Fitting Surge Functions to Data FITTING SURGE FUNCTIONS Sheldon P. Gordon ADDRESS: Department of Mathematics, Farmingdale State University of New York, Farmingdale NY 11735 USA. [email protected] ABSTRACT: The problem of fitting a surge function to a set of data such as that for a drug response curve is considered. A variety of differenttechniques are applied, including using some fundamental ideas fromcalculus, the use of a CAS package, and the use of Excel's regressionfeatures for fitting a multivariate linear function to a set of trans-formed data. The results of the different approaches are contrastedand discussed.
QUESTIONS ET RÉPONSES Conférence web — 9 février 2011 Web conference— February 8th, 2011 Doc, does my pet really need all the medications to treat his
Answers provided by speaker Dr. Lisa Carioto, DVM, DVSc, Diplomate ACVIM
I was told that liver enzymes in dogs should be 2-3x elevated for the value to be significant.
Is this true?
Classification of elevated liver enzyme activity:
• Mild: 2-3 x normal
• Moderate: 5-10 x normal
• Severe: >10 x normal
Normally one looks at the degree of elevation of the liver enzymes and they are considered significant once
they are 2-3x the normal reference range. However, one should not ignore even mildly elevated liver enzymes in breeds that are predisposed to developing liver disease. These dogs may have only very mildly elevated liver enzymes on blood work (i.e. sometimes less than 2-3 x normal) and in my opinion, should probably not be ignored as an early diagnosis and treatment could often have a more favourable outcome.
In addition, one should also keep in mind that some individuals with end stage liver disease will not necessarily have an adequate population of hepatocytes to produce enzymes and may actually have liver enzyme activities within the normal reference range.
Therefore, when evaluating the results of a dog with elevated liver enzyme activities, one should consider the dog's history and clinical signs and interpret them as a whole.
Reactive hepatopathies, such as periodontal disease may cause elevated liver enzyme activities, therefore prior to embarking on further diagnostics, which can be very costly, one should first and foremost ensure that the animal was fasted at the time of the blood work and also consider re-evaluating the liver enzymes a few weeks later. If they are persistently elevated, as in Taz's case and it is a breed that is predisposed to certain diseases, further diagnostics may be considered at that time, or if the client is not ready to pursue further Why or how do steroids affect canine liver enzymes?
The ALP steroid-isoenzyme will be induced once glucocorticoids are initiated, thereby increasing the results of
the liver enzymes on blood work.
Therefore, when steroids are prescribed for the treatment of a liver disease, it can be difficult to use ALP value to determine response to therapy. The dog's liver enzymes could have increased due to progressive liver disease vs. induction of the liver enzymes secondary to the use of steroids.
Web conference— February 8th Web conference— February 8 , 2011 Do cats have a bone isoenzyme of ALP? Can you have a normal mild increase in kittens
secondary to growth?
Yes, cats have a bone isoenzyme of ALP and yes, kittens may have a mild increase due to growth.
What is the interpretation for serum bile acid (SBA) tests?
• Very sensitive (Se) and specific (Sp) test (>30 umol/L considered significant)
• ↑ (Se) if measuring pre and post prandial samples
• Sensitive indicator of hepatobiliary disease, hepatocellular dysfunction, vascular anomalies (PSS) and
• Hemolysis and lipemia can affect results• Not indicated if animal is icteric. If the bilirubin is elevated and pre and post-prandial causes have been ruled out, in addition to hemolysis due to handling of the sample, then SBA are not useful (they would be abnormal).
• No information regarding specific diagnosis or prognosis• Useful in deciding whether further diagnostics are required• Often within normal values with hepatic neoplasia• Occasionally, the pre-prandial sample will be more elevated than the post. This may be due to mislabeling of tubes, spontaneous contraction of gall bladder or a delay in GI transit time What is considered normal/well-controlled when repeating SBA in an animal with liver
Depending upon the cause of the elevated SBA, one does not necessarily have to monitor SBA to assess how
well a disease process is being controlled and they may not always return to within normal limits. It is may be more worthwhile to monitor parameters (for trends) such as urea, glucose, cholesterol and albumin.
