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Chelsea football club did the least expected thing by winning the Champions League Trophy when everybody else had written them off. It was the tricks of talismanic striker Didier Drogba that did it for the day. Chelsea deserve the eulogy as they finally got a touch to a trophy that has always been eluding them. Congratulations Chelsea!
Sie's feelings
I am of the opinion that people have to love, be tolerant and help those that are in need!. I think these are the qualities of God
It's a happy Independence Day for Zimbabweans
It's a happy Independence Day for Zimbabweans
I would want to congratulate all Zimbabweans on this special Independence day. It is my sincere hope that I find everybody in a jovial mood as we celebrate 32 years of self rule!.
Despite all our differences; political, social, ideological, tribal, racial and educational; we must still find ourselves loving each other. It does not pay to maim each other, rape and become intolerant for our differences in all the above issues I have mentioned!. Let us not divide ourselves because of those petty issues.
Marriage boob – A recently married Muzarabani woman had her affair exposed when members of the United Family International Ministries turned up for a prayer meeting when she was in the matrimonial bedroom with a boyfriend. The cheating married woman, Prudence Makiyi, 22, was HUMILIATED after her adulterous affair with her old boyfriend came to light, only 22 days after she had tied the knot. The cheating married woman, Prudence Makiyi, 22, was HUMILIATED after her adulterous affair with her old boyfriend came to light, only 22 days after she had tied the knot. Word going round the neighbourhood is that the UFI members were told to hold the prayer meeting by the church's leader, Prophet Emmanuel Makandiwa. The cheating married woman, Prudence Makiyi, 22, was HUMILIATED after her adulterous affair with her old boyfriend came to light, only 22 days after she had tied the knot. Prudence tied the knot with Tenson Giant Chiwanza at the new UFI assembly in Muzarabani on December 10 last year. She however, still had unfinished business with her old boyfriend. Prudence is an Agricultural Extension field worker while Chiwanza is a general hand at Cottco in the district. The incident took place on January 2 when an unnamed prison officer was caught red-handed by church members having quality time with Prudence in her matrimonial bedroom. Reports say Makandiwa had assigned Muzarabani UFI pastor, Onias Hwata, after informing him about the prophecy he had. There was need to hold a prayer meeting at Chiwanza's household in a bid to expose Prudence's old boyfriend. Hwata referred H-Metro to one of his senior pastors, Baba Mabhon'a who narrated the story. "It is true we received that report but I can not speak on behalf of the church. Try to contact me after I have spoken to Prophet Makandiwa," said Mabhon'a. Mambhon'a was unreachable for further clarification at the time of going to print. However, an insider who preferred anonymity confirmed the incident saying many people were now flocking the Muzarabani assembly as a result of the prophecy. "Yes, that incident occurred and that's why many people are now attending the church. Of course some of the church elders might want to conceal it but what we know is that the incident occurred. However, some people are now regretting ever giving this couple some presents after that illicit affair came out. "As for some of us, we now have faith in Makandiwa after he made that prophecy during one of our church meetings," said the insider. When H-Metro attended the Sunday service where Pastor Mabhon'a shared word, a grim-faced Chiwanza could be seen meditating near the door. "To be honest I heard about it from the grapevine and the issue is being handled by the church. I was not at home and people are spreading the story but no one has ever approached me over the issue maybe they feel shy to discuss that with me," said Chiwanza. In another interview, Prudence CONFIRMED that her old boyfriend visited her and took the blame for failing to inform him that she was now a married woman. "People have misunderstood what exactly happened and they are spreading falsehoods," said Prudence. "The guy was once my boyfriend before he relocated to a far away place and I did not let him know that I was married. "He came here for his own deals before we met. He was hungry and asked for food before we went to the shops to buy beans – he wanted beans. It was dark and people thought that we were doing immoral things, which was not the case. He is my workmate stationed at a different station and we were seated here in the house not caressing each other. "I explained this to my husband after it reached him and he understood. No one found us having sex and I did not go to church today because I am going to Harare for a funeral. I will ask the guy for his permission to give you his details first if you want to know his name and where he works," said Prudence.
What a misdemeanor!
How were we created?
I always wonder what we humans want! There is nobody with a desire to see his or her counterpart succeed or to just divulge to his/her colleague how he/she attained his/her success. Hope God will give us all a tolerant and merciful heart!


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Seanfhocal . . . Sorrows . . . NRA farce . . . Wives
AFTER reading D K Henderson's letter on December 24 ('Drop Irish to claw back lost school time'), the only thing that springs to mind is a seanfhocal: Tír gan teanga, tír gan anam. Remember that, Mr Henderson.
Emma Kelly
Newport, Co Mayo
- I SYMPATHISE with all my heart with the wife and family of the late Gerry Ryan. They should be left in peace.
Two years ago I lost my darling wife, Anna. I am only one of thousands who are mourning today.

subset: commoncrawl


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Release Date: 23 October 2000 | Certificate: Suitable for 18 years and over
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A mother and son living in a small community are not like anyone else. They're Sleepwalkers, creatures who feed on young, innocent girls... Stephen King appears briefly.
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Cartier black watch from Designated Survivor seen with Jessica Kirkman (Natascha McElhone)
As Seen on Jessica Kirkman (Natascha McElhone) in Designated Survivor - Season 1 Preview
Jessica Kirkman (Natascha McElhone) is seen with what looks like the black Cartier Tank Solo Ladies Gold & Steel Watch in Designated Survivor, Season 1, Preview. Find Watches, Jewelry and Women's Fashion from Designated Survivor below.
When the US Capitol suffers its biggest attack in history in Designated Survivor, it's up to one man to lead his country out of the darkness. His name is Tom Kirkman (Kiefer Sutherland), and he needs all the help he can get. Standing by his side through the darkest hours is his loyal wife Jessica Kirkman (Natascha McElhone), a strong woman who maintains stoic grace in demure cardigans.
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This is the nciku Reader edition of 钓鱼技艺 ("Fishing Skills and Techniques"), by the Chinese author 刘铭昌 (Liu Mingchang). nciku Reader helps you read Chinese ...
