Panorama

Panorama 9In Medicine

د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

A useful diagnostic and prognostic tool for acute appendicitis and acute pancreatitis

BMJ 28 February 2012

Watson and colleagues did not cover the diagnostic and prognostic value of raised inflammatory markers in common surgical conditions, such as acute appendicitis and acute pancreatitis.
Interest in C reactive protein (CRP) and white cell count as diagnostic markers for acute appendicitis has grown recently because, when combined, sensitivity increases to 0.98—normal values for both tests are extremely unlikely in confirmed appendicitis. Khan and colleagues report positive predictive values for white cell count and CRP as 92% and 96%, respectively, in confirmed appendicitis.

Ranson scores and Glasgow scores are commonly used to predict the severity of acute pancreatitis, but lactate dehydrogenase and CRP are similarly effective in diagnosing severity in the early
stages. The diagnostic accuracy of both CRP and the Ranson score is 50% on the third day, and it was concluded that lactate dehydrogenase and CRP are simple and economical tests that help to predict complications in acute pancreatitis.


High CRP values can be used prognostically to identify patients who are more likely to develop complications or those with severe disease that is not obvious at the outset. A Finnish study of
1050 acute pancreatitis cases concluded that none of the cases where leucocyte counts and CRP values were normal on admission was life threatening.

Clark and colleagues do not cite large vessel vasculitis as an important and readily treatable cause of a discrepancy in blood pressure recordings between limbs. For example, Takayasu’s arteritis is a rare granulomatous large vessel vasculitis and adifference in systolic blood pressure between arms of greater
than 10 mm Hg is included in the 1990 American College of Rheumatology classification criteria for this disease.
Don’t forget the vasculitides
BMJ 24 April 2012

Another very important, and common, clinical sign in Takayasu’s arteritis is reduced or absent peripheral arterial pulses, particularly the brachial pulse. Failure to appreciate the importance of these signs can delay the diagnosis of a condition associated with considerable morbidity and mortality.

Giant cell arteritis is a more common and well recognised form of large vessel vasculitis and may also cause blood pressure discrepancy and reduced or absent peripheral pulses. Both of these vasculitides should therefore be considered in any patient
with a significant difference in blood pressure between arms, particularly in the context of relevant constitutional symptoms; limb claudication and other ischaemic symptoms; or an unexplained persistently raised erythrocyte sedimentation rate and C reactive protein concentration.

The adipokines or adipocytokines (Greek adipo-, fat; cyto-, cell; and -kinos, movement) are cytokines (cell-to-cell signaling proteins) secreted by adipose tissue.
Members include:
chemerin[1]
interleukin-6 (IL-6)[2]
plasminogen activator inhibitor-1 (PAI-1)
retinol binding protein 4 (RBP4)
tumor necrosis factor-alpha (TNFα)
visfatin
Leptin
Adiponectin
Apelin[3]


As of 2008, the current terminology refers to a cytokine as an immunomodulating agent. However, conflicting data exists about what is termed a cytokine and what is termed a hormone and more research is needed in this area of defining cytokines and hormones. Under the current terminology, adiponectin, leptin (Ob ligand), and resistin are not appropriately considered adipokines (cytokines) as they do not act on the immune system. (Harrison's Principles of Internal Medicine). Often, these peptides (adiponectin, leptin, and resistin) are referred to as adipokines, however they can be more accurately put into the larger, growing list of adipose derived hormones.

ScienceDaily (May 20, 2009) — The ghrelin hormone not only stimulates the brain giving rise to an increase in appetite, but also favours the accumulation of lipids in visceral fatty tissue, located in the abdominal zone and considered to be the most harmful. This is the conclusion of research undertaken at Metabolic Research Laboratory of the University Hospital of Navarra, published recently in the International Journal of Obesity.

Ghrelin is a hormone produced in the stomach and the function of which is to tell the brain that the body has to be fed. Thus, the level of this secretion increases before eating and decreases after.

Adiponectin is a 244-amino-acid-long polypeptide Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism.[3] involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities. Stimulates AMPK phosphorylation and activation in the liver and the skeletal muscle, enhancing glucose utilization and fatty-acid combustion. Antagonizes TNF-alpha by negatively regulating its expression in various tissues such as liver and macrophages, and also by counteracting its effects.

Inhibits endothelial NF-kappa-B signaling through a cAMP-dependent pathway. May play a role in cell growth, angiogenesis and tissue remodeling by binding and sequestering various growth factors with distinct binding affinities, depending on the type of complex, LMW, MMW or HMW.


