MECHANISM OF DIABETIC KETOACIDOSIS

MECHANISM OF DIABETIC KETOACIDOSIS 

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances. DKA results from a shortage of insulin; in response the body switches to burning fatty acids and producing acidic ketone bodies that cause most of the symptoms and complications.^[1]

DKA may be the first symptom of previously undiagnosed diabetes, but it may also occur in people known to have diabetes as a result of a variety of causes, such as intercurrent illness or poor compliance with insulin therapy. Vomiting, dehydration, deep gasping breathing, confusion and occasionally coma are typical symptoms. DKA is diagnosed with blood and urine tests; it is distinguished from other, rarer forms of ketoacidosis by the presence of high blood sugar levels. Treatment involves intravenous fluids to correct dehydration, insulin to suppress the production of ketone bodies, treatment for any underlying causes such as infections, and close observation to prevent and identify complications.^[1][2]

DKA is a medical emergency, and without treatment it can lead to death. DKA was first described in 1886; until the introduction of insulin therapy in the 1920s it was almost universally fatal.^[3] It now carries a mortality of less than 1% with adequate and timely treatment.^[4]

Signs and symptoms

The symptoms of an episode of diabetic ketoacidosis usually evolve over the period of about 24 hours. Predominant symptoms are nausea and vomiting, pronounced thirst, excessive urine production and abdominal pain that may be severe. Those who measure their glucose levels themselves may notice hyperglycemia (high blood sugar levels). In severe DKA, breathing becomes labored and of a deep, gasping character (a state referred to as "Kussmaul respiration").^[5] The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation.^[5] Coffee ground vomiting (vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosion of the esophagus.^[3] In severe DKA, there may be confusion, lethargy, stupor or even coma (a marked decrease in the level of consciousness).^[5][4]

On physical examination there is usually clinical evidence of dehydration, such as a dry mouth and decreased skin turgor. If the dehydration is profound enough to cause a decrease in the circulating blood volume, tachycardia (a fast heart rate) and low blood pressure may be observed. Often, a "ketotic" odor is present, which is often described as "fruity", often compared to the smell of pear drops whose scent is a ketone. If Kussmaul respiration is present, this is reflected in an increased respiratory rate.^[5]

Small children with DKA are relatively prone to cerebral edema (swelling of the brain tissue), which may cause headache, coma, loss of the pupillary light reflex, and progress to death. It occurs in 0.3–1.0% of children with DKA, and has been described in young adults, but is overall very rare in adults.^[1][5][6] It carries a 20–50% mortality.^[7]

[edit]Cause

DKA most frequently occurs in those who already have diabetes, but it may also be the first presentation in someone who had not previously been known to be diabetic. There is often a particular underlying problem that has led to the DKA episode; this may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine. Young patients with recurrent episodes of DKA may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain.^[5]

Diabetic ketoacidosis may occur in those previously known to have diabetes mellitus type 2 or in those who on further investigations turn out to have features of type 2 diabetes (e.g. obesity, strong family history); this is more common in African, African-American and Hispanic people. Their condition is then labeled "ketosis-prone type 2 diabetes".^[1][8]

[edit]Mechanism

Diabetic ketoacidosis arises because of a lack of insulin in the body. The lack of insulin and corresponding elevation of glucagon leads to increased release of glucose by the liver (a process that is normally suppressed by insulin) fromglycogen via glycogenolysis and also through gluconeogenesis. High glucose levels spill over into the urine, taking water and solutes (such as sodium and potassium) along with it in a process known as osmotic diuresis.^[1] This leads to polyuria, dehydration, and compensatory thirst and polydipsia. The absence of insulin also leads to the release of free fatty acids from adipose tissue (lipolysis), which are converted, again in the liver, into ketone bodies (acetoacetateand β-hydroxybutyrate). β-Hydroxybutyrate can serve as an energy source in absence of insulin-mediated glucose delivery, and is a protective mechanism in case of starvation. The ketone bodies, however, have a low pKa and therefore turn the blood acidic (metabolic acidosis). The body initially buffers the change with the bicarbonate buffering system, but this system is quickly overwhelmed and other mechanisms must work to compensate for the acidosis.^[1] One such mechanism is hyperventilation to lower the blood carbon dioxide levels (a form of compensatory respiratory alkalosis). This hyperventilation, in its extreme form, may be observed as Kussmaul respiration.^[5]

In various situations such as infection, insulin demands rise but are not matched by the failing pancreas. Blood sugars rise, dehydration ensues, and resistance to the normal effects of insulin increases further by way of a vicious circle.^[1][3]

As a result of the above mechanisms, the average adult DKA patient has a total body water shortage of about 6 liters (or 100 mL/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium andcalcium. Glucose levels usually exceed 13.8 mmol/L or 250 mg/dL.^[9]

β-hydroxybutyrate, despite chemically containing a carboxylic acid instead of a ketone, is the principal "ketone body" in diabetic ketoacidosis.