Discontinued App
Educational | iPhone, iPad
Educational | iPhone, iPad
This is the nciku Reader edition of 钓鱼技艺 ("Fishing Skills and Techniques"), by the Chinese author 刘铭昌 (Liu Mingchang). nciku Reader helps you read Chinese books by providing convenient dictionary and pinyin functions to help you understand the original text: - Tap on the first character of a word to see its definition from the built-in nciku Chinese dictionary. - Tap a button to see each paragraph's pinyin, generated by the nciku Sentence Mode tool. - Switch the application's interface between English and Simplified Chinese. _______________________________________ About the Book Fishing, as a healthy and soothing activity, has attracted many enthusiasts. This book describes the ties between fishing and health, explains the different types of fishing gear, and focuses on the best way to catch fish, unique baits, innovations of fishing tackle, tips to get certain fish in certain water depths, tips for fishing tournaments, and the skills for catching more fish of different species. Some of these tips and skills are scarcely seen in other books of same type. Mainly, the book will tell you how to fish and how to catch more fish through the understanding of the following factors: time of year, water depth, location, gears, choosing baits, pole lifting and pulling. _______________________________________ Beijing DFHL Company is a Beijing-based developer of Chinese and English language learning tools. Our other products include the nciku.com online Chinese dictionary and the nciku Chinese Dictionary for iPhone, which contains definitions for over 153,000 entries and 95,000 example sentences. Our newest line of products is the nciku Reader series of Chinese e-books, which help you to read Chinese content on your phone by providing pinyin and dictionary support. If you have comments or suggestions about the book app, please feel free to send us emails at firstname.lastname@example.com. Also please visit nciku Community at hi.nciku.com to discuss the latest books and other topics. Download it for free now!
Version: 1.0
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Day of release: 2010-08-8
Recommended age: 12+


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There's nothing commonplace or stale about the refreshing Cliche collection. Clear, cubic pattern glass arches seemingly float atop an inner frosted glass diffuser. Included halogen bulbs cast bright white illumination and are fully dimmable for customized lighting levels.
California residents: see Proposition 65 information
- Chrome finish
- Clear textured glass with etched diffuser
- 29-3/4 in. W x 5-1/2 in. H
- Uses (4) 35-Watt halogen (G9, 120-Volt) bulbs (included)


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By following these unique tips on how to improve your business credit profile, you should be able to avoid excessive charges, and maintain your credit rating as you use your card to make purchases. As long as your business credit profile, and you keep track of your monthly expenditures, your credit rating should improve, especially if you continue to pay your bill off in full on time.
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Ways to Improve Your Business Credit Profile
by: www.badcreditresources.com
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Be sure that all relevant credit activities are recorded properly
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AIKEN COUNTY, S.C. (WJBF) – In a last effort to stop the Department of Labor's new Overtime Rule, 21 states filed a motion to temporarily block the order.
The Overtime Rule nearly doubles the current overtime salary threshold to $47,476.
South Carolina is one of the states seeking an injunction because it would cost employers more than $2 million dollars to be in compliance with the law.
If you're annual salary is between $23,660 to $47,476 and you work more than 40 hours a week, your employer will have to compensate you for the extra hours or increase your salary to the new threshold.
This goes into effect on December 1, but due to the payroll cycle some employers have no option but to enact the rule Friday.
"We have 72 people in that range," Aiken County Human Resources Director Gayle Wolman told WJBF NewsChannel 6.
Wolman says right now the plan is to make sure no one exceeds their 40 hour work week.
However, if the Overtime Rule sticks, Aiken County currently doesn't have the money to pay workers for their extra hours and a contingency fund was not included in the 2017 fiscal budget.
"Salaried workers here, tend to work a lot longer hours." Wolman said. "They work many more than 40 hours. Some of that is because we are very lean here in the county. We don't have a lot of employees to do a lot of jobs."
People who work for the county government tend to wear many hats, requiring them to put in more time at the office.
Wolman says she's tracked the overtime and it would cost taxpayers an extra $140,000 dollars to compensate workers.
Still there are exceptions to the rule. It's those departments that can't stick to the regular 40 hour week.
"That would be our Emergency Management, medical services, our sheriff's office and our Detention Center," said Wolman. "So those 3 areas will continue to operate as they always have, they will be calculated for overtime and they will received that time."
Aiken County Councilman Andrew Siders says the county aims to be fair when it comes to paying their employees, and feels the Department of Labor is going to send many employers into turmoil.
"It's going to cause a tremendous burden on a lot of people," said Siders. "Not just big companies but small companies as well."
The lawsuit challenging the Overtime Rule was filed in Texas.
A ruling could be made within the next week.
Count on WJBF NewsChannel 6 to bring you the latest on this developing story.


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A White House press release detailing a Wednesday evening conference call may exemplify the Obama administration's expertise on foreign policy.
The press release, which provides a transcript for comments given by several White House senior officials, breaks down key points laid out in President Obama's Sept. 10 speech on ISIS.
One specific senior official, whose name was not provided, told conference call listeners that Saudi Arabia shared an "extensive" border with Syria when attempting to describe the alleged regional threat of ISIS.
"ISIL has been I think a galvanizing threat around the Sunni partners in the region. They view it as an existential threat to them," he said. "Saudi Arabia has an extensive border with Syria. The Jordanians are experiencing a destabilizing impact of over a million refugees from the Syrian conflict, and are profoundly concerned that ISIL, who has stated that their ambitions are not confined to Iraq and Syria, but rather to expand to the broader region."
The blunder is a microcosm of the Obama administration's failure throughout the middle east, specifically seen most recently in Libya and Syria.
The President announced his plan this week to fight ISIS jihadists in Iraq and Syria by arming the "moderate" Syrian rebels, despite the fact that the alleged rebels have openly aligned themselves with the Islamic State.
Just this week, a commander with the Free Syrian Army admitted to regularly working with several terrorist groups including ISIS, proving no difference between the two groups.
"We are collaborating with the Islamic State and the Nusra Front by attacking the Syrian Army's gatherings in… Qalamoun," Idriss said. "Let's face it: The Nusra Front is the biggest power present right now in Qalamoun and we as FSA would collaborate on any mission they launch as long as it coincides with our values."
Retired Syrian Army Colonel Abu Fidaa reiterated Idriss' comments, saying "a very large number of FSA members have joined ISIS…"
In fact, Abu Mohammad al-Golani, the leader of Syria's largest rebel group, openly pledged allegiance to radical jihadists early last year.
Jamal Maarouf, the leader of the Syrian Revolutionary Front (SRF), told reporters with The Independent that his group regularly worked alongside Al Qaeda and Al-Nusra as well.
The situation was nearly identical in Libya, where the President armed and funded alleged "rebel" groups clearly aligned with Al Qaeda.
Abdel-Hakim al-Hasidi, the Libyan rebel leader, told The Telegraph in 2011 that his fighters included Al Qaeda members who admitted to killing US troops in Iraq.
Earlier this year, these same "rebel" groups from Libya and Syria merged with ISIS on the Syria-Iraq border to help the growth of the Islamic State.
Meanwhile, the President has remained silent on the United States' biggest allies – Saudi Arabia, Kuwait, Turkey and Qatar – arming and funding ISIS.
While countless geopolitical analysts have highlighted the absurdity of those assisting the President's foreign policy, the overall strategy can be linked to a 2001 plan for regime change in the middle east.
