Alzheimer's disease

Alzheimer's disease (AD), also called Alzheimer disease, senile dementia of the Alzheimer type, primary degenerative dementia of the Alzheimer's type, or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.

Although the course of Alzheimer's disease is unique for every individual, there are many common symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most common symptom is inability to acquire new memories, observed as difficulty in recalling recently observed events. When AD is suspected, the diagnosis is usually confirmed with behavioural assessments and cognitive tests, often followed by a brain scan if available.

As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. Gradually, bodily functions are lost, ultimately leading to death. Individual prognosis is difficult to assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is approximately seven years. Fewer than three percent of individuals live more than fourteen years after diagnosis.

The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain. Currently used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are, as of yet, available. As of 2008, more than 500 clinical trials have been conducted for identification of a possible treatment for AD, but it is unknown if any of the tested intervention strategies will show promising results. A number of non-invasive, life-style habits have been suggested for the prevention of Alzheimer's disease, but there is a lack of adequate evidence for a link between these recommendations and reduced degeneration. Mental stimulation, exercise, and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.

Because AD cannot be cured and is degenerative, management of patients is essential. The role of the main caregiver is often taken by the spouse or a close relative.  Alzheimer's disease is known for placing a great burden on caregivers; the pressures can be wide-ranging, involving social, psychological, physical, and economic elements of the caregiver's life. In developed countries, AD is one of the most costly diseases to society.

Characteristics

The disease course is divided into four stages, with progressive patterns of cognitive and functional impairments.

Pre-dementia

The first symptoms are often mistakenly attributed to aging or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD. These early symptoms can affect the most complex daily living activities. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.

Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute.

Early

In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.  AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser degree than new facts or memories.

Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of adequately communicating basic ideas. While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities.

Moderate

Progressive deterioration eventually hinders independence; with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases.  During this phase, memory problems worsen, and the person may fail to recognise close relatives.  Long-term memory, which was previously intact, becomes impaired.

Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of patients develop illusionary misidentifications and other delusional symptoms.  Subjects also lose insight of their disease process and limitations (anosognosia).  Urinary incontinence can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.

Advanced

During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, patients can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. Patients will ultimately not be able to perform even the simplest tasks without assistance.  Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness, with the cause of death typically being an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.

Causes

Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.

In 1991, the amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age. Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.

An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication. One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt-Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.

In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21). DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.

A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss. This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade.[36] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.  Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene. 

Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau.

Oxidative stress and dys-homeostasis of biometal (biology) metabolism may be significant in the formation of the pathology.

AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its neurotransmitter role) that locally diffuses from "varicosities" as an endogenous antiinflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ. This suggests that degeneration of the locus ceruleus might be responsible for increased Aβ deposition in AD brains.

Diagnosis

Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.

Assessment of intellectual functioning including memory testing can further characterise the state of the disease.  Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practicing physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.

Prevention

At present, there is no definitive evidence to support that any particular measure is effective in preventing AD.[111] Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD.

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,  statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease. The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease.  Its beneficial cardiovascular effect has been proposed as the mechanism of action.  There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.

Reviews on the use of vitamins have not found enough evidence of efficacy to recommend vitamin C, E, or folic acid with or without vitamin B12, as preventive or treatment agents in AD. Additionally vitamin E is associated with important health risks. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. Docosahexaenoic acid, an Omega 3 fatty acid, has not been found to slow decline.

Long-term usage of non-steroidal anti-inflammatory drug (NSAIDs) is associated with a reduced likelihood of developing AD. Human postmortem studies, in animal models, or in vitro investigations also support the notion that NSAIDs can reduce inflammation related to amyloid plaques. However trials investigating their use as palliative treatment have failed to show positive results while no prevention trial has been completed. Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain damage in mouse models due to its anti-inflammatory properties. Hormone replacement therapy, although previously used, is no longer thought to prevent dementia and in some cases may even be related to it. There is inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia, and a recent study concludes that it has no effect in reducing the rate of AD incidence. A 21-year study found that coffee drinkers of 3–5 cups per day at midlife had a 65% reduction in risk of dementia in late-life.

People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of AD syndrome, but is not related to earlier death after diagnosis. Learning a second language even later in life seems to delay getting Alzheimer disease. Physical activity is also associated with a reduced risk of AD.

Medical marijuana appears to be effective in delaying Alzheimer's Disease. The active ingredient in marijuana, THC, prevents the formation of deposits in the brain associated with Alzheimer's disease. THC was found to inhibit acetylcholinesterase more effectively than commercially marketed drugs. THC was also found to delay amylogenesis.

Some studies have shown an increased risk of developing AD with environmental factors such the intake of metals, particularly aluminium, or exposure to solvents. The quality of some of these studies has been criticised, and other studies have concluded that there is no relationship between these environmental factors and the development of AD.

While some studies suggest that extremely low frequency electromagnetic fields may increase the risk for Alzheimer's disease, reviewers found that further epidemiological and laboratory investigations of this hypothesis are needed. Smoking is a significant AD risk factor. Systemic markers of the innate immune system are risk factors for late-onset AD

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Curcumin

Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family (Zingiberaceae). The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric. Curcumin can exist in at least two tautomeric forms, keto and enol. The enol form is more energetically stable in the solid phase and in solution.

Curcumin can be used for boron quantification in the curcumin method. It reacts with boric acid forming a red colored compound, known as rosocyanine.

Curcumin is brightly yellow colored and may be used as a food coloring. As a food additive, its E number is E100.

Chemistry

Curcumin incorporates several functional groups. The aromatic ring systems, which are polyphenols are connected by two α,β-unsaturated carbonyl groups. The diketones form stable enols or are easily deprotonated and form enolates, while the α,β-unsaturated carbonyl is a good Michael acceptor and undergoes nucleophilic addition. The structure was first identified in 1910 by J. Miłobędzka, Stanisław Kostanecki and Wiktor Lampe.

Curcumin is used as a reagent for boron in EPA Method 212.3.

Biosynthesis

The biosynthetic route of curcumin has proven to be very difficult for researchers to determine. In 1973 Roughly and Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involved a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylized into a curcuminoid. The second mechanism involved two cinnamate units being coupled together by malonyl-CoA. Both mechanisms use cinnamic acid as their starting point, which is derived from the amino acid phenylalanine. This is noteworthy because plant biosyntheses employing cinnamic acid as a starting point are rare compared to the more common use of p-coumaric acid. Only a few identified compounds, such as anigorufone and pinosylvin, use cinnamic acid as their start molecule. An experimentally backed route was not presented until 2008. This proposed biosynthetic route follows both the first and second mechanisms suggested by Roughley and Whiting. However, the labeling data supported the first mechanism model in which 5 malonyl-CoA molecules react with cinnamic acid to form curcumin. However, the sequencing in which the functional groups, the alcohol and the methoxy, introduce themselves onto the curcuminoid seems to support more strongly the second proposed mechanism. Therefore, it was concluded the second pathway proposed by Roughly and Whiting was correct.