DKA is common in type 1 diabetes as this form of diabetes is associated with an absolute lack of insulin production by the islets of Langerhans. In type 2 diabetes, insulin production is present but is insufficient to meet the body's requirements as a result of end-organ insulin resistance. Usually, these amounts of insulin are sufficient to suppress ketogenesis. If DKA occurs in someone with type 2 diabetes, their condition is called "ketosis-prone type 2 diabetes".^[8] The exact mechanism for this phenomenon is unclear, but there is evidence both of impaired insulin secretion and insulin action.^[1][8] Once the condition has been treated, insulin production resumes and often the patient may be able to resume diet or tablet treatment as normally recommended in type 2 diabetes.^[1]

The clinical state of DKA is associated, in addition to the above, with the release of various counterregulatory hormones such as glucagon and adrenaline as well as cytokines, the latter of which leads to increased markers of inflammation, even in the absence of infection.^[1][2]

Cerebral edema, which is the most dangerous DKA complication, is probably the result of a number of factors. Some authorities suggest that it is the result from overvigorous fluid replacement, but the complication may develop before treatment has been commenced.^[6][7] It is more likely in those with more severe DKA,^[2] and in the first episode of DKA.^[6] Likely factors in the development of cerebral edema are dehydration, acidosis and low carbon dioxide levels; in addition, the increased level of inflammation and coagulation may, together with these factors, lead to decreased blood flow to parts of the brain, which then swells up once fluid replacement has been commenced.^[6] The swelling of brain tissue leads to raised intracranial pressure ultimately leading to death.^[2][7]

[edit]Diagnosis

[edit]Investigations

Diabetic ketoacidosis may be diagnosed when the combination of hyperglycemia (high blood sugars), ketones in the blood or on urinalysis and acidosis are demonstrated. Arterial blood gas measurement is usually performed to demonstrate the acidosis; this requires taking a blood sample from an artery. Subsequent measurements (to ensure treatment is effective), may be taken from a normal blood test taken from a vein, as there is little difference between the arterial and the venous pH.^[4]

In addition to the above, blood samples are usually taken to measure urea and creatinine (measures of kidney function, which may be impaired in DKA as a result of dehydration) and electrolytes. Furthermore, markers of infection (complete blood count, C-reactive protein) and acute pancreatitis (amylase and lipase) may be measured. Given the need to exclude infection, chest radiography and urinalysis are usually performed.^[1]

If cerebral edema is suspected because of confusion, recurrent vomiting or other symptoms, computed tomography may be performed to assess its severity and to exclude other causes such as stroke.^[7]

[edit]Criteria

Diabetic ketoacidosis is distinguished from other diabetic emergencies by the presence of large amounts of ketones in blood and urine, and marked metabolic acidosis. Hyperosmolar hyperglycemic state (HHS, sometimes labeled "hyperosmolar non-ketotic state" or HONK) is much more common in type 2 diabetes and features increased plasma osmolarity (above 320 mosm/kg) due to profound dehydration and concentration of the blood; mild acidosis and ketonemia may occur in this state, but not to the extent observed in DKA. There is a degree of overlap between DKA and HHS, as in DKA the osmolarity may also be increased.^[1]

Ketoacidosis is not always the result of diabetes. It may also result from alcohol excess and from starvation; in both states the glucose level is normal or low. Metabolic acidosis may occur in people with diabetes for other reasons, such as poisoning with ethylene glycol or paraldehyde.^[1]

The American Diabetes Association categorizes DKA in adults into one of three stages of severity:^[1]

• Mild: blood pH mildly decreased to between 7.25 and 7.30 (normal 7.35–7.45); serum bicarbonate decreased to 15–18 mmol/l (normal above 20); the patient is alert
• Moderate: pH 7.00–7.25, bicarbonate 10–15, mild drowsiness may be present
• Severe: pH below 7.00, bicarbonate below 10, stupor or coma may occur

A 2004 statement by the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society (for children) uses slightly different cutoffs, where mild DKA is defined by pH 7.20–7.30 (bicarbonate 10–15 mmol/l), moderate DKA by pH 7.1–7.2 (bicarbonate 5–10) and severe DKA by pH<7.1 (bicarbonate below 5).^[2]

[edit]Prevention

Attacks of DKA can be prevented in those known to have diabetes to an extent by adherence to "sick day rules"; these are clear-cut instructions to patients on how to treat themselves when unwell. Instructions include advice on how much extra insulin to take when sugar levels appear uncontrolled, an easily digestible diet rich in salt and carbohydrates, means to suppress fever and treat infection, and recommendations when to call for medical help.^[1][4]

[edit]Management

The main aims in the treatment of diabetic ketoacidosis are replacing the lost fluids and electrolytes while suppressing the high blood sugars and ketone production with insulin. Admission to an intensive care unit or similar high-dependency area or ward for close observation may be necessary.^[4]

