stay on track, here’s a satisfying treat. Sugar is NOT an added ingredient. This versatile recipe is one of the easiest and quickest things to prepare, on the planet. It was baked on Friday, and by Sunday, just about gone. (BTW, your kitchen will have a heavenly smell of apples, oats and cinnamon).


This all fruit delight is versatile because you can serve it as a dessert with or without a dollop of fat-free Cool Whip, a snack, or a yummy healthy breakfast or brunch treat, perfect with coffee and/or tea.


On Sunday afternoon, we warmed a few pieces up, and it was as soft but chewy as when it first came out of the oven on Friday. We recommend highly!



Going  –  ©Joyce Hays, Target Health Inc.



Going  –  ©Joyce Hays, Target Health Inc.



Just about   Gone!  –  ©Joyce Hays, Target Health Inc.

Bon Appetit!!!!