During a 2007 interview, Wesley Clark, a retired 4-star general, revealed the contents of a paper he was shown in 2001 while visiting the Pentagon.
According to Clark, the paper detailed a plan to overthrow 7 different countries including Libya and Syria. The fact that Clark made such statements before Obama's presidency reveals that the President has merely continued with the same foreign policy of his predecessor George W. Bush.


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Neurodegenerative disorders are characterized by progressive and irreversible loss of neurons from specific regions of the brain. Prototypical neurodegenerative disorders include Parkinson disease (PD) and Huntington disease (HD), where loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement; Alzheimer disease (AD), where the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability; and amyotrophic lateral sclerosis (ALS), where muscular weakness results from the degeneration of spinal, bulbar, and cortical motor neurons. Currently available therapies for neurodegenerative disorders alleviate the disease symptoms but do not alter the underlying neurodegenerative process.
SELECTIVE VULNERABILITY. A striking feature of neurodegenerative disorders is the exquisite specificity of the disease processes for particular types of neurons. For example, in PD there is extensive destruction of the dopaminergic neurons of the substantia nigra, whereas neurons in the cortex and many other areas of the brain are unaffected. In contrast, neural injury in AD is most severe in the hippocampus and neocortex, and even within the cortex, the loss of neurons is not uniform but varies dramatically in different functional regions. In HD the mutant gene responsible for the disorder is expressed throughout the brain and in many other organs, yet the pathological changes are most prominent in the neostriatum. In ALS, there is loss of spinal motor neurons and the cortical neurons that provide their descending input. The diversity of these patterns of neural degeneration suggests that the process of neural injury results from the interaction of genetic and environmental influences.
GENETICS AND ENVIRONMENT. Each of the major neurodegenerative disorders may be familial in nature. HD is exclusively familial; it is transmitted by autosomal dominant inheritance, and the molecular mechanism of the genetic defect has been defined. Nevertheless, environmental factors importantly influence the age of onset and rate of progression of HD symptoms. PD, AD, and ALS are mostly sporadic without clear pattern of inheritance. But for each there are well-recognized genetic forms. For example, there are both dominant (α-synuclein, LRRK2) and recessive (parkin, DJ-1, PINK1) gene mutations that may give rise to PD. In AD, mutations in the genes coding for the amyloid precursor protein (APP) and proteins known as the presenilins (involved in APP processing) lead to inherited forms of the disease. Mutations in the gene coding for copper-zinc superoxide dismutase (SOD1) account for about 2% of the cases of adult-onset ALS. There are also genetic risk factors that influence the probability of disease onset and modify the phenotype. For example, the apolipoprotein E (apoE) genotype constitutes an important risk factor for AD. Three distinct isoforms of this protein exist. Although all isoforms carry out their primary role in lipid metabolism equally well, individuals who are homozygous for the apoE4 allele ("4/4") have a much higher lifetime risk of AD than do those homozygous for the apoE2 allele ("2/2").
Environmental factors including infectious agents, environmental toxins, and acquired brain injury have been proposed in the etiology of neurodegenerative disorders. Traumatic brain injury has been suggested as a trigger for neurodegenerative disorders. At least one toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can induce a condition closely resembling PD. More recently, evidence has linked pesticide exposure with PD. Exposure of soldiers to neurotoxic chemicals has been implicated in ALS (as part of "Gulf War syndrome").
COMMON CELLULAR MECHANISMS OF NEURODEGENERATION. Despite their varied phenotypes, the neurodegenerative disorders share some common features. For example, misfolded and aggregated proteins are found in every major neurodegenerative disorder: alpha-synuclein, in PD; amyloid-β (Aβ) and tau in AD; huntingtin in HD; and SOD and TDP-43 in ALS. The accumulation of misfolded proteins may result from either genetic mutations producing abnormal structure, or from impaired cellular clearance.
The term excitotoxicity describes the neural injury that results from the presence of excess glutamate in the brain. Glutamate is used as a neurotransmitter to mediate most excitatory synaptic transmission in the mammalian brain (see Table 14–1). The presence of excessive amounts of glutamate can lead to excitotoxic cell death (see Figure 14–8). The destructive effects of glutamate are mediated by glutamate receptors, particularly those of the N-methyl-D-aspartate (NMDA) type. Excitotoxic injury contributes to the neuronal death that occurs in acute processes such as stroke and head trauma. The role of excitotoxicity is less certain in the chronic neurodegenerative disorders; nevertheless, regional and cellular differences in susceptibility to excitotoxic injury, conveyed, e.g., by differences in types of glutamate receptors, may contribute to selective vulnerability. This has led to the development of glutamate antagonists as neuroprotective therapies, with 2 such agents (memantine and riluzole, described later) currently in clinical use.
Aging is associated with a progressive impairment in the capacity of neurons for oxidative metabolism with consequent production of reactive compounds such as hydrogen peroxide and oxygen radicals. These reactive species can lead to DNA damage, peroxidation of membrane lipids, and neuronal death. This has led to pursuit of drugs that can enhance cellular metabolism (such as the mitochondrial cofactor coenzyme Q10) and antioxidant strategies as treatments to prevent or retard degenerative diseases.
CLINICAL OVERVIEW. Parkinsonism is a clinical syndrome with 4 cardinal features:
• Bradykinesia (slowness and poverty of movement)
• Muscular rigidity
• Resting tremor (which usually abates during voluntary movement)
• An impairment of postural balance leading to disturbances of gait and to falling
The most common form of parkinsonism is idiopathic PD, first described by James Parkinson in 1817 as paralysis agitans, or the "shaking palsy." The pathological hallmark of PD is the loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies. A loss of 70-80% of these dopamine-containing neurons accompanies symptomatic PD.
Without treatment, PD progresses over 5-10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. The availability of effective pharmacological treatment has radically altered the prognosis of PD; in most cases, good functional mobility can be maintained for many years. Life expectancy of adequately treated patients is increased substantially, but overall mortality remains higher than that of the general population. In addition, while DA neuron loss is the most prominent feature of the disease, the disorder affects a wide range of other brain structures, including the brainstem, hippocampus, and cerebral cortex. This pathology is likely responsible for the "non-motor" features of PD, which include sleep disorders, depression, and memory impairment.
Several disorders other than idiopathic PD also may produce parkinsonism, including some relatively rare neurodegenerative disorders, stroke, and intoxication with DA-receptor antagonists. Drugs that may cause parkinsonism include antipsychotics such as haloperidol and chlorpromazine (see Chapter 16) and antiemetics such as prochlorperazine and metoclopramide (see Chapter 46). The distinction between idiopathic PD and other causes of parkinsonism is important because parkinsonism arising from other causes usually is refractory to all forms of treatment.