[edit]Fluid replacement

The amount of fluid depends on the estimated degree of dehydration. If dehydration is so severe as to cause shock (severely decreased blood pressure with insufficient blood supply to the body's organs), or a depressed level of consciousness, rapid infusion of saline (1 liter for adults, 10 ml/kg in repeated doses for children) is recommended to restore circulating volume.^[1][10] Slower rehydration based on calculated water and sodium shortage may be possible if the dehydration is moderate, and again saline is the recommended fluid.^[10][11] Very mild ketoacidosis with no associated vomiting and mild dehydration may be treated with oral rehydration and subcutaneous rather than intravenous insulin under observation for signs of deterioration.^[10][11]

A special but unusual consideration is cardiogenic shock, where the blood pressure is decreased not due to dehydration but due to inability of the heart to pump blood through the blood vessels. This situation requires ICU admission, monitoring of the central venous pressure (which requires the insertion of a central venous catheter in a large upper body vein), and the administration of medication that increases the heart pumping action and blood pressure.^[1]

[edit]Insulin

Some guidelines recommend a bolus (initial large dose) of insulin of 0.1 unit of insulin per kilogram of body weight. This can be administered immediately after the potassium level is known to be higher than 3.3 mmol/l; if the level is any lower, administering insulin could lead to a dangerously low potassium level (see below).^[1][4] Other guidelines recommend delaying the initiation of insulin until fluids have been administered.^[10]

In general, insulin is given at 0.1 unit/kg per hour to reduce the blood sugars and suppress ketone production. Guidelines differ as to which dose to use when blood sugar levels start falling; some recommend reducing the dose of insulin once glucose falls below 16.6 mmol/l (300 mg/dl)^[1] but other recommend infusing glucose in addition to saline to allow for ongoing infusion of higher doses of insulin.^[4][10]

[edit]Potassium

Potassium levels can fluctuate severely during the treatment of DKA, because insulin decreases potassium levels in the blood by redistributing it into cells. A large part of the shifted extracellular potassium would have been lost in urine because of osmotic diuresis. Hypokalemia (low blood potassium concentration) often follows treatment. This increases the risk of dangerous irregularities in the heart rate. Therefore, continuous observation of the heart rate is recommended,^[10] as well as repeated measurement of the potassium levels and addition of potassium to the intravenous fluids once levels fall below 5.3 mmol/l. If potassium levels fall below 3.3 mmol/l, insulin administration may need to be interrupted to allow correction of the hypokalemia.^[1]

[edit]Bicarbonate

The administration of sodium bicarbonate solution to rapidly improve the acid levels in the blood is controversial. There is little evidence that it improves outcomes beyond standard therapy, and indeed some evidence that while it may improve the acidity of the blood, it may actually worsen acidity inside the body's cells and increase the risk of certain complications. Its use is therefore discouraged,^[2][4][11] although some guidelines recommend it for extreme acidosis (pH<6.9), and smaller amounts for severe acidosis (pH 6.9–7.0).^[1]

[edit]Cerebral edema

Cerebral edema, if associated with coma, often necessitates admission to intensive care, artificial ventilation, and close observation. The administration of fluids is slowed. The ideal treatment of cerebral edema in DKA is not established, but intravenous mannitol and hypertonic saline (3%) are used—as in some other forms of cerebral edema—in an attempt to reduce the swelling.^[2]

[edit]Resolution

Resolution of DKA is defined as general improvement in the symptoms, such as the ability to tolerate oral nutrition and fluids, normalization of blood acidity (pH>7.3), and absence of ketones in blood (<1 mmol/l) or urine. Once this has been achieved, insulin may be switched to the usual subcutaneously administrered regimen, one hour after which the intravenous administration can be discontinued.^[4][10]

In patients with suspected ketosis-prone type 2 diabetes, determination of antibodies against glutamic acid decarboxylase and islet cells may aid in the decision whether to continue insulin administration long-term (if antibodies are detected), or whether to withdraw insulin and attempt treatment with oral medication as in type 2 diabetes.^[8]

[edit]Epidemiology

Diabetic ketoacidosis occurs in 4.6–8.0 per 1000 people with type 1 diabetes annually.^[9] In the United States, 135,000 hospital admissions occur annually as a result of DKA, at an estimated cost of $2.4 billion or a quarter to a half the total cost of caring for people with type 1 diabetes. There has been a documented increasing trend to hospital admissions.^[1] The risk is increased in those with an ongoing risk factor, such as an eating disorder, and those who cannot afford insulin.^[1] About 30% of children with type 1 diabetes receive their diagnosis after an episode of DKA.^[12]