Are urine bile acids (UBA) an accurate test?
UBA are a reflection of SBA. The advantages are that there is no need to fast and only one urine sample is
required. Ideally, the urine sample should be obtained 4-8 hours after eating. It is important to ensure that the animal is not suffering from chronic renal insufficiency or cystitis when interpreting the results.
UBA were found to be as Sp (88%) as SBA and to have similar Se (UBA = 85%, SBA = 87%). They may be elevated UBA compatible with hepatic insufficiency, cholestasis and PSS. Results within normal limits (WNL) do not exclude hepatic disease Therefore, if clinical signs are compatible with hepatic disease despite UBA WNL, further diagnostics are required
The Sp of UBA (100%) is higher than SBA (pre +/or post (67%)), but they had a lower Se (UBA 61%, SBA 78%). Elevated UBA are compatible with hepatic insufficiency, cholestasis and PSS.
What organisms are most likely to be cultured from liver biopsies?
E. coli, Enterobacter sp., Streptococcus, Klebsiella, Clostridium, and Bacteroides. They tend to be similar
organisms to those cultured from the bile and are often secondary to an ascending infection from the GI tract. Another possibility is an infection secondary to bacterial translocation if the intestinal barrier is altered.
Web conference— February 8th Web conference— February 8 , 2011 Label instructions for small cats and dogs are ½ of a tablet of Zentonil 200 mg. But now you are
saying not to divide the tablets. Please explain.
The old formulation of Zentonil could not be crushed or divided. However, with the newer products, i.e. the
Zentonil Plus and Zentonil Advanced, the SAMe within the product is now microencapsulated and the tablets are therefore scored. As a result, the tablets can now be split or crushed without reducing their efficacy.
Are there indications for the use of SAMe alone, or would you always use it with silymarin?
Cognitive dysfunction is the condition that I tend to use SAMe alone.
How long does it take milk thistle to be therapeutic?
I was unable to find a specific answer to this question, however based upon the veterinary literature, I found the
following information: Silybin was found to be completely protective against A phalloides intoxication in Beagles at a dose of 50-150 mg/kg when given 5-24 hours after ingesting an LD50 dose of A phalloides (Vogel et al., 1984). Data from an uncontrolled study suggest that use of silymarin up to 48 hours after ingestion is effective in preventing severe hepatotoxicity (Levy et al., 2004). Bile concentrations of silymarin are 100 times those seen in serum (Center et al., 2004).
Do you use Zentonil® lifelong?
It depends upon the underlying disease; it can be used for a number of weeks to months in acute conditions,
while others require lifelong therapy.
Is there any toxicity of over dosage of Zentonil® Advanced?
I am not aware of any toxicity in human or animal studies for SAMe or silymarin. In veterinary medicine, I have
seen the occasional dog and cat develop gastrointestinal side effects secondary to SAMe, such as nausea, vomiting or diarrhea. Potential side effects of silymarin are very mild and very rare in humans (headaches, gastrointestinal upset, etc.).
Are there any foods that are high in SAMe or is it only available to us as a supplement?
Small quantities of SAMe may be found in some foods (amino acid), however, it is so highly unstable that one
cannot rely on obtaining adequate concentrations of the molecule via food. It is therefore only effective as a supplement and its efficacy is dependent upon how the molecule is packaged.
Is the dose of SAMe the same when treating liver disease vs. cognitive dysfunction?
Yes, the dose is 18-20 mg/kg PO per day.
Web conference— February 8th, 2011 How helpful are hepatic diets in the management of liver disease?
They tend to be very helpful as the protein source tends to be of high quality and easily digestible and they are
often supplemented with the appropriate vitamins and restricted in the heavy metals, such as copper and iron. However, not all hepatic diets are created equally; some are severely restricted in protein, while others are not, but are in fact restricted in copper, iron and salt, and supplemented with vitamins, etc. Therefore, it is very important to evaluate not only each commercial diet, but most importantly the stage of the liver disease that the animal is suffering from prior to initiating it. A protein restricted diet should only be initiated once the animal is demonstrating signs of hepatic encephalopathy.