PATHOPHYSIOLOGY. The dopaminergic deficit in PD arises from a loss of the neurons in the substantia nigra pars compacta that provide innervation to the striatum (caudate and putamen). The current understanding of the pathophysiology of PD is based on the finding that the striatal DA content is reduced in excess of 80%, with a parallel loss of neurons from the substantia nigra, suggesting that replacement of DA could restore function. We now have a model of the function of the basal ganglia that, while incomplete, is still useful.
DOPAMINE SYNTHESIS, METABOLISM, AND RECEPTORS. DA, a catecholamine, is synthesized in the terminals of dopaminergic neurons from tyrosine and stored, released, reaccumulated, and metabolized by processes described in Chapter 13 and summarized in Figure 22–1. The actions of DA in the brain are mediated by DA receptor, of which there are 2 broad classes. D1 and D2, with 5 distinct subtypes, D1-D5 (see Figure 13–6). All the DA receptors are G protein–coupled receptors (GPCRs). Receptors of the D1 group (D1 and D5 subtypes) couple to Gs and thence to activation of the cyclic AMP pathway. The D2 group (D2, D3, and D4 receptors) couple to Gi to reduce the adenylyl cyclase activity and voltage-gated Ca2+ currents while activating K+ currents (see Chapters 3 and 13 for details). Each of the 5 DA receptors has a distinct anatomical pattern of expression in the brain (see Figure 13–6). D1 and D2 proteins are abundant in the striatum and are the most important receptor sites with regard to the causes and treatment of PD. The D4 and D5 proteins are largely extrastriatal, whereas D3 expression is low in the caudate and putamen but more abundant in the nucleus accumbens and olfactory tubercle.
Figure 22–1 Dopaminergic nerve terminal. Dopamine (DA) is synthesized from tyrosine in the nerve terminal by the sequential actions of tyrosine hydrolase (TH) and aromatic amino acid decarboxylase (AADC). DA is sequestered by VMAT2 in storage granules and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2 receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 transporters. Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron, and by catechol-O-methyl transferase (COMT) and MAO/ALDH in non-neuronal cells; the final metabolic product is homovanillic acid (HVA). See structures in Figure 22–4. PH, phenylalanine hydroxylase.
NEURAL MECHANISM OF PARKINSONISM: A MODEL OF BASAL GANGLIA FUNCTION. Considerable effort has been devoted to understanding how the loss of dopaminergic input to the neurons of the neostriatum gives rise to the clinical features of PD. The basal ganglia can be viewed as a modulatory side loop that regulates the flow of information from the cerebral cortex to the motor neurons of the spinal cord (Figure 22–2).
Figure 22–2 Schematic wiring diagram of the basal ganglia. The striatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of cerebral cortex. The striatum contains projection neurons expressing predominantly D1 or D2 dopamine receptors, as well as interneurons that use ACh as a neurotransmitter. Outflow from the striatum proceeds along 2 routes. The direct pathway, from the striatum to the substantia nigra pars reticulata (SNpr) and globus pallidus interna (GPi), uses the inhibitory transmitter GABA. The indirect pathway, from the striatum through the globus pallidus externa (GPe) and the subthalamic nucleus (STN) to the SNpr and GPi, consists of 2 inhibitory GABA-ergic links and 1 excitatory glutamatergic projection (Glu). The substantia nigra pars compacta (SNpc) provides dopaminergic innervation to the striatal neurons, giving rise to both the direct and indirect pathways, and regulates the relative activity of these 2 paths. The SNpr and GPi are the output structures of the basal ganglia and provide feedback to the cerebral cortex through the ventroanterior and ventrolateral nuclei of the thalamus (VA/VL).
The neostriatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of the cortex. Most neurons within the striatum are projection neurons that innervate other basal ganglia structures. A small but important subgroup of striatal neurons consists of interneurons that connect neurons within the striatum but do not project beyond its borders. Acetylcholine (ACh) and neuropeptides are used as transmitters by these striatal interneurons.
The outflow of the striatum proceeds along 2 distinct routes, termed the direct and indirect pathways. The direct pathway is formed by neurons in the striatum that project directly to the output stages of the basal ganglia, the substantia nigra pars reticulata (SNpr) and the globus pallidus interna (GPi); these, in turn, relay to the ventroanterior and ventrolateral thalamus, which provides excitatory input to the cortex. The neurotransmitter of both links of the direct pathway is γ-aminobutyric acid (GABA), which is inhibitory, so that the net effect of stimulation of the direct pathway at the level of the striatum is to increase the excitatory outflow from the thalamus to the cortex.
The indirect pathway is composed of striatal neurons that project to the globus pallidus externa (GPe). This structure, in turn, innervates the subthalamic nucleus (STN), which provides outflow to the SNpr and GPi output stage. The first 2 links—the projections from striatum to GPe and GPe to STN—use the inhibitory transmitter GABA; however, the final link—the projection from STN to SNpr and GPi—is an excitatory glutamatergic pathway. Thus, the net effect of stimulating the indirect pathway at the level of the striatum is to reduce the excitatory outflow from the thalamus to the cerebral cortex. The key feature of this model of basal ganglia function, which accounts for the symptoms observed in PD as a result of loss of dopaminergic neurons, is the differential effect of DA on the direct and indirect pathways (Figure 22–3).
Figure 22–3 The basal ganglia in Parkinson disease. The primary defect is destruction of the dopaminergic neurons of the SNpc. The striatal neurons that form the direct pathway from the striatum to the SNpr and GPi express primarily the excitatory D1 DA receptor, whereas the striatal neurons that project to the GPe and form the indirect pathway express the inhibitory D2 dopamine receptor. Thus, loss of the dopaminergic input to the striatum has a differential effect on the 2 outflow pathways; the direct pathway to the SNpr and GPi is less active (structures in purple), whereas the activity in the indirect pathway is increased (structures in red). The net effect is that neurons in the SNpr and GPi become more active. This leads to increased inhibition of the VA/VL thalamus and reduced excitatory input to the cortex. Light blue lines indicate primary pathways with reduced activity. (See legend to Figure 22–2 for definitions of anatomical abbreviations.)
The dopaminergic neurons of the substantia nigra pars compacta (SNpc) innervate all parts of the striatum; however, the target striatal neurons express distinct types of DA receptors. The striatal neurons giving rise to the direct pathway express primarily the excitatory D1 dopamine receptor protein, whereas the striatal neurons forming the indirect pathway express primarily the inhibitory D2 type. Thus, DA released in the striatum tends to increase the activity of the direct pathway and reduce the activity of the indirect pathway, whereas the depletion that occurs in PD has the opposite effect. The net effect of the reduced dopaminergic input in PD is to increase markedly the inhibitory outflow from the SNpr and GPi to the thalamus and reduce excitation of the motor cortex. There are several limitations of this model of basal ganglia function. The anatomical connections are considerably more complex and many of the pathways involved use several neurotransmitters. Nevertheless, the model is useful and has important implications for the rational design and use of pharmacological agents in PD.