[edit]History

The first full description of diabetic ketoacidosis is attributed to Julius Dreschfeld, a German pathologist working in Manchester, United Kingdom. In his description, which he gave in an 1886 lecture at the Royal College of Physicians in London, he drew on reports by Adolph Kussmaul as well as describing the main ketones, acetoacetate and β-hydroxybutyrate, and their chemical determination.^[13] The condition remained almost universally fatal until the discovery of insulin in the 1920s; by the 1930s, mortality had fallen to 29%,^[3] and by the 1950s it had become less than 10%.^[14] The entity of cerebral edema due to DKA was described in 1936 by a team of doctors from Philadelphia.^[7][15]

Numerous research studies since the 1950s have focused on the ideal treatment for diabetic ketoacidosis. A significant proportion of these studies have been conducted at the University of Tennessee Health Science Center and Emory University School of Medicine.^[14] Treatment options studied have included high- or low-dose intravenous, subcutaneous or intramuscular (e.g. the "Alberti regime") insulin, phosphate supplementation, need for a loading dose of insulin, and appropriateness of using bicarbonate therapy in moderate DKA.^[14] Various questions remain unanswered, such as whether bicarbonate administration in severe DKA makes any real difference to the clinical course, and whether an insulin loading dose is needed in adults.^[14]

The entity of ketosis-prone type 2 diabetes was first fully described in 1987 after several preceding case reports. It was initially thought to be a form of maturity onset diabetes of the young,^[16] and went through several other descriptive names (such as "idiopathic type 1 diabetes", "Flatbush diabetes", "atypical diabetes" and "type 1.5 diabetes") before the current terminology of "ketosis-prone type 2 diabetes" was adopted.^[1][8]

[edit]References

1. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x} Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN (July 2009). "Hyperglycemic crises in adult patients with diabetes". Diabetes Care 32 (7): 1335–43. doi:10.2337/dc09-9032.PMC 2699725. PMID 19564476.
2. ^ ^{a b c d e f g} Dunger DB, Sperling MA, Acerini CL, et al. (February 2004). "European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents". Pediatrics 113 (2): e133–40. doi:10.1542/peds.113.2.e133. PMID 14754983.
3. ^ ^a b c d Eledrisi MS, Alshanti MS, Shah MF, Brolosy B, Jaha N (May 2006). "Overview of the diagnosis and management of diabetic ketoacidosis". American Journal of Medical Science 331 (5): 243–51.doi:10.1097/00000441-200605000-00002. PMID 16702793.
4. ^ ^{a b c d e f g h i} Joint British Diabetes Societies Inpatient Care Group (March 2010). "The Management of Diabetic Ketoacidosis in Adults" (PDF). NHS Diabetes. Retrieved 2012-05-01.
5. ^ ^{a b c d e f g} Powers AC (2005). "Diabetes mellitus". In Kasper DL, Braunwald E, Fauci AS, et al.. Harrison's Principles of Internal Medicine (16th ed.). New York, NY: McGraw-Hill. pp. 2152–2180. ISBN 0-07-139140-1.
6. ^ ^a b c d Glaser N (June 2006). "New perspectives on the pathogenesis of cerebral edema complicating diabetic ketoacidosis in children". Pediatric Endocrinology Reviews 3 (4): 379–86. PMID 16816806.
7. ^ ^{a b c d e} Brown TB (March 2004). "Cerebral oedema in childhood diabetic ketoacidosis: Is treatment a factor?".Emergency Medical Journal 21 (2): 141–4. doi:10.1136/emj.2002.001578. PMC 1726262. PMID 14988335.
8. ^ ^{a b c d e} Umpierrez GE, Smiley D, Kitabchi AE (March 2006). "Narrative review: ketosis-prone type 2 diabetes mellitus". Annals of Internal Medicine 144 (5): 350–7. PMID 16520476.
9. ^ ^a b Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA (December 2006). "Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association". Diabetes Care 29 (12): 2739–48.doi:10.2337/dc06-9916. PMID 17130218.
10. ^ ^{a b c d e f g} Edge J (May 2009). "BSPED Recommended DKA Guidelines 2009". British Society for Paediatric Endocrinology and Diabetes. Retrieved 2009-07-12.
11. ^ ^a b c National Institute for Health and Clinical Excellence. Clinical guideline 15: Diagnosis and management of type 1 diabetes in children, young people and adults . London, 2004.
12. ^ Silverstein J, Klingensmith G, Copeland K, et al. (January 2005). "Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association". Diabetes Care 28 (1): 186–212.doi:10.2337/diacare.28.1.186. PMID 15616254.
13. ^ Dreschfeld J (1886). "The Bradshawe Lecture on Diabetic Coma". British Medical Journal 2 (1338): 358–63.doi:10.1136/bmj.2.1338.358. PMC 2256374. PMID 20751675.
14. ^ ^a b c d Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB (May 2008). "Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state". Journal of Clinical Endocrinology and Metabolism 93 (5): 1541–52. doi:10.1210/jc.2007-2577. PMC 2386681. PMID 18270259.
15. ^ Dillon ES, Riggs HE, Dyer WW (1936). "Cerebral lesions in uncomplicated fatal diabetic acidosis". American Journal of the Medical Sciences 3 (3): 360–365. doi:10.1097/00000441-193609000-00007.
16. ^ Winter WE, Maclaren NK, Riley WJ, Clarke DW, Kappy MS, Spillar RP (February 1987). "Maturity-onset diabetes of youth in black Americans". New England Journal of Medicine 316 (6): 285–91.doi:10.1056/NEJM198702053160601. PMID 3543673.