What specific diets do you recommend for liver disease (not insufficiency)?
I look for a diet consisting of high quality protein that makes up a minimum of >14% of the daily caloric
requirements, and ideally ≥ 20%. That is, one should not feed a protein restricted diet if an animal is suffering from liver disease unless signs of hepatic encephalopathy. It should also be rich in soluble fibre in order to decrease the availability and production of ammonia at the level of the GI tract and to bind noxious BAs, and endotoxins. It should also be supplemented with vitamin B complex, as well as K+, Zn2+, Ca2+, arginine, taurine, and carnitine. One should avoid diets that are high in iron, copper and sodium. If ascites is present, the sodium content should be <0.5 g Na/1000 kcal. I usually recommend a vegetarian based diet, whether plant based or dairy based as animals with liver disease tend to metabolize these protein sources more easily than animal based proteins. Small, frequent meals to avoid protein and ammonia overload of the liver.
Any home cooked recipes for liver disease in dogs?
I don't have any specific homemade diets that I can recommend; however, you may want to consult certain
websites, such as balanceit.com or petdiets.com. These websites allow a client to pay for a nutritionist to formulate a diet that is specific for your patient. A Canadian website one can consult is www.hilarywatson.com. It is imperative that homemade diets are well balanced in order for these pets to obtain the required nutrients, vitamins and minerals.
Why did he have the hepatic disease in the first place? Was his diet changed or modified to rule
out food reaction/allergy/IBD?
The cause of his liver disease (early stages of lobular dissecting fibrosis) was never identified. His referring
veterinarian treated him with an elimination diet consisting of duck and sweet potato and a multivitamin for approximately 10 weeks to which he seemed to respond as the degree of pruritus improved. However, Taz still develops bouts of pruritus during the summer months that seem to respond clinically to anti-histamines. A liver diet was never initiated due to the positive response he had to the elimination diet and the fact that his liver enzymes remained within normal limits.
What do you recommend if the owner cannot afford biopsy or ultrasound?
Most of the details are present in the slides of the Webinar, however, treatment will often consist of a
broad-spectrum antibiotic, in addition to a hepatoprotective product, such as SAMe/silybin. I will NOT administer Ursodiol® without an abdominal ultrasound.
Web conference— February 8th, 2011 If funds are limited, and biopsy is not possible, when do you use pred or not for liver disease in cats?
I usually start with the administration of a broad-spectrum antibiotic and a hepatoprotective agent and if there is
no response within 2-4 days, I will recommend initiating an anti-inflammatory dose of prednisolone of 1 mg/kg When do you take a cat off prednisolone in relation to the antibiotics and Zentonil when you
don't have follow up testing?
This will depend on the animal, i.e. if the pet improved tremendously after having added the prednisolone, then
I will start weaning the pet off the prednisolone but maintain the minimum dose that is effective in controlling the clinical signs for at least 2-3 months. I would probably discontinue the antibiotics after 4 weeks. I would continue the Zentonil® and the prednisolone, but once I achieve alternate day dosing of steroids, I will administer the Zentonil® on the days that the animal is not receiving steroids. I will continue the Zentonil® for approximately 2 weeks – 1 month after having discontinued the prednisolone in order to have some form of hepatoprotection ‘on board' while trying to determine how the pet will respond to the discontinuation of the steroids.
Would you really see a noticeable improvement in clinical signs in 2-4 days on your plan B protocol?
If the underlying cause is due to an ascending infection, and one has chosen an appropriate antibiotic, then, yes,
one tends to see an improvement within the first 72 hours of treatment.
How helpful is Ursodiol® in the management of hepatic disease?
Ursodeoxycholic acid (Ursodiol®) is very helpful in the management of hepatic disease, for a variety of reasons.