Table 22–1 summarizes commonly used medications for the treatment of PD.
Table 22–1
Commonly Used Medications for the Treatment of Parkinson Disease
LEVODOPA. Levodopa (L-dopa, LARODOPA, L-3,4-dihydroxyphenylalanine), the metabolic precursor of DA, is the single most effective agent in the treatment of PD.
The effects of levodopa result from its decarboxylation to DA. When administered orally, levodopa is absorbed rapidly from the small bowel by the transport system for aromatic amino acids. Concentrations of the drug in plasma usually peak between 0.5 and 2 h after an oral dose. The t1/2 in plasma is short (1-3 h). The rate and extent of absorption of levodopa depends on the rate of gastric emptying, the pH of gastric juice, and the length of time the drug is exposed to the degradative enzymes of the gastric and intestinal mucosa. Administration of levodopa with high-protein meals delays absorption and reduces peak plasma concentrations. Entry of the drug into the CNS across the blood-brain barrier is mediated by a membrane transporter for aromatic amino acids. In the brain, levodopa is converted to DA by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the striatum. The DA produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT) (Figure 22–4).
Figure 22–4 Metabolism of levodopa (L-dopa). AADC, aromatic L-amino acid decarboxylase; ALDH, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; DβH, dopamine-β-hydroxylase; MAO, monoamine oxidase.
In clinical practice, levodopa is almost always administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa or benserazide (available outside the U.S.), drugs that do not penetrate well into the CNS. If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites so that relatively little unchanged drug reaches the cerebral circulation and probably < 1% penetrates the CNS. In addition, DA release into the circulation by peripheral conversion of levodopa produces undesirable effects, particularly nausea. Inhibition of peripheral decarboxylase markedly increases the fraction of administered levodopa that remains unmetabolized and available to cross the blood-brain barrier (Figure 22–5) and reduces the incidence of GI side effects.
Figure 22–5 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of COMT (e.g., tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of L-dopa and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AADC, aromatic L-amino acid decarboxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; MAO, monoamine oxidase; 3MT, 3-methoxyltyramine; 3-OMD, 3-O-methyl DOPA.
A daily dose of 75 mg carbidopa is generally sufficient to prevent the development of nausea. For this reason, the most commonly prescribed form of carbidopa/levodopa (SINEMET, ATAMET, others) is the 25/100 form, containing 25 mg carbidopa and 100 mg levodopa. With this formulation, dosage schedules of 3 or more tablets daily provide acceptable inhibition of decarboxylase in most individuals.
Levodopa therapy can have a dramatic effect on all the signs and symptoms of PD. Early in the course of the disease, the degree of improvement in tremor, rigidity, and bradykinesia may be nearly complete. With long-term levodopa therapy, the "buffering" capacity is lost, and the patient's motor state may fluctuate dramatically with each dose of levodopa, producing the motor complications of levodopa.
A common problem is the development of the "wearing off" phenomenon: Each dose of levodopa effectively improves mobility for a period of time, perhaps 1-2 h, but rigidity and akinesia return rapidly at the end of the dosing interval. Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias, excessive and abnormal involuntary movements. In the later stages of PD, patients may fluctuate rapidly between being "off," having no beneficial effects from their medications, and being "on" but with disabling dyskinesias (the on/off phenomenon). A sustained-release formulation consisting of carbidopa/levodopa in an erodable wax matrix (SINEMET CR) is helpful in some cases, but absorption of the sustained-release formulation is not entirely predictable.
Does levodopa alter the course of the underlying disease or merely modify the symptoms? A recent randomized trial has provided evidence that levodopa does not have an adverse effect on the course of the underlying disease, but has also confirmed that high doses of levodopa are associated with early onset of dyskinesias. Most practitioners have adopted a pragmatic approach, using levodopa only when the symptoms of PD cause functional impairment and other treatments are inadequate or not well tolerated.
A frequent and troubling adverse effect is the induction of hallucinations and confusion, especially in elderly patients or in patients with preexisting cognitive dysfunction. Conventional antipsychotic agents, such as the phenothiazines, are effective against levodopa-induced psychosis but may cause marked worsening of parkinsonism, probably through actions at the D2 DA receptor. An alternative approach has been to use "atypical" antipsychotic agents (see Chapter 16). The 2 drugs that are most effective and best tolerated in patients with advanced PD are clozapine and quetiapine. Peripheral decarboxylation of levodopa and release of DA into the circulation may activate vascular DA receptors and produce orthostatic hypotension. Administration of levodopa with nonspecific inhibitors of MAO accentuates the actions of levodopa and may precipitate life-threatening hypertensive crisis and hyperpyrexia; nonspecific MAO inhibitors always should be discontinued at least 14 days before levodopa is administered [note that this prohibition does not include the MAO-B subtype-specific inhibitors selegiline and rasagiline (AZILECT)]. Abrupt withdrawal of levodopa or other dopaminergic medications may precipitate the neuroleptic malignant syndrome of confusion, rigidity, and hyperthermia, a potentially lethal adverse effect.
DOPAMINE RECEPTOR AGONISTS. The DA receptor agonists in clinical use have durations of action substantially longer than that of levodopa; they are often used in the management of dose-related fluctuations in motor state, and may be helpful in preventing motor complications. It has been suggested that DA receptor agonists may have the potential to modify the course of PD by reducing endogenous release of DA as well as the need for exogenous levodopa, thereby reducing free radical formation.
Two orally administered DA receptor agonists are commonly used for treatment of PD: ropinirole (REQUIP) and pramipexole (MIRAPEX). Ropinirole and pramipexole have selective activity at D2 class sites (specifically at the D2 and D3 receptor) and little or no activity at D1 class sites. Both are well absorbed orally and have similar therapeutic actions. Like levodopa, they can relieve the clinical symptoms of PD. The duration of action of the DA agonists (8-24 h) often is longer than that of levodopa (6-8 h), and they are particularly effective in the treatment of patients who have developed on/off phenomena. Ropinirole is also available in a once-daily sustained-release formulation (REQUIP XL), which is more convenient and may reduce adverse effects related to intermittent dosing. Both pramipexole and ropinirole may produce hallucinosis or confusion, similar to that observed with levodopa, and may cause nausea and orthostatic hypotension. They should be initiated at low dose and titrated slowly to minimize these effects. The DA agonists, as well as levodopa itself, are also associated with fatigue and somnolence. Practitioners prefer a DA agonist as initial therapy in younger patients in order to reduce the occurrence of motor complications. In older patients or those with substantial comorbidity, levodopa/carbidopa is generally better tolerated.