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Helicobacter pylori virulence factors and the host immune response: implications for therapeutic vaccination.

Prinz C, Hafsi N, Voland P.

Source

Department of Medicine II, Technical University, Ismaningerstr. 22, 81675 Munich, Germany. christian.prinz@lrz.tum.edu

Abstract

Helicobacter pylori colonizes the human gastric mucosa and is associated with specific gastric disease. Virulence factors, such as urease, the vacuolating toxin (VacA), the cytotoxin-associated antigen CagA or blood-group-antigen-binding adhesin (BabA), an adherence factor, might account for the development of different diseases. Vaccination trials exploiting the antigenic properties of some of these proteins have not been successful in preventing infection in humans. A more in-depth understanding of the immune response to H. pylori infection as well as additional information on suitable epitopes and adjuvants will be required before a successful vaccine can be developed.

Among people infected with Helicobacter pylori, the virulence of the infecting strain is a major determinant of who develops disease. Strains producing vacuolating cytotoxin activity are more commonly isolated from people with peptic ulcers than without. The gene encoding the toxin, vacA, varies between strains, especially in its signal sequence and mid regions. vacA genotype influences cytotoxin activity, and signal sequence type correlates closely with peptic ulceration. Infection with strains possessing cag>4 (cytotoxin associated gene A) is more common among people with peptic ulceration or gastric adenocarcinoma than without. cagA is a marker for the cag pathogenicity island, which includes genes necessary for the enhanced inflammation induced by pathogenic strains. Serological detection of infection with cagA* strains is at present the best practical test for virulence. However, before a strategy of screening and selective treatment can be considered, it is important to assess whether cagA- strains are entirely non-pathogenic.

Helicobacter pylori infection is the main cause of duodenal and gastric ulceration and a major risk factor for gastric adenocarcinoma and lymphoma. However, these diseases only occur in about 15% of infected persons1. Of those infected, who will develop disease is influenced by the virulence of the infecting H. pylori strain, the genetic susceptibility of the host and environmental co-factors. Of these, bacterial virulence factors are the most studied2 . Bacterial virulence factors are characteristics present in some bacteria which enable them, rather than others, to cause disease. For H. pylori, it is still unclear whether all or only some strains are pathogenic. All strains cause a long-lasting histological gastritis characterised by lymphocytic and some degree of neutrophilic infiltration, although this gastritis per se is clinically silent. Whether all strains can potentially cause peptic ulceration or gastric carcinoma is unclear, although the risks associated with some are certainly much greater than those associated with others. Certain characteristics are present in only some strains and have been linked with disease. These are, firstly, vacuolating cytotoxin production and certain types of vacA (vacuolating cytotoxin gene A) alleles; secondly, CagA (cytotoxin associated gene product A) and genes in the cag (cytotoxin associated gene) pathogenicity island; and thirdly, the ability to strongly and rapidly stimulate neutrophils to degranulate. Host susceptibility may be relevant both in determining who becomes infected with H. pylori and who amongst those infected develops disease3 . There is growing evidence that the host's HLA type4 , and blood group antigen type and expression5  are important, at least as genetic markers of susceptibility. Important environmental factors include childhood living conditions (the strongest environmental correlate of who becomes infected6 ), smoking (a major risk factor for duodenal ulceration amongst H. pylori-infected persons7 ) and dietary factors (important risk factors for gastric adenocarcinoma8 ).

Many characteristics of H. pylori are necessary for disease and thus are potential therapeutic targets and important subjects for research. Gastric colonisation is a prerequisite for H. pylori-associated disease, and for this both motility (derived from flagella) and urease have been shown to be important: mutant strains lacking these features cannot establish infection in animal models9 -10. Following colonisation, H.pylori must acquire nutrients in the gastric mucus niche, and as for all bacterial parasites, acquisition of iron from the host is a particular challenge11. Infection is virtually lifelong in the absence of treatment, implying that evasion of the host response is efficient, and this is discussed in the accompanying paper on inflammation and autoimmunity. Adhesion is important for the enhanced inflammatory response seen for some pathogenic strains: for example, these strains only stimulate cultured epithelial cells to produce the pro-inflammatory cytokine interleukin 8 if they are allowed to adhere12. Other H. pylori components are also pro-inflammatory: urease is an important stimulant of both local and systemic immunity as are many other surface expressed and cytoplasmic proteins13 . However, none of these shared factors can explain differences in disease outcome unless they differ qualitatively or quantitively between strains, and in the rare instances where differences have been shown13 , these have not correlated with disease. 