Potential medical uses

Turmeric has been used historically as a component of Indian Ayurvedic medicine since 1900 BC to treat a wide variety of ailments. Research in the latter half of the 20th century has identified curcumin as responsible for most of the biological activity of turmeric. In vitro and animal studies have suggested a wide range of potential therapeutic or preventive effects associated with curcumin. At present, these effects have not been confirmed in humans. However, as of 2008, numerous clinical trials in humans were underway, studying the effect of curcumin on various diseases, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis, and Alzheimer's disease.

In vitro and animal studies have suggested curcumin may have antitumor, antioxidant, antiarthritic, antiamyloid, anti-ischemic, and anti-inflammatory properties. Anti-inflammatory properties may be due to inhibition of eicosanoid biosynthesis. In addition it may be effective in treating malaria, prevention of cervical cancer, and may interfere with the replication of the human immunodeficiency virus (HIV). In HIV, it appears to act by interfering with P300/CREB-binding protein (CBP). It is also hepatoprotective. A 2008 study at Michigan State University showed low concentrations of curcumin interfere with Herpes simplex virus-1 (HSV-1) replication . The same study showed curcumin inhibited the recruitment of RNA polymerase II to viral DNA, thus inhibiting its transcription. This effect was shown to be independent of effect on histone acetyltransferase activities of p300/CBP. A previous (1999) study performed at University of Cincinnati indicated curcumin is significantly associated with protection from infection by HSV-2 in animal models of intravaginal infections.

Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. Curcuminoids induce glutathione S-transferase and are potent inhibitors of cytochrome P450.

The Siegel Life Project funded an initial study on curcumin for Alzheimer's in 1997-1998 through the UCLA Center on Aging. UCLA/VA researchers Drs. Cole and Frautschy presented potent anti-Alzheimer's effects in 1997 and 2000 at the Society for Neuroscience. These data were then published in 2001, demonstrating that curcumin was particularly effective in reducing neurodegeneration, oxidative damage, diffuse plaque deposition, aberrant inflammation and impaired inflammatory clearance following beta-amyloid infusion, which was published in 2001. This led to testing in a transgenic animal model where it was shown to dramatically diminish plaque burden and overall inflammation, but also increase plaque associated inflammatory cells suggesting clearance. In 2004 this UCLA/Veterans group demonstrated that the effect was in part to the highly specific binding effects to beta-amyloid, whereby it could break apart amyloid aggregates in vitro, bind to plaques in vivo, and because of its fluroescent properties, it could be determined that plaques of transgenic mice ingesting curcumin fluoresced green, demonstrating brain penetration. A Harvard group showed that 7 days of tail vein injections of curcumin shrunk plaque size and reduced dystrophic neurites. The UCLA group also showed curcumin synerigizing with fish oil working to protect against cognitive deficits in another transgenic model. However humans show much more glucuronidation than rodents, and glucuronidated curcumin does not pass the blood brain barrier (See section on curcumin formulations). Free curcumin but not glucuronidated curcumin readily passes through the barrier. But extensive glucuronidation in humans is the major barrier to translation in neurodegenerative diseases. Human intestinal cells glucuronidate more than rodent intestine (Ireson)

There is also circumstantial evidence curcumin improves mental functions; a survey of 1010 Asian people who ate yellow curry and were between the ages of 60 and 93 showed those who ate the sauce "once every six months" or more had higher MMSE results than those who did not. From a scientific standpoint, though, this does not show whether the curry caused it, or people who had healthy habits also tended to eat the curry, or some completely different relationship.

Numerous studies have demonstrated curcumin, amongst only a few other things, such as high impact exercise, learning, bright light, and antidepressant usage, has a positive effect on neurogenesis in the hippocampus and concentrations of brain-derived neurotrophic factor (BDNF), reductions in both of which are associated with stress, depression, and anxiety. Curcumin has also been demonstrated to be a selective monoamine oxidase inhibitor (MAOI) of type MAO-A. Fluorescent imaging in a mouse model of Alzheimer's disease showed that curcumin crosses the blood-brain barrier. Several studies have demonstrated that unlike glucuronidated curcumin, free curcumin, which is lipophilic, readily passes the blood brain barrier

In 2009, an Iranian group demonstrated the combination effect of curcumin with 24 antibiotics against Staphylococcus aureus. In that study, in the presence of a subinhibitory concentration of curcumin, the antibacterial activities of cefixime, cefotaxime, vancomycin and tetracycline were increased against test strain. The increase in inhibition zone surface area for these antibiotics were 52.6% (cefixime), 24.9% (cephotaxime), 26.5% (vancomycin ) and 24.4% (tetracycline). Also it showed curcumin has an antagonist effect on the antibacterial effect of nalidixic acid against the test strain.

Although many preclinical studies suggest curcumin may be useful for the prevention and treatment of several diseases, the effectiveness of curcumin has not yet been demonstrated in randomized, placebo-controlled, double-blind clinical trials.

In 2008 scientists at the Salk Institute (Drs. Dave Schubert and Pam Maher) performed high throughput screening, identifying a curcumin pyrazole derivative, which improved memory, is broadly neuroprotective, stimulates BDNF in vitro and in vivo. This group showed in collaboration with UCLA that it was protective in brain trauma  and in collaboration with Cedars Sinai/UCSD groups that it was protective in stroke.

Anticarcinogenic effects

Its potential anticancer effects stem from its ability to induce apoptosis in cancer cells without cytotoxic effects on healthy cells. Curcumin can interfere with the activity of the transcription factor NF-κB, which has been linked to a number of inflammatory diseases such as cancer.

A 2009 study suggested curcumin may inhibit mTOR complex I via a novel mechanism.

Another 2009 study on curcumin effects on cancer states it "modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK)".

A 2010 study in malignant brain tumors showed curcumin effectively inhibits tumor cell proliferation, as well as migration and invasion, and these effects may be mediated through interference with the STAT3 signaling pathway.

When 0.2% curcumin is added to diet given to rats or mice previously given a carcinogen, it significantly reduces colon carcinogenesis.

Curcumin has recently been shown to have phyto-estrogenic activity that might contribute to activity against breast cancer. In the murine model of breast cancer metastasis, curcumin inhibits the formation of lung metastases  probably through the NF-kappa-B dependent regulation of protumorigenic inflammatory cytokines.

Bioavailability

There have been several commercial products developed to provide an alternate route to curcumin. Several trials with unformulated curcumin show extensive glucuronidation and sulfation and typically undetectable levels of free curcumin. For example, trials show that ingestion from 2 to 10 grams of unformulated curcumin lead to undetectable or very low serum levels of free curcumin. For neurodegenerative diseases, it is important that curcumin is absorbed predominantly as 'free" as opposed to glucuronidated, since glucuronidated curcumin does not penetrate the blood brain barrier, while free curcumin is readily brain penetrant.

The first formulation to improve bioavailability was curcumin supplements with piperine ("bioperine", manufactured by Sabinsa Corp, New Jersey) and distributed by several companies. Co-supplementation with 20 mg of piperine (extracted from black pepper) significantly increased the absorption of curcumin by 2000% in a study funded by the manufacturer of piperine. However, the increase in absorption in plasma only occurred during the first hour, after which the difference between the piperine curcumin and the regular curcumin was almost the same as far as absorption. It is important to recognize that rapid clearance from plasma after acute administration does not necessarily represent levels in tissues such as adispose, breast or brain. Glucuronidation inhibitors should be taken cautiously (if at all) by individuals taking other medications, but whether the doses of piperine used can dramatically alter pharmacokinetics of other drugs is unclear.