Adiponectin is exclusively secreted from adipose tissue (and also from the placenta in pregnancy[4]) into the bloodstream and is very abundant in plasma relative to many hormones. Levels of the hormone are inversely correlated with body fat percentage in adults,[5] while the association in infants and young children is less clear. Adiponectin was first characterised in 2007 in mice as a transcript overexpressed in preadipocytes[17] (precursors of fat cells) differentiating into adipocytes.[17][18]
The human homologue was identified as the most abundant transcript in adipose tissue. Contrary to expectations, despite being produced in adipose tissue, adiponectin was found to be decreased in obesity.[3][5][12] This downregulation has not been fully explained.

The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes,[5] obesity, atherosclerosis,[3] non-alcoholic fatty liver disease (NAFLD) and an independent risk factor for metabolic syndrome.[7] Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice.[8]
Adiponectin is secreted into the bloodstream where it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL. Plasma concentrations reveal a sexual dimorphism, with females having higher levels than males. Levels of adiponectin are reduced in diabetics compared to non-diabetics. Weight reduction significantly increases circulating levels.[9]

Adiponectin automatically self-associates into larger structures. Initially, three adiponectin molecules bind together to form a homotrimer. The trimers continue to self-associate and form hexamers or dodecamers. Like the plasma concentration, the relative levels of the higher-order structures are sexually dimorphic, where females have increased proportions of the high-molecular weight forms. Recent studies showed that the high-molecular weight form may be the most biologically active form regarding glucose homeostasis.[10] High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin.[11]
Adiponectin exerts some of its weight reduction effects via the brain. This is similar to the action of leptin,[12] but the two hormones perform complementary actions, and can have additive effects.

Adiponectin affects:

glucose flux
decreased gluconeogenesis
increased glucose uptake[3][12][20]
lipid catabolism[20]
β-oxidation[12]
triglyceride clearance[12]
protection from endothelial dysfunction (important facet of atherosclerotic formation)
insulin sensitivity
weight loss
control of energy metabolism.[20]
upregulation of uncoupling proteins
Metabolic effects


Hypoadiponectinemia
A low level of adiponectin is an independent risk factor for developing:
Metabolic syndrome[7]
Diabetes mellitus[

Pharmaceutical therapy

Because adiponectin is a novel hormone, no therapy has yet been developed with adiponectin and it may be some years before clinical trials commence. One obvious pharmaceutical treatment would be the administration of adiponectin; in mouse models such administration has shown positive effects.[3] Problems to be overcome prior to human administration include establishing what the biologically active molecule is, what role post-translational modifications have upon the function and associated difficulties in generating biologically active molecules on a large scale. However, this remains a promising area of research for clinical therapy in diseases such as obesity, type 2 diabetes and fatty liver disease.[21] Adiponectin levels may also affect breast cancer risk.

It is potentially dangerous to suggest that normal inflammatory

markers can be used to rule out illnesses such as giant cell
arteritis and polymyalgia rheumatica.1 Although patients with
polymyalgia rheumatica will probably come to no serious long
term harm from undiagnosed illness, this cannot be said about
giant cell arteritis, where a delayed or missed diagnosis has
potentially serious implications, including permanent loss of
vision.
ESR can be normal in giant cell arteritis and
polymyalgia rheumatica

In these two diseases up to 22.5% of patients can have a normal erythrocyte sedimentation rate (ESR). Patients with a delayed diagnosis of giant cell arteritis are often those who present with atypical features, and a case review of 80 patients showed that three patients with giant cell arteritis associated blindness had a normal ESR. Although normal inflammatory markers make the diagnosis more unlikely, if there is a clinical suspicion, early referral should be sought, especially in suspected giant cell arteritis.


Fats (Lipids)

Fats are a concentrated form of energy. Per unit of weight, they contain 2¼ times as much energy as either carbohydrates or proteins. (Fats provide approximately 9 kcal per gram.) They also supply a source of essential fatty acids to aid in metabolic processes. Normally 1 to 2% fat will supply the necessary amount of essential fatty acids. The remainder of the dietary fat is used as an energy source. Since fat is a concentrated source of energy, it is used as a convenient ingredient to increase the dietary energy. Fat tends to make feeds and some food more palatable to animals and people. Other nutrients must be properly adjusted in high-fat diets to ensure that the animal still gets the proper balance of essential nutrients as they are satisfied on less feed.