APOMORPHINE. Apomorphine (APOKYN) is a dopaminergic agonist that can be administered by subcutaneous injection. It has high affinity for D4 receptors; moderate affinity for D2, D3, D5, and adrenergic α1D, α2B, and α2C receptors; and low affinity for D1 receptors. Apomorphine is FDA-approved as a "rescue therapy" for the acute intermittent treatment of "off" episodes in patients with a fluctuating response to dopaminergic therapy.
Apomorphine has the same side effects as the oral DA agonists. Apomorphine is highly emetogenic and requires pre- and posttreatment antiemetic therapy. Oral trimethobenzamide (TIGAN), at a dose of 300 mg 3 times daily, should be started 3 days prior to the initial dose of apomorphine and continued at least during the first 2 months of therapy. Profound hypotension and loss of consciousness have occurred when apomorphine was administered with ondansetron; hence, the concomitant use of apomorphine with antiemetic drugs of the 5-HT3 antagonist class is contraindicated. Other potentially serious side effects of apomorphine include QT prolongation, injection-site reactions, and the development of a pattern of abuse characterized by increasingly frequent dosing leading to hallucinations, dyskinesia, and abnormal behavior. Because of these potential adverse effects, use of apomorphine is appropriate only when other measures, such as oral DA agonists or COMT inhibitors, have failed to control the "off" episodes. Apomorphine therapy should be initiated with a 2-mg test dose in a setting where the patient can be monitored carefully. If tolerated, it can be titrated slowly up to a maximum dosage of 6 mg. For effective control of symptoms, patients may require 3 or more injections daily.
CATECHOL-O-METHYLTRANSFERASE INHIBITORS. When levodopa is administered orally, most is converted by aromatic L-amino acid decarboxylase (AADC) to DA (seeFigure 22–5), which causes nausea and hypotension. Addition of an AADC inhibitor such as carbidopa reduces the formation of DA but increases the fraction of levodopa that is methylated by COMT. COMT inhibitors block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma t1/2 of levodopa as well as the fraction of each dose that reaches the CNS.
The COMT inhibitors tolcapone (TASMAR) and entacapone (COMTAN) reportedly reduce significantly the "wearing off" symptoms in patients treated with levodopa/carbidopa. The 2 drugs differ only in their pharmacokinetic properties and adverse effects: tolcapone has a relatively long duration of action, and appears to act by both central and peripheral inhibition of COMT. Entacapone has a short duration of action (2 h) and principally inhibits peripheral COMT. Common adverse effects of these agents include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An important adverse effect associated with tolcapone is hepatotoxicity. At least 3 fatal cases of fulminant hepatic failure in patients taking tolcapone have been observed, leading to addition of a black box warning to the label. Tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring for hepatic injury. Entacapone has not been associated with hepatotoxicity. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (STALEVO).
SELECTIVE MAO-B INHIBITORS. Two isoenzymes of MAO oxidize catecholamines: MAO-A and MAO-B. MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of DA in the brain. Selective MAO-B inhibitors are used for the treatment of PD: selegiline (ELDEPRYL, EMSAM, ZELAPAR) and rasagiline (AZILECT). These agents selectively and irreversibly inactivate MAO-B. Both agents exert modest beneficial effects on the symptoms of PD. The basis of this efficacy is, presumably, inhibition of breakdown of DA in the striatum.
Selective MAO-B inhibitors do not substantially inhibit the peripheral metabolism of catecholamines and can be taken safely with levodopa. These agents also do not exhibit the "cheese effect," the potentially lethal potentiation of catecholamine action observed when patients on nonspecific MAO inhibitors ingest indirectly acting sympathomimetic amines such as the tyramine found in certain cheeses and wine.
Selegiline is generally well tolerated in younger patients for symptomatic treatment of early or mild PD. In patients with more advanced PD or underlying cognitive impairment, selegiline may accentuate the adverse motor and cognitive effects of levodopa therapy. Metabolites of selegiline include amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms. Selegiline has become available in an orally disintegrating tablet (ZELAPAR) as well as a transdermal patch (EMSAM). Both of these delivery routes are intended to reduce hepatic first-pass metabolism and limit the formation of the amphetamine metabolites.
Unlike selegiline, rasagiline does not give rise to undesirable amphetamine metabolites. Rasagiline monotherapy is effective in early PD. Adjunctive therapy with rasagiline significantly reduces levodopa-related "wearing off" symptoms in advanced PD. Although selective MAO-B inhibitors are generally well tolerated, drug interactions can be troublesome. Similar to the nonspecific MAO inhibitors, selegiline can lead to the development of stupor, rigidity, agitation, and hyperthermia when administered with the analgesic meperidine. Although the mechanics of this interaction is uncertain, selegiline or rasagiline should not be given in combination with meperidine. Adverse effects, although uncommon, have been reported from coadministration of MAO-B inhibitors with tricyclic antidepressants or with serotonin-reuptake inhibitors.
MUSCARINIC RECEPTOR ANTAGONISTS. Antimuscarinic drugs currently used in the treatment of PD include trihexyphenidyl and benztropine mesylate, as well as the antihistaminic diphenhydramine hydrochloride, which also interacts at central muscarinic receptors. The biological basis for the therapeutic actions of muscarinic antagonists is not completely understood. They may act within the neostriatum through the receptors that normally mediate the response to intrinsic cholinergic innervation of this structure, which arises primarily from cholinergic striatal interneurons.
These drugs have relatively modest antiparkinsonian activity and are used only in the treatment of early PD or as an adjunct to dopamimetic therapy. Adverse effects result from their anticholinergic properties. Most troublesome are sedation and mental confusion. All anticholinergic drugs must be used with caution in patients with narrow-angle glaucoma (see Chapter 64). The pharmacology and signaling mechanisms of muscarinic receptors are thoroughly covered in Chapter 9.
AMANTADINE. Amantadine (SYMMETREL), an antiviral agent used for the prophylaxis and treatment of influenza A (see Chapter 58), has antiparkinsonian activity. Amantadine appears to alter DA release in the striatum, has anticholinergic properties, and blocks NMDA glutamate receptors. It is used as initial therapy of mild PD. It also may be helpful as an adjunct in patients on levodopa with dose-related fluctuations and dyskinesias. Amantadine is usually administered at a dose of 100 mg twice a day and is well tolerated. Dizziness, lethargy, anticholinergic effects, and sleep disturbance, as well as nausea and vomiting, these effects are mild and reversible.