The second major commercial innovation of curcumin bioavailability was made in 2006, when UC Regents and the Veterans Administration filed a provisional patent, which led to Longvida Optimized Curcumin. In July 2008, the inventors described a new form of "lipidated curcumin" from Verdure Sciences as "Longvida" that was noted to achieve more than 5 micromolar in the brain in vivo. Pharmacokinetics of Longvida in humans shows superior absorption of free curcumin. Extensive toxicity studies have been performed showing Longvida to have an excellent safety profile. as was found in the NIH cancer toxicity studies with tumeric oleoresin leading it to be placed on the FDA's GRAS (generally recognized as safe) list.

Another method to increase the bioavailability of curcumin was later developed as Meriva, patent pending since 2006 and involves a simple procedure creating a complex with soy phospholipids. However, there was no plasma concentration of free curcumin found in humans. In animals, free curcumin reaching 33.4 nanomolar while in humans, none was detected.

Another curcumin proprietary formulation was introduced in 2008 (BCM-95®, Biocurcumax, Arjuna) mixed with turmeric oils, was shown in human cross-over bioavailability comparison tests to have 8 times the bioavailability and greater blood retention time than standard 95% and up to 5 times more than curcumin combined with lecithin and piperine. This same formula was also shown to remain above 200 ng/g for 12 hours in a human clinical study. Plain curcumin remained above 200 ng/g for less than 2 hours. Two hours after ingestion, BCM-95 levels of free curcumin were 10-fold over that of plain curcumin.However these data were in contrast to a six-month placebo-controlled, double-blind clinical trial for Alzheimer's disease, individuals in the BCM-95 groups even doses as high as 4 g failed to yield any significant free curcumin in the plasma. Interestingly there was a non-significant increase in serum amyloid beta with the high dose, which may relate to some effect on amyloid clearance from the brain.

There are other formulations for curcumin in the pipeline, that have not yet become commercial. In 2007, a polymeric nanoparticle-encapsulated formulation of curcumin ("nanocurcumin"). Nanocurcumin particles have a size of less than 100 nanometers on average, and demonstrate comparable to superior efficacy compared to free curcumin in human cancer cell line models. However, actual in vivo absorption (injected or oral) should be tested with this nanoparticle.

In the year of 2010, a food-grade polymer micellar encapsulation system was shown to increase curcumin's water solubility and in vitro anti-cancer activity. It was found that hydrophobically modified starch, usually used to encapsulate flavors, was able to form polymer micelles. Using a simple high-speed homogenization method, it can load curcumin into its hydrophobic core, and thus solubilize curcumin. Cell culture experiments revealed an enhanced anti-cancer activity on HepG2 cell line. However, more in vivo studies are needed to further prove its efficacy in the aspect of bioavailability.

Populations ingesting high amounts of curcumin in foods may have reduced risk for some diseases (Parkinson's), which may be due to an effect of cooking or dissolution in oil. Some benefits of curcumin, such as the potential protection from colon cancer, may not require systemic absorption. Alternatively, dissolving curcumin in warm oils prior to ingestion increases bioavailability; however, other than abstracts presented at Society for Neuroscience in 2009 "Efficacy of curcumin formulations in relation to systemic availability in the brain and different blood compartments in neuroinflammatory and AD models. Society for Neuroscience, Oct 18. 2009, #211.7, Chicago Ill 36:2009", no manuscripts to date have documented this. The poor stability in aqueous solution as opposed to high stability in lipid solutions argues that cooking with curcumin and oil may increase absorption. Curcumin is not stable in water because it is prone to hydrolysis, that convert it to vanillin and ferulic acid. In addition to curries, one can purchase food products containing turmeric (~5% curcumin) such as Nutmeric, which provide turmeric in an oil-solubilized form similar to Indian curry preparations. But the exact amount of curcumin may be far less than 1% curcumin, questioning health relevance.

Potential risks and side effects

Extensive in vivo toxicity studies have been performed with turmeric Oleoresin (85% curcumin) which led to it being placed on the FDA's GRAS (generally recognized as safe) list . Kawanishi et al. (2005) remarked that curcumin, like many antioxidants, can be a "double-edged sword" where, in the test tube, anticancer and antioxidant effects may be seen in addition to pro-oxidant effects. Carcinogenic effects are inferred from interference with the p53 tumor suppressor pathway, an important factor in human colon cancer. Carcinogenic and LD50 tests in mice and rats, however, have failed to establish a clear relationship between tumorogenesis and administration of curcumin in turmeric oleoresin at >98% concentrations. Other in vitro and in vivo studies suggest that curcumin may cause carcinogenic effects under specific conditions.

Clinical studies in humans with high doses (2–12 grams) of curcumin have shown few side effects, with some subjects reporting mild nausea or diarrhea. More recently, curcumin was found to alter iron metabolism by chelating iron and suppressing the protein hepcidin, potentially causing iron deficiency in susceptible patients. Further studies seem to be necessary to establish the benefit/risk profile of curcumin.

There is no or little evidence to suggest curcumin is either safe or unsafe for pregnant women. However, there is still some concern medicinal use of products containing curcumin could stimulate the uterus, which may lead to a miscarriage, although there is not much evidence to support this claim. According to experiments done on rats and guinea pigs, there is no obvious effect (neither positive, nor negative) on the pregnancy rate or number of live or dead embryos. Curcumin has embryotoxic and teratogenic effects on zebrafishes (Danio rerio) embryos.

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Breast Cancer

Breast cancer (malignant breast neoplasm) is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk.  Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas.

The size, stage, rate of growth, and other characteristics of the tumor determine the kinds of treatment. Treatment may include surgery, drugs (hormonal therapy and chemotherapy), radiation and/or immunotherapy.  Surgical removal of the tumor provides the single largest benefit, with surgery alone being capable of producing a cure in many cases. To somewhat increase the likelihood of long-term disease-free survival, several chemotherapy regimens are commonly given in addition to surgery. Most forms of chemotherapy kill cells that are dividing rapidly anywhere in the body, and as a result cause temporary hair loss and digestive disturbances. Radiation may be added to kill any cancer cells in the breast that were missed by the surgery, which usually extends survival somewhat, although radiation exposure to the heart may cause heart failure in the future.  Some breast cancers are sensitive to hormones such as estrogen and/or progesterone, which makes it possible to treat them by blocking the effects of these hormones.

Prognosis and survival rate varies greatly depending on cancer type and staging. With best treatment and dependent on staging, 5-year relative survival varies from 98% to 23, with an overall survival rate of 85%.

Worldwide, breast cancer comprises 22.9% of all non-melanoma skin cancers in women.In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women). Breast cancer is more than 100 times more common in women than breast cancer in men, although males tend to have poorer outcomes due to delays in diagnosis.[

Classification

Breast cancers can be classified by different schemata. Every aspect influences treatment response and prognosis. Description of a breast cancer would optimally include multiple classification aspects, as well as other findings, such as signs found on physical exam. Classification aspects include stage (TNM), pathology, grade, receptor status, and the presence or absence of genes as determined by DNA testing:

Stage. The TNM classification for breast cancer is based on the size of the tumor (T), whether or not the tumor has spread to the lymph nodes (N) in the armpits, and whether the tumor has metastasized (M) (i.e. spread to a more distant part of the body). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis.