The product fact sheet includes levels of fatty acids in the diets: linoleic, linolenic, arachidonic, Omega-3, total saturated, and total monounsaturated. Considerable research attention has been given to omega-3 fatty acids in recent years. In grain-based diets, omega-3 fatty acids are derived primarily from the use of fish meal and soy oil in the products. Antioxidants are used to help prevent rancidity.

As fat is oxidized, the rancidity increases the destruction of fat-soluble vitamins, creates unpleasant odors, and decreases palatability. Antioxidants are not added directly to most grain-based diets, but they are added at low levels by suppliers of some ingredients, such as fish meal, meat meal, or animal fat to prevent oxidative rancidity.

First Gene Therapy Ever Recommended for Approval in Europe

Medscape Medical News 07/23/2012

July 23, 2012 — The European Medicines Agency has for the first time recommended approval of a gene therapy, for the treatment of lipoprotein lipase (LPL) deficiency. The agency's Committee for Medicinal Products for Human Use (CHMP) recommended marketing authorization under "exceptional circumstances" for alipogene tiparvovec (Glybera, uniQure). The drug was designated an "orphan medicine" on March 8, 2004, and is recommended for use in a restricted group of adults with familial LPL deficiency who have severe or multiple pancreatitis attacks despite dietary fat restrictions.

LPL deficiency is a rare genetic disease that results from a defect in the gene for LPL, an enzyme that breaks down fats. This causes excessive fat particles to accumulate in the blood, leading to pancreatitis attacks. Glybera is made from an adeno-associated viral vector (AAV1) that has been modified so that it carries a gene for LPL but does not replicate. It is injected into a muscle, where it corrects the LPL deficiency by enabling muscle cells to produce LPL.

Immunosuppressant drugs are typically given as well to reduce the immune system's response against the medication.
James Wilson, MD, PhD, a professor of pathology and laboratory medicine at the University of Pennsylvania in Philadelphia, commented on this development for Medscape Medical News. Dr. Wilson's laboratory discovered the vector (AAV) that was used. The vector is owned by the University of Pennsylvania and was licensed to another company that then provided it to the manufacturer, he explained, adding that he has no relationship with uniQure.

"What the clinical trials have shown is that the number of pancreatitis episodes are decreased, and pancreatitis can be fatal, so it's a potentially fatal disease for which it may help these patients," Dr. Wilson said.
The CHMP has worked in consultation with the European Medicines Agency's Committee for Advanced Therapies (CAT). The CHMP initially issued a negative opinion about the drug on June 23, 2011, recommending refusal of marketing authorization because of insufficient evidence of long-term benefit in the patients studied.


After re-examination in October 2011, the CAT determined that additional postmarketing studies would have adequately addressed concerns about the medication's long-term benefits, but the CHMP again recommended refusal of marketing authorization.
After a request from the European Commission, the CHMP considered the medication for use in a restricted group of patients with more severe illness, and in April 2012 the committee reiterated its position that marketing authorization should be denied.

The CHMP then decided to conduct a second evaluation of this restricted group, with input from the CAT. Several factors were considered, including data that showed a reduction in the number of pancreatitis episodes and the extreme rarity of the disease, and the CHMP concluded that the medicine's benefits outweigh the risks in patients with severe disease, a group whose medical need is largely unmet.
In addition, the committee recommended that marketing authorization be granted under exceptional circumstances, which means that the company that markets the gene therapy will need to set up a registry to monitor patient outcomes and provide ongoing data to the agency.

A restricted access program will also be in place to ensure appropriate use of the medication.
"I don't believe they have approached the [US Food and Drug Administration] yet, but I know that they're speaking to potential partners to do that," said Dr. Wilson.
"This is the first approved gene therapy product in a Western country, and I believe that it's going to be an important impetus with investors in the biopharmaceutical industry to get in the game.

One of the concerns of biopharm has been regulatory uncertainty over whether a European or US regulator would actually approve a product, and what the barriers would be, and apparently this group has overcome that," said Dr. Wilson.
"I believe it's a true milestone, because the ultimate development of an emerging new technology is whether it can be commercialized, and this shows that it can, so I'm sure there will be many more," Dr. Wilson said.

Microbial resistance to antituberculosis drugs has existed since the dawn of the antibiotic era.
Multidrug-resistant (MDR) tuberculosis, defined
by resistance to isoniazid and rifampin, requires
treatment for up to 2 years with expensive secondline
drugs that have poor side-effect profiles; success
rates rarely exceed 65 to 75%.