NEUROPROTECTIVE TREATMENTS FOR PARKINSON DISEASE. Inhibition of MAO-B in the brain reduces the overall catabolism of DA, which may decrease the formation of potentially toxic-free radicals and consequently the rate of neurodegeneration in PD. In a recent study, rasagiline has been reported to have a neuroprotective effect. Another strategy under study is the use of compounds that augment cellular energy metabolism such coenzyme Q10, a cofactor required for the mitochondrial electron-transport chain. A small study has demonstrated that this drug is well tolerated in PD and has suggested that coenzyme Q10 may slow the course of the disease.
CLINICAL SUMMARY. Pharmacological treatment of PD should be tailored to the individual patient. Drug therapy is not obligatory in early PD; many patients can be managed for a time with exercise and lifestyle interventions. For patients with mild symptoms, MAO-B inhibitors, amantadine, or (in younger patients) anticholinergics are reasonable choices. In most patients, treatment with a dopaminergic drug, either levodopa or a DA agonist, is eventually required. Practitioners prefer DA agonist as initial therapy in younger patients in order to reduce the occurrence of motor complications. In older patients or those with substantial comorbidity, levodopa/carbidopa is generally better tolerated.
CLINICAL OVERVIEW. The brain region most vulnerable to neuronal dysfunction and cell loss in AD is the medial temporal lobe, including entorhinal cortex and hippocampus. Typical early AD symptoms are due to dysfunction of these structures resulting in anterograde episodic memory loss: repeated questions, misplaced items, missed appointments, and forgotten details of daily life. A typical patient presents with memory dysfunction that is noticeable but not severe enough to impair daily function. Because current diagnostic criteria for AD require the presence of dementia (i.e., cognitive impairments sufficient to reduce function), these patients are generally given a diagnosis of mild cognitive impairment (MCI). Patients with MCI progress at a rate of about 10% per year to AD, although not all MCI patients will develop AD. Gradual but relentless progression in AD involves other cognitive domains including visuospatial and executive function. The later stages of the disease are characterized by increasing dependence and progression toward the akinetic-mute state that typifies end-stage neurologic disease. Death, most often from a complication of immobility such as pneumonia or pulmonary embolism, usually ensues within 6-12 years of onset.
GENETICS. Mutations in 3 genes have been identified as causes of autosomal dominant, early onset AD: APP, which encodes amyloid-β, precursor protein, and PSEN1 and PSEN2, encoding presenilin 1 and 2. All 3 genes are involved in the production of amyloid-β peptides (Aβ). Aβ is generated by sequential proteolytic cleavage of APP by 2 enzymes, βsecretase and γ-secretase; the presenilins form the catalytic core of γ -secretase. The genetic evidence, combined with the fact that Aβ accumulates in the brain in the form of soluble oligomers and amyloid plaques, and is toxic when applied to neurons, forms the basis for the amyloid hypothesis of AD pathogenesis. Many genes have been identified as having alleles that increase AD risk. By far the most important of these is APOE, which encodes the lipid carrier protein apoE. Individuals inheriting the ε4 allele of APOE have a more than 3-fold higher risk of developing AD. While they make up less than one-fourth of the population, they account for more than half of all AD cases.
PATHOPHYSIOLOGY. The pathological hallmarks of AD are amyloid plaques, which are extracellular accumulations of Aβ, and intracellular neurofibrillary tangles composed of the microtubule-associated protein tau. While the development of amyloid plaques is an early and invariant feature of AD, tangle burden accrues over time in a manner that correlates more closely with the development of cognitive impairment. In autosomal dominant AD, Aβ accumulates due to mutations that cause its overproduction. Aggregation of Aβ is an important event in AD pathogenesis. While plaques consist of highly ordered fibrils of Aβ, it appears that soluble Aβ oligomers, perhaps as small as dimers, are more highly pathogenic. Tau also aggregates to form the paired helical filaments that make up neurofibrillary tangles. Posttranslational modifications of tau including phosphorylation, proteolysis, and other changes cause loss of tau's normal functions and increase its propensity to aggregate. Mechanisms by which Aβ and tau induce neuronal dysfunction and death may include direct impairment of synaptic transmission and plasticity, excitotoxicity, oxidative stress, and neuroinflammation.
NEUROCHEMISTRY. The most striking neurochemical disturbance in AD is a deficiency of acetylcholine. The anatomical basis of the cholinergic deficit is atrophy and degeneration of subcortical cholinergic neurons. The selective deficiency of ACh in AD and the observation that central cholinergic antagonists (e.g., atropine) can induce a confusional state resembling the dementia of AD, have given rise to the "-cholinergic hypothesis" that a deficiency of ACh is critical in the genesis of the AD symptoms. AD, however, is complex and also involves multiple neurotransmitter systems, including glutamate, 5-HT, and neuropeptides, and there is destruction of not only cholinergic neurons but also the cortical and hippocampal targets that receive cholinergic input.
At present, no disease-modifying therapy for AD is available; current treatment is aimed at alleviating symptoms.
TREATMENT OF COGNITIVE SYMPTOMS. Augmentation of the cholinergic transmission is currently the mainstay of AD treatment. Three drugs, donepezil, rivastigmine, and galantamine, are widely used for this purpose; a fourth, tacrine, is rarely used now because of its extensive side effects compared to the newer agents (Table 22–2). All 4 agents are reversible antagonists of cholinesterases (seeChapter 10). Cholinesterase inhibitors are the usual first-line therapy for symptomatic treatment of cognitive impairments in mild or moderate AD. They are also widely used to treat other neurodegenerative diseases with cholinergic deficits, including dementia with Lewy bodies and vascular dementia. The drugs are usually well tolerated, with the most common side effects being GI distress, muscle cramping, and abnormal dreams. They should be use with caution in patients with bradycardia or syncope.
Table 22–2
Cholinesterase Inhibitors Used for the Treatment of Alzheimer Disease
Memantine (NAMENDA) is used either as an adjunct or an alternative to cholinesterase inhibitors in AD, and is also commonly used to treat other neurodegenerative dementias. Memantine is a noncompetitive antagonist of the NMDA-type glutamate receptor. Memantine significantly reduces the rate of clinical deterioration in patients with moderate to severe AD. Adverse effects of memantine include mild headache or dizziness. The drug is excreted by the kidneys, and dosage should be reduced in patients with severe renal impairment.
TREATMENT OF BEHAVIORAL SYMPTOMS. In addition to cognitive decline, behavioral and psychiatric symptoms in dementia (BPSD) are common, particularly in middle stages of the disease. These symptoms include irritability and agitation, paranoia and delusional thinking, wandering, anxiety, and depression. Treatment can be difficult, and nonpharmacological approaches should generally be first-line.