The main stages are:

Stage 0 is a pre-cancerous or marker condition, either ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS).

Stages 1–3 are defined as 'early' cancer with a good prognosis.

Stage 4 is defined as 'advanced' and/or 'metastatic' cancer with a poor prognosis.

Histopathology. Breast cancer is usually classified primarily by its histological appearance. Most breast cancers are derived from the epithelium lining the ducts or lobules, and these cancers are classified as ductal or lobular carcinoma. Carcinoma in situ is growth of low grade cancerous or precancerous cells in particular tissue compartment such as the mammary duct without invasion of the surrounding tissue. In contrast, invasive carcinoma does not confine itself to the initial tissue compartment and invades the surrounding tissue.

Grade (Bloom-Richardson grade). When cells become differentiated, they take different shapes and forms to function as part of an organ. Cancerous cells lose that differentiation. In cancer grading, tumor cells are generally classified as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade). Poorly differentiated cancers have a worse prognosis.

Receptor status. Cells have receptors on their surface and in their cytoplasm and nucleus. Chemical messengers such as hormones bind to these receptors, and this causes changes in the cell. Breast cancer cells may or may not have three important receptors: estrogen receptor (ER), progesterone receptor (PR), and HER2/neu.

ER+ cancer cells depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g. tamoxifen), and generally have a better prognosis.

HER2+ breast cancer had a worse prognosis,  but HER2+ cancer cells respond to drugs such as the monoclonal antibody, trastuzumab, (in combination with conventional chemotherapy) and this has improved the prognosis significantly.  Cells with none of these receptors are called basal-like or triple negative.

DNA assays of various types including DNA microarrays have compared normal cells to breast cancer cells. The specific changes in a particular breast cancer can be used to classify the cancer in several ways, and may assist in choosing the most effective treatment for that DNA type.

Signs and symptoms

Breast cancer showing an inverted nipple, lump, skin dimpling

The first noticeable symptom of breast cancer is typically a lump that feels different from the rest of the breast tissue. More than 80% of breast cancer cases are discovered when the woman feels a lump. The earliest breast cancers are detected by a mammogram. Lumps found in lymph nodes located in the armpits  can also indicate breast cancer.

Indications of breast cancer other than a lump may include changes in breast size or shape, skin dimpling, nipple inversion, or spontaneous single-nipple discharge. Pain ("mastodynia") is an unreliable tool in determining the presence or absence of breast cancer, but may be indicative of other breast health issues.

Inflammatory breast cancer is a special type of breast cancer which can pose a substantial diagnostic challenge. Symptoms may resemble a breast inflammation and may include pain, swelling, nipple inversion, warmth and redness throughout the breast, as well as an orange-peel texture to the skin referred to as peau d'orange.

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes such as redness and mild flaking of the nipple skin. As Paget's advances, symptoms may include tingling, itching, increased sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately half of women diagnosed with Paget's also have a lump in the breast.

In rare cases, what initially appears as a fibroadenoma (hard movable lump) could in fact be a phyllodes tumor. Phyllodes tumors are formed within the stroma (connective tissue) of the breast and contain glandular as well as stromal tissue. Phyllodes tumors are not staged in the usual sense; they are classified on the basis of their appearance under the microscope as benign, borderline, or malignant.

Occasionally, breast cancer presents as metastatic disease, that is, cancer that has spread beyond the original organ. Metastatic breast cancer will cause symptoms that depend on the location of metastasis. Common sites of metastasis include bone, liver, lung and brain. Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. These symptoms are "non-specific", meaning they can also be manifestations of many other illnesses.

Most symptoms of breast disorder do not turn out to represent underlying breast cancer. Benign breast diseases such as mastitis and fibroadenoma of the breast are more common causes of breast disorder symptoms. The appearance of a new symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.

Risk factors

The primary risk factors for breast cancer are sex,  age,lack of childbearing or breastfeeding, higher hormone levels,  race, economic status and dietary iodine deficiency.

Most cases of breast cancer cannot be prevented through any action on the part of the affected person. The World Cancer Research Fund estimated that 38% of breast cancer cases in the US are preventable through reducing alcohol intake, increasing physical activity levels and maintaining a healthy weight.  It also estimated that 42% of breast cancer cases in the UK could be prevented in this way, as well as 28% in Brazil and 20% in China.

Smoking tobacco also increases the risk of breast cancer with the greater the amount smoking and the earlier in life smoking begins the higher the risk.

In a study of attributable risk and epidemiological factors published in 1995, later age at first birth and not having children accounted for 29.5% of U.S. breast cancer cases, family history of breast cancer accounted for 9.1% and factors correlated with higher income contributed 18.9% of cases. Attempts to explain the increased incidence (but lower mortality) correlated with higher income include epidemiologic observations such as lower birth rates correlated with higher income and better education, possible overdiagnosis and overtreatment because of better access to breast cancer screening, and the postulation of as yet unexplained lifestyle and dietary factors correlated with higher income. One such factor may be past hormone replacement therapy, which was typically more widespread in higher income groups.

The genes associated with hereditary breast-ovarian cancer syndromes usually increase the risk slightly or moderately; the exception is women and men who are carriers of BRCA mutations. These people have a very high lifetime risk for breast and ovarian cancer, depending on the portion of the proteins where the mutation occurs. Instead of a 12 percent lifetime risk of breast cancer, women with one of these genes have a risk of approximately 60 percent.

In more recent years, research has indicated the impact of diet and other behaviors on breast cancer. These additional risk factors include a high-fat diet, alcohol intake, obesity, and environmental factors such as tobacco use, radiation, endocrine disruptors and shiftwork. Although the radiation from mammography is a low dose, the cumulative effect can cause cancer.

In addition to the risk factors specified above, demographic and medical risk factors include:

Personal history of breast cancer: A woman who had breast cancer in one breast has an increased risk of getting a second breast cancer.

Family history: A woman's risk of breast cancer is higher if her mother, sister, or daughter had breast cancer, the risk becomes significant if at least two close relatives had breast or ovarian cancer. The risk is higher if her family member got breast cancer before age 40. An Australian study found that having other relatives with breast cancer (in either her mother's or father's family) may also increase a woman's risk of breast cancer and other forms of cancer, including brain and lung cancers.

Certain breast changes: Atypical hyperplasia and lobular carcinoma in situ found in benign breast conditions such as fibrocystic breast changes are correlated with an increased breast cancer risk.

Those with a normal body mass index at age 20 who gained weight as they aged had nearly double the risk of developing breast cancer after menopause in comparison to women who maintained their weight. The average 60-year-old woman's risk of developing breast cancer by age 65 is about 2 percent; her lifetime risk is 13 percent.

Prevention

Exercise may decrease breast cancer risk. Also avoiding alcohol and obesity. Prophylactic bilateral mastectomy may be considered in patients with BRCA1 and BRCA2 mutations.A 2007 report concluded that women can somewhat reduce their risk by maintaining a healthy weight, drinking less alcohol, being physically active and breastfeeding their children.