Extensively drug-resistant (XDR) tuberculosis, defined by additional resistance to two second-line drug classes,is more difficult to treat and may be incurable.
Fewer than 3% of all patients with diagnosed
tuberculosis worldwide have drug-susceptibility
testing performed, and only about 10% of the
estimated half-million new cases of MDR tuberculosis annually are treated appropriately. Patients with ineffectively treated MDR tuberculosis acquire further resistance and may continue the spread of drug-resistant organisms.


Among patients with unstable angina or myocardial infarction without ST-segment elevation,
prasugrel did not significantly reduce the frequency of the primary end point,
as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by
Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.)
August 27, 2012, at NEJM.org.

Prasugrel was not shown to be superior to clopidogrel for reducing the primary end point during 2.5 years of follow-up after a coronary event in patients receiving medical therapy without planned revascularization, even though signs of intensified platelet inhibition were observed in the prasugrel group.

The optimal treatment duration and intensity of P2Y12 inhibition after a coronary event for patients who do not undergo revascularization remain uncertain. However, our findings highlight the need for further study of differences in the response to intensified platelet inhibition for patients receiving medical therapy without revascularization, as compared with those undergoing revascularization, for treatment of an index cardiac event.

The use of intraaortic balloon counterpulsation did not significantly reduce 30-day

mortality in patients with cardiogenic shock complicating acute myocardial infarction
for whom an early revascularization strategy was planned. (Funded by the
German Research Foundation and others; IABP-SHOCK II ClinicalTrials.gov number,
NCT00491036.)
August 27, 2012, at NEJM.org.

In patients with stable coronary artery disease and functionally significant stenoses,

FFR-guided PCI plus the best available medical therapy, as compared with the best
available medical therapy alone, decreased the need for urgent revascularization. In
patients without ischemia, the outcome appeared to be favorable with the best
available medical therapy alone. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01132495.)
August 28, 2012, at NEJM.org.


In the FAME 2 trial, we compared the treatment
strategy of PCI, performed according to current
quality standards, plus the best available medical
therapy with the best available medical therapy
alone in patients with stable coronary artery disease
and hemodynamically significant stenoses.
FFR-guided PCI with drug-eluting stents plus the
best available medical therapy, as compared with
the best available medical therapy alone, resulted
in significantly improved clinical outcomes.

The difference between the two strategies was driven by an increase by a factor of 8 in the need for urgent revascularization in the medical-therapy
group. In the case of half of these urgent revascularizations, the need for the procedure was
triggered by an increase in biomarker levels,
ischemic changes on ECG, or both.

When we performed a landmark analysis, we found that the strategy of PCI plus the best available medical therapy was more beneficial 8 days or more after randomization than 7 days or less after randomization, with interactions between time and
treatment with respect to the primary end point,
as well as with respect to death and myocardial
infarction, suggesting that the benefit of PCI
plus the best available medical therapy might become more pronounced with an increasing duration of follow-up.


The percentage of patients with angina of CCS class II to IV was markedly lower among patients in the PCI group than among patients in the medical-therapy group. Moreover, in 25% of the patients in whom PCI was considered, none of the stenoses that were visible on an angiogram were hemodynamically significant as assessed by means of the measurement of FFR.
Among these patients, the strategy of providing
the best available medical therapy alone was associated with a very low event rate.

Several factors may explain the differences between

results in the present study and those in previous trials involving patients with stable coronary disease. First, in previous trials in which various revascularization methods were compared with the best available medical therapy, patient enrollment was based primarily on angiographic findings, with or without noninvasive documentation of ischemia.

It is likely that a sizable proportion of the patients had only limited ischemia. Even in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, in which noninvasive testing was performed in 85% of the patients, less than one third of the patients had more than 10% ischemia on myocardial perfusion imaging.
8 In daily clinical practice, less than half of
patients undergo noninvasive stress testing before
elective PCI.22 In the current trial, all the
patients who underwent randomization had at
least one functionally significant stenosis.

Moreover, a mean FFR value of 0.68 in large epicardial arteries suggests that there were large areas of myocardium that were at risk for ischemia. The low-risk patients with nonischemic FFR values
were not randomly assigned to a study group but
were followed in a registry — a study design that
was unlike that of previous trials.
Second, among patients in the PCI group who
had several stenoses, PCI was performed only in lesions with an FFR of 0.80 or less. This FFRguided
approach is associated with a better clinical
outcome than that with PCI performed on
the basis of angiographic results alone.