It should no longer be viewed as ‘a drug to thin the bile'. It is a choleretic, but it also changes the BA pool to a less hepatotoxic form and it stimulates bile flow. It has anti-apoptotic effects, as well as anti-oxidant effects, and has both anti-inflammatory and immunomodulating activity. It stabilizes cellular mitochondriae and has cytoprotective effects that have been demonstrated in hepatocytes, cardiomyocytes, GI epithelial cells and Is Ursodiol® not contraindicated in possible bile duct obstruction? Does cholestasis not have you
wondering about a bile duct obstruction?
Yes, it is contraindicated in cases of bile duct obstruction, however, the presence of cholestasis does not
necessarily imply an obstruction; it may just signify the suppression of normal bile flow or slightly thickened bile, such as presence of sludge. However, an abdominal ultrasound is required in order to exclude the presence of an obstruction (whether complete or partial). In the cases that I presented (Taz and Toby), ultrasound ruled out the presence of an obstruction.
To clarify – it is okay to give Ursodiol when there is intrahepatic cholestasis but not with an
Web conference— February 8th, 2011 If the client does not want to perform a diagnostic work-up and you are unsure of an
obstruction, would you still start Ursodiol®? What are the chances of a biliary rupture?
No, I would not take the chance of using Ursodiol® if I don't have an ultrasound. If the animal has a cholelith
that is causing a partial obstruction or if he/she has a mucocoele with a thin and necrotic gall bladder wall, the Ursodiol® will increase bile flow (contractions of the GB and biliary system), which in turn may cause a rupture of the GB or a bile duct.
PANCREATITIS AND MICROVASCULAR HYPOPLASIA
Are there any consistent biochemical profile abnormalities that help warrant running an fPLI?
No, unfortunately, there are not. I rely on the history of the cat, clinical signs and physical examination findings.
Cats may present with pancreatitis in a variety of ways and should be considered a differential diagnosis in any cat with a history of chronic, intermittent vomiting, weight loss, anorexia, and fever with or without the presence of abdominal pain.
Is SAMe helpful in pancreatitis?
Yes, it is potentially helpful in pancreatitis due to its anti-inflammatory and anti-oxidant properties.
What treatment would you recommend for a dog with hepatic portal venous hypoplasia
(formerly known as microvascular dysplasia)?
I might recommend a vegetarian based diet or dairy based diet as animal protein is more difficult to metabolize
compared to a vegetable or dairy based diet. I would also suggest using hepatoprotective agents, such as SAMe/ silybin, and Ursodiol®. Depending upon finances and the owners' ease at administering medications, I may consider administering vitamin E & B and omega-3 fatty acids.
Can hepatic portal venous hypoplasia (formerly known as microvascular dysplasia) cause a
progressive increase of ALP?
Yes, hepatic portal venous hypoplasia can cause progressive increases in all liver enzyme activities, as well as
progressive liver dysfunction (i.e. decreases in the urea, glucose, cholesterol, etc.).
What is the dose of vitamin B12?
The doses published vary depending upon the source referenced. I tend to use the following:
• Cats & Small dogs: 250ug
• Medium-size dogs: 500 ug
• Large-size dogs: 1000ug
Subcutaneous injection once a week for 4 weeks, then once every 2 weeks for 2-3 doses and then once a month
thereafter for 3-6 months depending upon the condition that I am treating.
Do you recommend carnitine supplementation orally?
I don't tend to recommend it in liver disease; not because I don't think it is beneficial, but because it is very
difficult to obtain and tends to be very costly, however, if I have a client who has the financial means and the animal refuses to eat a hepatic diet, then I might suggest it.
Web conference— February 8th, 2011 What analgesic did you use with Toby? How long would you use analgesia and which one in cats?
A constant rate infusion (CRI) of fentanyl was used. You may also consider a CRI of butorphanol. Buprenorphine
is another analgesic that one can consider.
The duration of the analgesia will be dependent upon the status of the patient. If the cat looks very comfortable after 24 hours, I will start weaning the dose over the next 24 hours and titrate the dose according to the cat's response to gentle palpation of the abdomen, appetite and overall demeanour.
What is your favourite anti-emetic and appetite stimulant in cats?
I tend to use mirtazapine as an appetite stimulant and it also has some anti-emetic effect.