Mastitis

Mastitis is the inflammation of breast tissue. S. aureus is the most common etiological organism responsible, but S. epidermidis and streptococci are occasionally isolated as well

Terminology

Popular usage of the term mastitis varies by geographic region. Outside the US it is commonly used for puerperal and nonpuerperal cases, in the US the term nonpuerperal mastitis is rarely used and alternative names such as duct ectasia, subareolar abscess and plasma cell mastitis are more frequently used.

Chronic cystic mastitis is a different (older) name for fibrocystic disease.

American usage: mastitis usually refers to puerperal (occurring to breastfeeding mothers) mastitis with symptoms of systemic infection. Lighter cases of puerperal mastitis are often called breast  engorgement.

In this article mastitis is used in the original sense of the definition as inflammation of the breast with additional qualifiers where appropriate.

Types

It is called puerperal mastitis when it occurs in lactating mothers and non-puerperal otherwise. Mastitis can occur in men, albeit rarely. Inflammatory breast cancer has symptoms very similar to mastitis and must be ruled out.

The popular misconception that mastitis in humans is an infection is highly misleading and in many cases incorrect. Infections play only a minor role in the pathogenesis of both puerperal and nonpuerperal mastitis in humans and many cases of mastitis are completely aseptic under normal hygienic conditions. Infection as primary cause of mastitis is presumed to be more prevalent in veterinary mastitis and poor hygienic conditions.

The symptoms are similar for puerperal and nonpuerperal mastitis but predisposing factors and treatment can be very different.

Puerperal

Puerperal mastitis is the inflammation of breast in connection with pregnancy, breastfeeding or weaning. Since one of the most prominent symptoms is tension and engourgement of the breast, it is thought to be caused by blocked milk ducts or milk excess. It is relatively common, estimates range depending on methodology between 5-33%. However only about 0.4-0.5% of breastfeeding mothers develop an abscess.

Nonpuerperal

The term nonpuerperal mastitis describes inflammatory lesions of the breast occurring unrelated to pregnancy and breastfeeding. This article includes description of mastitis as well as various kinds of mammary abscesses. Skin related conditions like dermatitis and foliculitis are a separate entity.

Names for non-puerperal mastitis are not used very consistently and include Mastitis, Subareolar Abscess, Duct Ectasia, Periductal Inflammation, Zuska's Disease and others.

Symptoms

Lactation mastitis usually affects only one breast and the symptoms can develop quickly. The signs and symptoms usually appear suddenly and they include:

Breast tenderness or warmth to the touch

General malaise or feeling ill

Swelling of the breast

Pain or a burning sensation continuously or while breast-feeding

Skin redness, often in a wedge-shaped pattern

Fever of 101 F (38.3 C) or greater

The affected breast can then start to appear lumpy and red.

Some women may also experience flu-like symptoms such as:

Aches

Shivering and chills

Feeling anxious or stressed

Fatigue

Breast engorgement

Contact should be made with a health care provider with special breastfeeding competence as soon as the patient recognizes the combination of signs and symptoms. Most of the women first experience the flu-like symptoms and just after they may notice a sore red area on the breast. Also, women should seek medical care if they notice any abnormal discharge from the nipples, if breast pain is making it difficult to function each day or they have prolonged, unexplained breast pain.

Causes

Since the 1980s mastitis has often been divided into non-infectious and infectious sub-groups. However, recent research  suggests that it may not be feasible to make divisions in this way. It has been shown that types and amounts of potentially pathogenic bacteria in breast milk are not correlated to the severity of symptoms. Moreover, although only 15% of women with mastitis in Kvist et al.'s study were given antibiotics, all recovered and few had recurring symptoms. Many healthy breastfeeding women wishing to donate breast milk have potentially pathogenic bacteria in their milk but have no symptoms of mastitis.

Mastitis typically develops when the milk is not properly removed from the breast. Milk stasis can lead to the milk ducts in the breasts becoming blocked, as the breast milk not being properly and regularly expressed. It has also been suggested that blocked milk ducts can occur as a result of pressure on the breast, such as tight-fitting clothing or an over-restrictive bra, although there is sparse evidence for this supposition . Mastitis may occur when the baby is not appropriately attached to the breast while feeding, when the baby has infrequent feeds or has problems suckling the milk out of the breast.

Experts are still unsure why breast milk can cause the breast tissue to become inflamed. One theory is that it may be due to the presence of cytokines in breast milk. Cytokines are special proteins that are used by the immune system and are passed on to the baby in order to help them resist infection. It may be the case that the woman's immune system mistakes these cytokines for a bacterial or viral infection and responds by inflaming the breast tissue in an attempt to stop the spread of what the body perceives as an infection.

Some women (approximately 15% in Kvist et al. study) will require antibiotic treatment for infection which is usually caused by bacteria from the skin or the baby's mouth that entering the milk ducts through skin lesions of the nipple or through the opening of the nipple. Infection is usually caused by staphylococcus aureus.

Mastitis is quite common among breastfeeding women. The WHO estimates that although incidences vary between 2.6% and 33%, the prevalence globally is approximately 10% of breastfeeding women. Most mothers who develop mastitis usually do so within the first few weeks after delivery. Most breast infections occur within the first or second month after delivery or at the time of weaning. However, in rare cases it affects women who are not breastfeeding.

Mastitis can also develop after nipple piercing. In some rare cases, however, Mastitis can occur in men.

Risk Factors

Women who are breastfeeding are at risk for developing mastitis especially if they have sore or cracked nipples or have had mastitis before while breastfeeding another baby. Also, the chances of getting mastitis increases if women use only one position to breastfeed or wear a tight-fitting bra, which may restrict milk flow

Women with diabetes, chronic illness, AIDS, or an impaired immune system may be more susceptible to the development of mastitis.

Complications

Complications that may arise from mastitis include recurrence, milk stasis and abscess. The abscess is the most severe complication that women can get from this condition. Also, women who have had mastitis once are likely to develop it again with a future child or with the same infant. Recurrence appears especially in cases of delayed or inadequate treatment.

Milk stasis is another complication that may arise from mastitis and it occurs when the milk is not completely drained from the breast. This causes increased pressure on the ducts and leakage of milk into surrounding breast tissue, which can lead to pain and inflammation.

Delayed treatment or inadequate treatment, especially in mastitis related to milk stasis, may lead to the formation of an abscess within the breast tissue. An abscess is a collection of pus that develops into the breast which ultimately requires surgical drainage.

Tests and diagnosis

The diagnosis of mastitis and breast abscess can usually be made based on a physical examination.The doctor will also take into account the signs and symptoms of the condition.

However, if the doctor is not sure whether the mass is an abscess or a tumor, an ultrasound may be performed. The ultrasound provides a clear image of the breast tissue and may be helpful in distinguishing between simple mastitis and abscess or in diagnosing an abscess deep in the breast. The test consists of placing an ultrasound probe over the breast.

In cases of infectious mastitis, cultures may be needed in order to determine what type of organism is causing the infection. Cultures are helpful in deciding the specific type of antibiotics that will be used in curing the disease. These cultures may be taken either from the breast milk or of the material aspirated from an abscess.