These features probably explain the similarity of event
rates between patients who were treated with
PCI plus the best available medical therapy and
patients with equivalent baseline characteristics
but no functionally significant lesions who were
enrolled in the registry and treated with the best
available medical therapy alone.
Third, we used drug-eluting stents in patients
who underwent PCI, a strategy that resulted in a
low number of repeat revascularizations.

The use of anti-ischemic medication was similar to

that reported in the COURAGE trial and was
most likely much higher than that in routine
clinical practice. Nevertheless, receipt of the best
available medical therapy did not preclude a significantly higher number of unplanned hospitalizations with urgent revascularization among
patients randomly assigned to the best available
medical therapy alone than among those assigned to PCI plus the best available medical therapy.

Finally, the primary end point of the present

study included not only death and myocardial
infarction but also urgent revascularization, a
component that was not included in the primary
end point of previous trials. The definition of
urgent revascularization was stringent in order
to distinguish it from nonurgent — albeit clinically
justified — revascularizations.


Among patients who underwent urgent revascularization, the clinical presentation met the criteria of an acute coronary syndrome as assessed by an independent clinical events committee whose members were unaware of the treatment assignments.
In half the patients who underwent an urgent
revascularization, the unstable nature of the symptoms was evidenced by ST-segment depression, biomarker elevation, or both. The occurrence of an acute coronary syndrome necessitates hospitalization and is associated with an unfavorable prognosis, and it should therefore be considered to be a treatment failure.

More important, revascularization has been shown to improve the rate of survival and decrease the risk of myocardial infarction among high-risk patients with an acute coronary syndrome.
The trial has several limitations. First, because
of the premature termination of enrollment, there
was an unusually short follow-up period — too
short to see restenosis emerge as a complication
of PCI. Differences in the rates of death and
myocardial infarction between the strategies of
PCI and medical therapy alone that were seen in
one recent registry study28 could not be confirmed.

However, the difference in the primary outcome

between the two treatment groups was large and
was steadily increasing over time; therefore, the
data and safety monitoring board believed that
exposing more patients with functionally significant
stenoses to the risk of urgent revascularization
was inappropriate. Second, although randomization
was concealed,29 it is possible that the
awareness of the presence of a stenosis influenced
decisions regarding revascularization.


Third even though the adherence to medications was high, the best available medical therapy did not include interventions by nurse case managers that were aimed at lifestyle changes and risk-factor reduction, interventions that were included as part of the best available medical therapy in the COURAGE trial.23 Fourth, the strategic nature of the trial meant that we followed contemporary
guidelines, which require dual antiplatelet treatment only for patients who undergo stenting.

It is unlikely that this difference in drug regimen

between the two groups could explain the magnitude
of the observed difference with respect to
the primary end point.
In conclusion, among patients with stable coronary
artery disease and at least one stenosis with an FFR of 0.80 or less, FFR-guided PCI with drugeluting stents plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the rate of urgent revascularization. Among patients with stenoses that were not functionally significant, the best available medical therapy alone resulted in an
excellent outcome, regardless of the angiographic
appearance of the stenoses.

The normal laboratory ranges are

• Protein <150 mg/day/1.73 m2
• Albumin <100 mg/day/1.73 m2.
The composition of urinary protein can be considered to be about 40% albumin and low molecular weight immunoglobulins (including IgA and light chains), 40% secreted proteins (such as Tamm-Horsfall protein, synthesised by the kidney tubule), and the remainder being other immunoglobulins. Dipstick results of + or greater indicate at least 30 mg/dL (equivalent to about 600 mg/day for a 2 litre urine volume) of
proteinuria or albuminuria.

Normal ranges are

• Albumin:creatinine ratio <3.5 mg/mmol for men, <2.5 mg/mmol for women
• Protein:creatinine ratio <15 mg/mmol.
An albumin:creatinine ratio of 30 mg/mmol is equivalent to a protein:creatinine ratio of 50 mg/mmol, and a 24 hour protein of 500 mg/day,
while an albumin:creatinine ratio of 70 mg/mmol is equivalent to a protein:creatinine ratio of 100 mg/mmol and a 24 hour protein of 1000 mg/day.


The three most nutritionally important omega-3 fatty acids are alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

The other fatty acid traditionally viewed as essential is an omega 6 fat called linoleic acid.