I will use metoclopramide as a CRI or maropitant (Cerenia®) once a day in cats as an anti-emetic. The dose of
maropitant that I tend to use is 1 mg/kg subcutaneously. I have not started using maropitant PO in cats.
However, owners need to realize that their use is considered ‘off label'.
Are you prescribing amoxicillin-clavulanic acid and metronidazole as your antibiotics of choice
in your plan B?
The antibiotic I tend to choose depends upon the history and clinical signs of the pet and I always try to
determine if the pet has a history of having a ‘sensitive GI tract' to certain antibiotics. Amoxicillinclavulanic acid and metronidazole will yield broad spectrum activity. If it is difficult to administer medications to the pet, particularly if it is a cat, I might start with just amoxicillin-clavulanic acid, particularly since metronidazole tends to be bitter tasting.
Why was Toby treated with antibiotics for so long (4 months)? Could they have been discontinued
I relied on the normalization of the liver enzymes and I usually continue antibiotics for a minimum of 2 weeks
after the liver enzymes have normalized. Toby's liver enzymes only normalized at his 12 week reevaluation; I usually continue the antibiotics a minimum of 2 weeks after normalization of the liver enzymes. If I remember correctly, the owner was unable to return after 2 weeks due to his schedule, so I continued them until he could return, which happened to be 4 weeks later.
SPECIFIC QUESTIONS REGARDING TAZ'S CASE
Taz's copper level was at the upper end of the normal reference range, so why didn't I consider
treatment to decrease his copper levels. Wouldn't copper levels reaching the upper end of
normal be indicative of hepatic disease or insufficiency?
There is a histochemical grading system for the assessment of canine liver tissue using the Rhodanine or
Rubeanic acid stains. A grading scale of 0 to 5 is used, with 0 having no copper. According to both staining methods, copper scores above 2 are considered abnormal. Based upon Taz's histochemical analysis and staining, there were no signs of copper accumulation. When measuring copper concentrations on a dry weight, normal reference ranges for Cu2+ are not considered to be clinically significant if < 300 ppm per dry weight.
Web conference— February 8th, 2011 Did Taz's condition improve with the metronidazole?
Taz's vomiting, diarrhea and hematochezia episode improved with the metronidazole, however, his SBA were
elevated when assessed one month after the initial episode as mentioned in the presentation and remained elevated once re-evaluated 6 months later. He continues to have intermittent episodes of diarrhea, that respond to metronidazole but the owners are not interested in pursuing further diagnostics to determine what the underlying cause is (ex. IBD). A baseline cortisol concentration excluded hypoadrenocorticism.
Did Taz's SBA return to normal with Zentonil® Advanced?
Taz's SBA decreased, but remained mildly elevated (post-prandial SBA 33 and 42 umol/L, respectively) when the
referring veterinarian re-evaluated him 3 and 6 months later. It is important to remember that depending upon the cause of the elevated SBA, they may not always return to within normal limits. It is may be more worthwhile to monitor parameters (for trends) such as urea, glucose, cholesterol and albumin. SBA monitoring is usually not indicated to assess how well a disease process is being controlled.
Neurofeedback – How Attention Takes Flight Pierre Walther and Stephan Ellinger Goethe University Frankfurt, Julius-Maximillians-University Würzburg (GERMANY) Attention Deficit Disorder (ADD) alone or in combination with Hyperactivity (ADHD) is one of the most common disorders in childhood and adolescence and even persists into adulthood. Children with ADHD show a higher amount of slow brain waves and a decreased amount of faster brain waves compared to children without ADHD (Barry et al., 2003). The basic idea of neurofeedback is to transfer the unconscious process of brain wave function into a conscious process by reporting it to the patient. The Brainfeeders project aims to evaluate the possibilities for integrating neurofeedback in a school setting. The primary goal of the study is to replicate results found in clinical trials without any additional human resources. We would like to evaluate how well a training programme like this fits in school settings and if results are comparable to clinical studies. We are interested in forming a transnational working group, integrating researchers who are working on similar projects or who are interested in working on Brainfeeders in their countries.