Mammograms or breast biopsies are normally performed on women who do not respond to treatment or on non-breastfeeding women. This type of tests is sometimes ordered to exclude the possibility of a rare type of breast cancer which causes symptoms similar to those of mastitis.

Breast cancer

Breast cancer may coincide with or mimic symptoms of mastitis. Only full resolution of symptoms and careful examination are sufficient to exclude the diagnosis of breast cancer.

Lifetime risk for breast cancer is significantly reduced for women who were pregnant and breastfeeding. Mastitis episodes do not appear to influence lifetime risk of breast cancer.

Mastitis does however cause great difficulties in diagnosis of breast cancer and delayed diagnosis and treatment can result in worse outcome.

Breast cancer may coincide with mastitis or develop shortly afterwards. All suspicious symptoms that do not completely disappear within 5 weeks must be investigated.

Breast cancer incidence during pregnancy and lactation is assumed to be the same as in controls. Course and prognosis are also very similar to age matched controls.However diagnosis during lactation is particularly problematic, often leading to delayed diagnosis and treatment.

Some data suggests that noninflammatory breast cancer incidence is increased within a year following episodes of nonpuerperal mastitis and special care is required for followup cancer prevention screening. So far only data from short term observation is available and total risk increase can not be judged. Because of the very short time between presentation of mastitis and breast cancer in this study it is considered very unlikely that the inflammation had any substantial role in carcinogenesis, rather it would appear that some precancerous lesions may increase the risk of inflammation (hyperplasia causing duct obstruction, hypersensitivity to cytokines or hormones) or the lesions may have common predisposing factors.

A very serious type of breast cancer called inflammatory breast cancer presents with similar symptoms as mastitis (both puerperal and nonpuerperal). It is the most aggressive type of breast cancer with the highest mortality rate. The inflammatory phenotype of IBC is thought to be mostly caused by invasion and blocking of dermal lymphatics, however it was recently shown that NF-κB target genes activation may significantly contribute to the inflammatory phenotype. Case reports show that inflammatory breast cancer symptoms can flare up following injury or inflammation making it even more likely to be mistaken for mastitis. Symptoms are also known to partially respond to progesterone and antibiotics, reaction to other common medications can not be ruled out at this point

Turmeric (Curcuma longa)

Turmeric (Curcuma longa) is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia and needs temperatures between 20 °C and 30 °C and a considerable amount of annual rainfall to thrive. Plants are gathered annually for their rhizomes, and propagated from some of those rhizomes in the following season.

When not used fresh, the rhizomes are boiled for several hours and then dried in hot ovens, after which they are ground into a deep orange-yellow powder commonly used as a spice in curries and other South Asian and Middle Eastern cuisine, for dyeing, and to impart color to mustard condiments. Its active ingredient is curcumin and it has a distinctly earthy, slightly bitter, slightly hot peppery flavor and a mustardy smell.

In medieval Europe, turmeric became known as Indian saffron, since it was widely used as an alternative to the far more expensive saffron spice.

Erode, a city in the south Indian state of Tamil Nadu, is the world's largest producer and most important trading center of turmeric in Asia. For these reasons, Erode in history is also known as "Yellow City" or "Turmeric City". Sangli, a town in the southern part of the Indian western state of Maharashtra, is the second largest and most important trading center for turmeric in Asia. Turmeric is commonly called haridra or haldi in India.

Composition

Turmeric contains up to 5% essential oils and up to 5% curcumin, a polyphenol. Curcumin is the active substance of turmeric and curcumin is known as C.I. 75300, or Natural Yellow 3. The systematic chemical name is (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione.

It can exist at least in two tautomeric forms, keto and enol. The keto form is preferred in solid phase and the enol form in solution. Curcumin is a pH indicator. In acidic solutions (pH <7.4) it turns yellow, whereas in basic (pH > 8.6) solutions it turns bright red.

Usage

Culinary uses

Turmeric grows wild in the forests of South and Southeast Asia. It has become the key ingredient for many Indian, Persian and Thai dishes such as in curry and many more.

In Indonesia, the turmeric leaves are used for Minangese or Padangese curry base of Sumatra, such as rendang, sate padang and many other varieties.

Although most usage of turmeric is in the form of root powder, in some regions (especially in Maharashtra), leaves of turmeric are used to wrap and cook food. This usually takes place in areas where turmeric is grown locally, since the leaves used are freshly picked. This imparts a distinct flavor.

In recipes outside South Asia, turmeric is sometimes used as an agent to impart a rich, custard-like yellow color. It is used in canned beverages and baked products, dairy products, ice cream, yogurt, yellow cakes, orange juice, biscuits, popcorn color, sweets, cake icings, cereals, sauces, gelatins, etc.[citation needed] It is a significant ingredient in most commercial curry powders. Turmeric is mostly used in savory dishes, as well as some sweet dishes, such as the cake sfouf.

Although usually used in its dried, powdered form, turmeric is also used fresh, much like ginger. It has numerous uses in Far Eastern recipes, such as fresh turmeric pickle, which contains large chunks of soft turmeric.

Turmeric (coded as E100 when used as a food additive) is used to protect food products from sunlight. The oleoresin is used for oil-containing products. The curcumin/polysorbate solution or curcumin powder dissolved in alcohol is used for water-containing products. Over-coloring, such as in pickles, relishes, and mustard, is sometimes used to compensate for fading.

In combination with annatto (E160b), turmeric has been used to color cheeses, yogurt, dry mixes, salad dressings, winter butter and margarine. Turmeric is also used to give a yellow color to some prepared mustards, canned chicken broths and other foods (often as a much cheaper replacement for saffron).

Turmeric is widely used as a spice in South Asian and Middle Eastern cooking. Many Persian dishes use turmeric as a starter ingredient for almost all Iranian fry ups (which typically consist of oil, onions and turmeric followed by any other ingredients that are to be included). In Nepal, turmeric is widely grown and is extensively used in almost every vegetable and meat dish in the country for its color, as well as for its medicinal value. In South Africa, turmeric is traditionally used to give boiled white rice a golden color.

In Goa and Dakshina Kannada (Karnataka state, India), turmeric plant leaf is used to prepare special sweet dishes, patoleo, by layering on the leaf — rice flour, and coconut-jaggery mixture, and then closing and steaming in a special copper steamer (goa).

Preliminary medical research

Turmeric is currently being investigated for possible benefits in Alzheimer's disease, cancer, arthritis, and other clinical disorders. As an example of preliminary laboratory research, turmeric ameliorated the severity of pancreatitis-associated lung injury in mice.

In the latter half of the 20th century, curcumin was identified as responsible for most of the biological effects of turmeric. According to a 2005 article in the Wall Street Journal, research activity into curcumin and turmeric is increasing. The U.S. National Institutes of Health currently has registered 61 clinical trials completed or underway to study use of dietary curcumin for a variety of clinical disorders (dated June 2011).