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Ternyata otak bisa rusak karena hal-hal berikut ini..

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Mereka yang tidak mengkonsumsi sarapan pagi memiliki kadar gula darah yang rendah, yang akibatnya suplai nutrisi ke otak menjadi kurang.

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3. MerokokZat dalam rokok yang terhisap akan mengakibatkan penyusutan otak secara cepat, serta dapat mengakibatkan penyakit Alzheimer.

4. Mengkonsumsi gula terlalu banyakKonsumsi gula yang terlalu banyak akan menyebabkan terganggunya penyerapan protein dan nutrisi, sehingga terjadi ketidakseimbangan gizi yang akan mengganggu perkembangan otak

5. Polusi UdaraOtak adalah konsumen oksigen terbesar dalam tubuh manusia. Menghirup udara yang berpolusi menurunkan suplai oksigen ke otak sehingga dapat menurunkan efisiensi otak.
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Virus H7N9 bermutasi, mampu jangkiti haiwan lain

BEIJING 4 April - Virus selesema burung, H7N9 di China, dipercayai telah bermutasi dan mampu menjangkiti haiwan lain, sekali gus meningkatkan potensi ancaman yang lebih besar kepada manusia, kata saintis, semalam.

Pengarah pusat selesema Pertubuhan Kesihatan Dunia di Hospital Penyelidikan Kanak-kanak St. Jude, di Memphis, Tennessee, Richard Webby berkata, turutan genetik H7N9 menimbulkan kebimbangan tentang potensi penyebaran wabak secara global.

Bagaimanapun, katanya, agak mustahil untuk memberikan anggaran tepat tentang perkara itu.

"Pada peringkat ini, tidak mungkin virus itu menjadi pandemik,'' kata beliau.

Webby menjelaskan bahawa H7N9 mempunyai penanda genetik menunjukkan virus itu mampu menjangkiti manusia.

Katanya, jika itu berlaku, satu wabak besar boleh tersebar, lebih buruk daripada penyebaran virus-virus selesema burung sebelum ini seperti H5N1 yang pernah muncul sedekad lalu.

Buat masa ini, H7N9 di China mengakibatkan empat kematian dan sekurang-kurangnya sembilan orang telah dijangkiti virus itu.

Masih tidak jelas bagaimana mangsa boleh dijangkiti virus itu dan masih tidak ada bukti H7N9 boleh merebak dengan mudah dalam kalangan manusia.

Apa yang pasti, H7N9 boleh berjangkit menerusi ternakan ayam dan itik tanpa membuatkan haiwan itu jatuh sakit, sekali gus menyukarkan saintis mengesan kuman itu dalam ternakan.

No proof China bird flu H7N9 spreading between humans: 

World Health Organization

Topics: china ♦ World Health Organization 

The World Health Organisation

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The World Health Organisation said Monday there is no evidence China’s bird flu is spreading between humans, but jitters over the outbreak that has killed six people saw airline and tourism shares slump.

China announced just over a week ago that H7N9 avian influenza had been found in humans for the first time, and the number of confirmed cases has since reached 21.

Like the more common H5N1 variant which typically spreads from birds to humans, experts fear the possibility that such viruses can mutate into a form easily transmissible between humans, with the potential to trigger a pandemic.

“Although we do not know the source of infection, at this time there is no evidence of sustained human-to-human transmission,” Michael O’Leary, the WHO’s representative in China, told a news conference.

“The human cases we know of are very serious. A large proportion have died,” he added.

Fears over the deaths sparked a fall in Shanghai shares, with hotel and tourism shares leading the decline.

China United Travel, a tourism agency based in the eastern city of Nanjing, slumped 3.38 percent and hotel operator Shanghai Jinjiang International Hotels Development fell 5.21 percent.

Flag carrier Air China was off 3.38 percent and China Eastern Airlines down 3.23 percent. But medical stocks rose.

Concerns over the outbreak were also blamed for a tumble in Hong Kong stocks on Friday, although shares recovered on Monday.

“The major cause of bird flu remains unknown and this will cause panic among people and affect consumption, which may affect market expectations for the trend of the domestic economy,” said BOC International analyst Shen Jun.

The outbreak has so far been confined to China’s developed eastern region, with four deaths in the commercial hub Shanghai and two in the neighbouring province of Zhejiang. Other infections have occurred in Jiangsu and Anhui provinces.

A Chinese expert said more H7N9 cases could be found in a wider area.

“We are tracking the source and cannot rule out the possibility of finding the virus in other regions,” said Feng Zijian, director of the emergency office for China’s disease control centre.

Another official, Shu Yuelong, said poultry infected with the H7N9 strain die more slowly than those with H5N1, giving the virus more time in which to infect people.

More than 365 people have died of H5N1 worldwide since a major outbreak in 2003, and it kills about 60 percent of people who develop it, according to WHO statistics.

The first deaths from H7N9 were not reported by Chinese authorities until three weeks after they occurred, prompting criticism the initial announcement was too slow.

But Chinese officials have said the delay in announcing the first results was because it took time to determine the cause of the illness. O’Leary praised China’s transparency, saying the WHO was “very satisfied and pleased with the level of information shared”.

China faced condemnation a decade ago on accusations it covered up the 2003 outbreak of Severe Acute Respiratory Syndrome which eventually killed about 800 people globally.

Users of China’s popular weibo microblogs have expressed scepticism about official assurances. “Although there is no human transmission, why does the number (of cases) increase daily? This makes people scared,” said user Li Xiao Lei.

The WHO said in a statement that it is possible the virus can spread to humans from animals, such as pigeons.

Shanghai has culled more than 111,000 birds, banned trading in live poultry and shut markets in a bid to curb the outbreak.

Nanjing city followed suit by banning live poultry trading while Hangzhou culled poultry after discovering infected quail.

The China Daily newspaper on Monday called for “high alert” nationwide and urged stronger regulation of the poultry trade.

“The rules for transporting and trading of live poultry in cities should be strengthened, because the bird flu can spread very fast in densely populated cities,” it said in an editorial.

Hope in fight against H7N9 bird flu deadly virus in China

A Hangzhou man who was close to death is on the mend and a four-year-old boy in Shanghai is recovering well from the H7N9 bird flu

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The Hangzhou H7BN9 patient's wife has new hope. Photo: Simon Song

Two H7N9 bird flu patients - a four-year-old boy in Shanghai and a 67-year-old man in Hangzhou - are recovering from the illness, bringing hope in the fight against the deadly new virus strain.

The wife and son of the Hangzhou patient, who was confirmed to be infected a week ago, saw him yesterday via a video telephone link at the First Affiliated Hospital of Zhejiang University. The four-year-old boy in Shanghai has recovered with no sign of respiratory illness, said Wu Fan, director of the municipal Centre for Disease Control.

Now I am the happiest person in the world. Doctors said he is not completely out of danger yet, but he can smile and hear us. We all see the hope

 The wife of the Hangzhou patient said: "I could not help but cry when I saw him via television. He was snatched from the jaws of death and I almost lost him. Now I am the happiest person in the world. Doctors said he is not completely out of danger yet, but he can smile and hear us. We all see the hope."

The man had been in an isolation ward for eight days and was once on the verge of respiratory failure. He developed a cough and fever on March 20, a few days after he bought two quail at a local wet market which also sold other poultry including doves and chickens.

Since Friday night, he has been able to urinate again, which his doctors said was a positive signal that his circulatory system was starting to work again.

Twelve doctors and 20 nurses had been busy taking care of him over the past week. His attending doctor, Li Lanjuan, one of the country's top infectious disease experts, told local media that the case could help offer clues to finding an effective therapy for H7N9 bird flu.

Li said the patient was injected with massive doses of antibiotics but only started to get better after her team stopped using antibiotics and turned to traditional therapy methods such as breath work and total parenteral nutrition (TPN).

This avoided further infection and was usually used on critical patients.

TPN is a way of supplying all the nutritional needs of the body by bypassing the digestive system and drip-feeding a nutrient solution directly into a vein.

Fang Qiang , director of the hospital's intensive care unit, told local newspapers that even though the man's condition had improved, they were still trying to clean the virus out of his body.

The patient's wife said she believed the strain of virus could not be transmitted from human to human because she had been with her husband around the clock after he fell ill on March 20. He had also been in contact with many people when seeing doctors on March 22 and March 25.

"We seldom ate poultry," she said. "My husband decided to cook quail for a change as I had lost my appetite. But I can't remember what the exact date was."

She said her husband went to a wet market and bought two slaughtered quail from a stall that also sold ducks, doves and chickens.

"The quail were slaughtered by the vendor," she said. "My husband just cleaned and cooked them for me. He did not even have a bite."

Her husband felt ill on March 20 and had a fever of 39 degrees Celsius. He went to see a doctor on March 22 at a local clinic and then at a hospital on March 25, where he was treated for pneumonia. He was transferred to the First Affiliated Hospital of Zhejiang University last Tuesday and confirmed to be infected with H7N9 later that day.

"My husband was very healthy before and never touched live poultry," his wife said. "We still have no idea how he got sick."

Click on each balloon for more information on individual patients infected with the avian flu virus: blue, patients infected with the H7N9 virus under treatment; red, those infected with the H7N9 who have died; and pink, those with H1N1 avian flu virus.