Uses in folk medicine

In Ayurvedic practices, turmeric has been used as an anti-inflammatory agent and remedy for gastrointestinal discomfort associated with irritable bowel syndrome and other digestive disorders. Raw turmeric strengthens cartilage and bone structure. It is traditionally taken in warm milk at night before sleep. Some may use turmeric in skin creams as an antiseptic agent for cuts, burns and bruises. It is popular as a tea in Okinawa, Japan.

Cosmetics

Turmeric paste is traditionally used by Indian women to keep them free of superfluous hair and as an antimicrobial. Turmeric paste, as part of both home remedies and Ayurveda, is also said to improve the skin and is touted as an anti-aging agent. Turmeric figures prominently in the bridal beautification ceremonies of India, Bangladesh, and Pakistan. Staining oneself with turmeric is believed to improve the skin tone and tan. Turmeric is currently used in the formulation of some sunscreens.

The government of Thailand is funding a project to extract and isolate tetrahydrocurcuminoids (THC) from turmeric. THCs are colorless compounds that might have antioxidant and skin-lightening properties, and might be used to treat skin inflammations, making these compounds useful in cosmetics formulations.

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Sinusitis

Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days. It is a common condition; for example, in the United States more than 24 million cases occur annually.

Classification

By duration

Sinusitis can be acute (going on less than four weeks), subacute (4–8 weeks) or chronic (going on for 8 weeks or more). All three types of sinusitis have similar symptoms, and are thus often difficult to distinguish. Acute sinusitis is very common. Roughly ninety percent of adults have had sinusitis at some point in their life.

Acute

Acute sinusitis is usually precipitated by an earlier upper respiratory tract infection, generally of viral origin. If the infection is of bacterial origin, the most common three causative agents are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.[4] Until recently, Haemophilus influenzae was the most common bacterial agent to cause sinus infections. However, introduction of the H. influenza type B (Hib) vaccine has dramatically decreased H. influenza type B infections and now non-typable H. influenza (NTHI) are predominantly seen in clinics. Other sinusitis-causing bacterial pathogens include Staphylococcus aureus and other streptococci species, anaerobic bacteria and, less commonly, gram negative bacteria. Viral sinusitis typically lasts for 7 to 10 days,[4] whereas bacterial sinusitis is more persistent. Approximately 0.5% to 2% of viral sinusitis results in subsequent bacterial sinusitis. It is thought that nasal irritation from nose blowing leads to the secondary bacterial infection.

Acute episodes of sinusitis can also result from fungal invasion. These infections are typically seen in patients with diabetes or other immune deficiencies (such as AIDS or transplant patients on immunosuppressive anti-rejection medications) and can be life threatening. With type I diabetes, ketoacidosis causes sinusitis by Mucormycosis.

Chemical irritation can also trigger sinusitis, commonly from cigarette smoke and chlorine fumes. Rarely, it may be caused by a tooth infection.

Chronic

Chronic sinusitis, by definition, lasts longer than three months and can be caused by many different diseases that share chronic inflammation of the sinuses as a common symptom. Symptoms of chronic sinusitis may include any combination of the following: nasal congestion, facial pain, headache, night-time coughing, an increase in previously minor or controlled asthma symptoms, general malaise, thick green or yellow discharge, feeling of facial 'fullness' or 'tightness' that may worsen when bending over, dizziness, aching teeth, and/or halitosis.[citation needed] Each of these symptoms has multiple other possible causes, which should be considered and investigated as well. Unless complications occur, fever is not a feature of chronic sinusitis.Often chronic sinusitis can lead to anosmia, a reduced sense of smell. In a small number of cases, acute or chronic maxillary sinusitis is associated with a dental infection. Vertigo, lightheadedness, and blurred vision are not typical in chronic sinusitis and other causes should be investigated.

Chronic sinusitis cases are subdivided into cases with polyps and cases without polyps. When polyps are present, the condition is called chronic hyperplastic sinusitis; however, the causes are poorly understood and may include allergy, environmental factors such as dust or pollution, bacterial infection, or fungus (either allergic, infective, or reactive). Non-allergic factors, such as vasomotor rhinitis, can also cause chronic sinus problems. Abnormally narrow sinus passages, such as having a deviated septum, can impede drainage from the sinus cavities and be a contributing factor. A combination of anaerobic and aerobic bacteria, are detected in conjunction with chronic sinusitis, Staphylococcus aureus (including methicilin resistant S.aureus )and coagulase-negative Staphylococci. Typically antibiotic treatment provides only a temporary reduction in inflammation, although hyperresponsiveness of the immune system to bacteria has been proposed as a possible cause of sinusitis with polyps (chronic hyperplastic sinusitis).

Attempts have been made to provide a more consistent nomenclature for subtypes of chronic sinusitis. The presence of eosinophils in the mucous lining of the nose and paranasal sinuses has been demonstrated for many patients, and this has been termed Eosinophilic Mucin RhinoSinusitis (EMRS).[citation needed] Cases of EMRS may be related to an allergic response, but allergy is not often documented, resulting in further subcategorization into allergic and non-allergic EMRS.

A more recent, and still debated, development in chronic sinusitis is the role that fungus plays in this disease. Fungus can be found in the nasal cavities and sinuses of most patients with sinusitis, but can also be found in healthy people as well.[citation needed] It remains unclear if fungus is a definite factor in the development of chronic sinusitis and if it is, what the difference may be between those who develop the disease and those who remain symptom free. Trials of antifungal treatments have had mixed results.

By location

There are several paired paranasal sinuses, including the frontal, ethmoid, maxillary and sphenoid sinuses. The ethmoid sinuses is further subdivided into anterior and posterior ethmoid sinuses, the division of which is defined as the basal lamella of the middle turbinate. In addition to the severity of disease, discussed below, sinusitis can be classified by the sinus cavity which it affects:

Maxillary – can cause pain or pressure in the maxillary (cheek) area (e.g., toothache, headache) .

Frontal – can cause pain or pressure in the frontal sinus cavity (located above eyes), headache .

Ethmoid – can cause pain or pressure pain between/behind the eyes and headaches .

Sphenoid – can cause pain or pressure behind the eyes, but often refers to the vertex, or top of the head

Recent theories of sinusitis indicate that it often occurs as part of a spectrum of diseases that affect the respiratory tract (i.e., the "one airway" theory) and is often linked to asthma.  All forms of sinusitis may either result in, or be a part of, a generalized inflammation of the airway, so other airway symptoms, such as cough, may be associated with it.

Signs and symptoms

Headache/facial pain or pressure of a dull, constant, or aching sort over the affected sinuses is common with both acute and chronic stages of sinusitis. This pain is typically localized to the involved sinus and may worsen when the affected person bends over or when lying down. Pain often starts on one side of the head and progresses to both sides.  Acute and chronic sinusitis may be accompanied by thick nasal discharge that is usually green in colour and may contain pus (purulent) and/or blood. Often a localized headache or toothache is present, and it is these symptoms that distinguish a sinus-related headache from other types of headaches, such as tension and migraine headaches. Infection of the eye socket is possible, which may result in the loss of sight and is accompanied by fever and severe illness. Another possible complication is the infection of the bones (osteomyelitis) of the forehead and other facial bones – Pott's puffy tumor.

Sinus infections can also cause inner ear problems due to the congestion of the nasal passages. This can be demonstrated by dizziness, "a pressurized or heavy head", or vibrating sensations in the head.

Recent studies suggest that up to 90% of "sinus headaches" are actually migraines.  The confusion occurs in part because migraine involves activation of the trigeminal nerves, which innervate both the sinus region and the meninges surrounding the brain. As a result, it is difficult to accurately determine the site from which the pain originates. Additionally, nasal congestion can be a common result of migraine headaches, due to the autonomic nerve stimulation that can also cause in tearing (lacrimation) and a runny nose (rhinorrhea). A study found that patients with "sinus headaches" responded to triptan migraine medications, but stated dissatisfaction with their treatment when they are treated with decongestants or antibiotics.  It is important to note that migraines will not produce the thick nasal discharge that is a common symptom of a sinus infection.

Complications

The close proximity of the brain to the sinuses makes the most dangerous complication of sinusitis, particularly involving the frontal and sphenoid sinuses, infection of the brain by the invasion of anaerobic bacteria through the bones or blood vessels. Abscesses,  meningitis, and other life-threatening conditions may result. In extreme cases the patient may experience mild personality changes, headache, altered consciousness, visual problems, seizures, coma, and possibly death.

Causes

Factors which may predispose someone to developing sinusitis include: allergies; structural abnormalities, such as a deviated septum, small sinus ostia or a concha bullosa; nasal polyps; carrying the cystic fibrosis gene, though research is still tentative; and prior bouts of sinusitis, because each instance may result in increased inflammation of the nasal or sinus mucosa and potentially further narrow the nasal passageways.

Second hand smoke may also be associated with chronic rhinosinusitis.

Another cause of chronic sinusitus can be from the maxillary sinuses that are situated within the cheekbones. Infections and inflammation are more common here than in any of the other paranasal sinuses. This is because the drainage of mucous secretions from the maxillary sinus to the nasal cavity is not very efficient.

Maxillary sinusitis may also be of dental origin and constitutes a significant percentage, given the intimacy of the relationship between the teeth and the sinus floor. Complementary tests based on conventional radiology techniques and modern are needed. Their indication is based on the clinical context.

Chronic sinusitis can also be caused indirectly through a common but slight abnormality within the auditory or Eustachian tube, which is connected to the sinus cavities and the throat. This tube is usually almost level with the eye sockets but when this sometimes hereditary abnormality is present, it is below this level and sometimes level with vestibule or nasal entrance. This almost always causes some sort of blockage within the sinus cavities ending in infection and usually resulting in chronic sinusitis.

Pathophysiology

It has been hypothesized that biofilm bacterial infections may account for many cases of antibiotic-refractory chronic sinusitis.  Biofilms are complex aggregates of extracellular matrix and inter-dependent microorganisms from multiple species, many of which may be difficult or impossible to isolate using standard clinical laboratory techniques.  Bacteria found in biofilms have their antibiotic resistance increased up to 1000 times when compared to free-living bacteria of the same species. A recent study found that biofilms were present on the mucosa of 75% of patients undergoing surgery for chronic sinusitis.

Diagnosis

Acute

Bacterial and viral acute sinusitis are difficult to distinguish. However, if symptoms last less than 10 days, it is generally considered viral sinusitis. When symptoms last more than 10 days, it is considered bacterial sinusitis (usually 30% to 50% are bacterial sinusitis). Hospital acquired acute sinusitis can be confirmed by performing a CT scan of the sinuses.

Chronic

For sinusitis lasting more than eight weeks,  diagnostic criteria are lacking. A CT scan is recommended, but this alone is insufficient to confirm the diagnosis. Nasal endoscopy, a CT scan, and clinical symptoms are all used to make a positive diagnosis.  A tissue sample for histology and cultures can also be collected and tested. Allergic fungal sinusitis (AFS) is often seen in people with asthma and nasal polyps. Examining multiple biopsy samples can be helpful to confirm the diagnosis. In rare cases, sinusoscopy may be made.

Nasal endoscopy involves inserting a flexible fiber-optic tube with a light and camera at its tip into the nose to examine the nasal passages and sinuses. This is generally a completely painless (although uncomfortable) procedure which takes between five to ten minutes to complete.

Treatment

Conservative

Nasal irrigation may help with symptoms of chronic sinusitis. Decongestant nasal sprays containing oxymetazoline may provide relief, but these medications should not be used for more than the recommended period. Longer use may cause rebound sinusitis. Other recommendations include applying a warm, moist washcloth several times a day; drinking sufficient fluids in order to thin the mucus and inhaling steam two to four times a day.

Antibiotics

The vast majority of cases of sinusitis are caused by viruses and will therefore resolve without antibiotics. However, if symptoms do not resolve within 10 days, amoxicillin is a reasonable antibiotic to use first for treatment with amoxicillin/clavulanate (Augmentin) being indicated when the patient's symptoms do not improve on amoxicillin alone. The presence of aerobic and anaerobic beta-lactamase producing organisms may account for this failure. These organisms can "protect" even non beta lactamase producing bacteria from penicillins. Fluoroquinolones, and a newer macrolide antibiotic such as clarithromycin or a tetracycline like doxycycline, are used in patients who are allergic to penicillins. One study found 60 to 90% of people do not experience resolution of maxillary sinusitis using antibiotics. A short-course (3–7 days) of antibiotics seems to be effective for patients who present without severe disease or any complicating factors.

Corticosteroids

For unconfirmed acute sinusitis, intranasal corticosteroids have not been found to be better than placebo either alone or in combination with antibiotics. However for cases confirmed by radiology or nasal endoscopy treatment with corticosteroids alone or in combination with antibiotics is supported.

Surgery

For chronic or recurring sinusitis, referral to an otolaryngologist specialist may be indicated, and treatment options may include nasal surgery. Surgery should only be considered for those patients who do not experience sufficient relief from optimal medication.

A relatively recent advance in the treatment of sinusitis is a type of surgery called functional endoscopic sinus surgery (FESS). This surgery removes anatomical and pathological obstructions associated with sinusitis in order to restore normal clearance of the sinuses. This replaces prior open techniques requiring facial or oral incisions and refocuses the technique to the natural openings of the sinuses instead of promoting drainage by gravity, the idea upon which the Caldwell-Luc surgery was based.

A number of surgical approaches can be used to access the sinuses and these have generally shifted from external/extranasal approaches to intranasal endoscopic ones. The benefit of the Functional Endoscopic Sinus Surgery FESS is its ability to allow for a more targeted approach to the affected sinuses, reducing tissue disruption, and minimizing post-operative complications.

Another recently developed treatment is balloon sinuplasty. This method, similar to balloon angioplasty used to "unclog" arteries of the heart, utilizes balloons in an attempt to expand the openings of the sinuses in a less invasive manner. The utility of this treatment for sinus disease is still under debate but appears promising.

For persistent symptoms and disease in patients who have failed medical and the functional endoscopic approaches, older techniques can be used to address the inflammation of the maxillary sinus, such as the Caldwell-Luc radical antrostomy. This surgery involves an incision in the upper gum, opening in the anterior wall of the antrum, removal of the entire diseased maxillary sinus mucosa and drainage is allowed into inferior or middle meatus by creating a large window in the lateral nasal wall.)

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