This article first appeared in the South China Morning Post print edition on Apr 09, 2013 as Hope in fight against deadly virus

H7N9 virus claims its seventh victim

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Chinese officials and the WHO's Michael O'Leary at yesterday's briefing on H7N9 bird flu. Photo: AP

The H7N9 virus claimed another life yesterday, and health authorities said detecting and controlling its spread would be more difficult than other avian flu outbreaks because it has only a relatively mild effect on birds.

A 64-year-old man who developed a high fever on Wednesday was admitted to Ruijin Hospital in Huangpu district on Sunday and died that evening, Shanghai authorities confirmed yesterday.

Meanwhile in Jiangsu , an 85-year-old man in Nanjing and a 25-year-old woman in Zhenjiang were fighting for their lives, authorities said.

By last night, the virus had claimed seven lives and infected at least 24 people.

National Influenza Centre director Shu Yuelong said the challenge of preventing and controlling H7N9 infections was "very great".

Unlike H5N1 bird flu, which made birds very sick, studies indicated H7N9 only affected birds mildly, and they showed few if any visible symptoms. Humans, though, were far more seriously affected, Shu said yesterday at a joint briefing by the National Health and Family Planning Commission and the World Health Organisation.

Feng Zijian , head of emergency response for the national Centre for Disease Control and Prevention, advised the public not to buy live poultry and have it butchered at wet markets.

Millions of chickens have been culled since H5N1 jumped the species barrier in 1997 in Hong Kong and killed six of 18 people infected. Since then there have been sporadic outbreaks of H5N1, in which 60 per cent of victims have died, but without any human-to-human transmission.

Noting that H7N9 only recently jumped from poultry to people, Shu said: "It is more likely to infect humans than the H5N1 virus, but it is not as contagious as seasonal flu viruses."

H7N9 had mutated from three viruses, but it remained unclear how it may develop because flu viruses constantly change, Shu said. The country's 500 flu-monitoring hospitals and 400 laboratories would watch closely for changes in the virus.

The WHO said yesterday it did not advise special screening at border crossings, nor imposing travel or trade restrictions.

"So far, we really only have sporadic cases of a rare disease, and perhaps it will remain that way. So this is not a time for overreaction or panic," its representative in Beijing, Dr Michael O'Leary, said. "These are a relatively small number of serious cases with personal health [and] medical implications", but no public health implications.

The WHO had confidence in China's efforts to track and control the outbreak, he said, and was "very satisfied and pleased with the level of information shared".

Click on each balloon for more information on individual patients infected with the avian flu virus: blue, patients infected with the H7N9 virus under treatment; red, those infected with the H7N9 who have died; and pink, those with H1N1 avian flu virus.

 Tiada Kes Selesema Burung H7N9 Dikesan Di

 Negara Ini - Kementerian Kesihatan

KUALA LUMPUR, 6 April (Bernama) -- Kementerian Kesihatan mengesahkan tiada sebarang kes selesema burung (H7N9) dalam kalangan unggas dikesan berlaku di negara ini, berdasarkan hasil pemantauan oleh Jabatan Perkhidmatan Veterinar.

Ketua Pengarahnya, Datuk Dr Noor Hisham Abdullah berkata mengikut Pertubuhan Kesihatan Sedunia (WHO) tiada bukti menunjukkan H7N9 boleh menular daripada manusia kepada manusia.

Bagaimanapun, beliau menasihatkan orang ramai mengelak daripada mengunjungi pasar menjual unggas hidup di negara yang terlibat dengan jangkitan avian influenza.

"Mereka yang pulang dari Shanghai, Anhui, Jiangsu dan Zhejiang, China dengan gejala pernafasan dinasihat memakai topeng muka dan segera mendapatkan rawatan perubatan, seterusnya memaklumkan sejarah perjalanan mereka kepada doktor," katanya dalam satu kenyataan hari ini.

Orang ramai juga dinasihat tidak memegang unggas yang ditemui mati, mengamalkan kebersihan diri serta segera mendapatkan rawatan di klinik berhampiran jika mendapat gejala serupa influenza (ILI) terutama mereka yang terlibat dengan pengendalian unggas, katanya.

Noor Hisham juga mengingatkan penternak dan pengusaha ladang unggas agar mematuhi nasihat serta panduan Jabatan Perkhidmatan Veterinar dan melaporkan sebarang kejadian kluster ILI kepada pejabat kesihatan daerah terdekat.

Beliau berkata kementerian akan terus memantau perkembangan semasa melibatkan jangkitan virus itu, yang disahkan menular di China mulai 29 Mac lepas.

Sehingga 5 April, WHO mengesahkan 16 kes dengan enam kematian disebabkan H7N9 dilaporkan di Shanghai, Anhui, Jiangsu dan Zhejiang, China.

Bagaimanapun, katanya, WHO setakat ini tidak mengeluarkan sebarang nasihat perjalanan atau kenyataan berhubung larangan melawat ke China.

-- BERNAMA