A variety of pharmacological options are also available. Both cholinesterase inhibitors and memantine reduce some BPSD. However, their effects are modest, and they do not treat some of the most troublesome symptoms, such as agitation. Atypical antipsychotics, such as risperidone, olanzapine, and quetiapine (see Chapter 16), are the most efficacious therapy for agitation and psychosis in AD. Risperidone and olanzapine are effective, but their use is often limited by adverse effects, including parkinsonism, sedation, and falls. In addition, the use of atypical antipsychotics in elderly patients with dementia-related psychosis has been associated with a higher risk of stroke and overall mortality. Benzodiazepines (see Chapter 17) can be used for occasional control of acute agitation, but are not recommended for long-term management because of their adverse effects on cognition and other risks in the elderly population. The typical antipsychotic haloperidol (see Chapter 16) may be useful for aggression, but sedation and extrapyramidal symptoms limit its use to control of acute episodes. Antidepressants (see Chapter 15) can be useful for BPSD, particularly when depression or anxiety contribute. Trazodone has modest benefits, but for the most part, selective serotonin reuptake inhibitors (SSRIs) are the preferred class of drugs.
CLINICAL SUMMARY. The typical AD patient presenting in early stages of disease should probably be treated with a cholinesterase inhibitor. Patients and families should be counseled that a realistic goal of therapy is to induce a temporary reprieve from progression, or at least a reduction in the rate of decline, rather than long-term recovery of cognition. As the disease progresses, memantine can be added to the regimen. Behavioral symptoms are often treated with a serotonergic antidepressant or, if they are severe enough to warrant the risk of higher mortality, an atypical antipsychotic. Eliminating drugs likely to aggravate cognitive impairments, particularly anticholinergics, benzodiazepines, and other sedative/hypnotics, from the patient's regimen is another important aspect of AD pharmacotherapy.
HD is a dominantly inherited disorder characterized by the gradual onset of motor incoordination and cognitive decline in midlife. Symptoms develop insidiously, either as a movement disorder manifest by brief, jerk-like movements of the extremities, trunk, face, and neck (chorea) or as personality changes or both. Fine-motor incoordination and impairment of rapid eye movements are early features. As the disorder progresses, the involuntary movements become more severe, dysarthria and dysphagia develop, and balance is impaired. The cognitive disorder manifests first as slowness of mental processing and difficulty in organizing complex tasks. Memory is impaired, but affected persons rarely lose their memory of family, friends, and the immediate situation. Such persons often become irritable, anxious, and depressed. The outcome of HD is invariably fatal; over a course of 15-30 years, the affected person becomes totally disabled and unable to communicate, requiring full-time care; death ensues from the complications of immobility.
PATHOLOGY AND PATHOPHYSIOLOGY. HD is characterized by prominent neuronal loss in the striatum (caudate/putamen) of the brain. Atrophy of these structures proceeds in an orderly fashion, first affecting the tail of the caudate nucleus and then proceeding anteriorly from mediodorsal to ventrolateral. Other areas of the brain also are affected. Interneurons and afferent terminals are largely spared, whereas the striatal projection neurons (the medium spiny neurons) are severely affected. This leads to large decreases in striatal GABA concentrations, whereas somatostatin and DA concentrations are relatively preserved.
Selective vulnerability also appears to underlie the development of chorea. In most adult-onset cases, the medium spiny neurons that project to the GPi and SNpr (the indirect pathway) appear to be affected earlier than those projecting to the GPe (the direct pathway; see Figure 22–2). The disproportionate impairment of the indirect pathway increases excitatory drive to the neocortex, producing involuntary choreiform movements (Figure 22–6). In some individuals, rigidity rather than chorea is the predominant clinical feature; this is especially common in juvenile-onset cases. Here, the striatal neurons giving rise to both the direct and indirect pathways are impaired to a comparable degree.
Figure 22–6 The basal ganglia in Huntington disease. HD is characterized by loss of neurons from the striatum. The neurons that project from the striatum to the GPe and form the indirect pathway are affected earlier in the course of the disease than those that project to the GPi. This leads to a loss of inhibition of the GPe. The increased activity in this structure, in turn, inhibits the STN, SNpr, and GPi, resulting in a loss of inhibition to the VA/VL thalamus and increased thalamocortical excitatory drive. Structures in purple have reduced activity in HD, whereas structures in red have increased activity.Light blue lines indicate primary pathways of reduced activity. (See legend to Figure 22–2 for definitions of anatomical abbreviations.)
GENETICS. HD is an autosomal dominant disorder with nearly complete penetrance. The average age of onset is between 35 and 45 years, but the range varies from as early as age 2 to as late as the middle 80s. Although the disease is inherited equally from mother and father, more than 80% of those developing symptoms before age 20 inherit the defect from the father. Known homozygotes for HD show clinical characteristics identical to the typical HD heterozygote, indicating that the unaffected chromosome does not attenuate the disease symptomatology.
A region near the end of the short arm of chromosome 4 contains a polymorphic (CAG)n trinucleotide repeat that is significantly expanded in all individuals with HD. The expansion of this trinucleotide repeat is the genetic alteration responsible for HD. The range of CAG repeat length in normal individuals is between 9 and 34 triplets, with a median repeat length on normal chromosomes of 19. The repeat length in HD varies from 40 to over 100. Repeat length is correlated inversely with age of onset of HD. The younger the age of onset, the higher the probability of a large repeat number. The mechanism by which the expanded trinucleotide repeat leads to the clinical and pathological features of HD is unknown. The HD mutation lies within a large gene (10 kilobases) designated IT15. It encodes a protein of ~348,000 Da. The trinucleotide repeat, which encodes the amino acid glutamine, occurs at the 5′ end of IT15 and is followed directly by a second, shorter repeat of (CCG)n that encodes proline. The protein,huntingtin, does not resemble any other known protein, and the normal function of the protein has not been identified.
SYMPTOMATIC TREATMENT. None of the currently available medications slows the progression of the disease.
Symptomatic treatment is needed for patients who are depressed, irritable, paranoid, excessively anxious, or psychotic. Depression can be treated effectively with standard antidepressant drugs with the caveat that drugs with substantial anticholinergic profiles can exacerbate chorea. Fluoxetine (see Chapter 15) is effective treatment for both the depression and the irritability manifest in symptomatic HD. Carbamazepine (see Chapter 21) also has been found to be effective for depression. Paranoia, delusional states, and psychosis are treated with antipsychotic drugs, but usually at lower doses than those used in primary psychiatric disorders (see Chapter 16). These agents also reduce cognitive function and impair mobility and thus should be used in the lowest doses possible and should be discontinued when the psychiatric symptoms resolve. In individuals with predominantly rigid HD, clozapine, quetiapine (see Chapter 16), or carbamazepine may be more effective for treatment of paranoia and psychosis.
Tetrabenazine (XENAZINE, NITOMAN) is available for the treatment of large-amplitude chorea associated with HD. Tetrabenazine, and the related drug reserpine, are inhibitors of the vesicular monoamine transporter 2 (VMAT2), and cause presynaptic depletion of catecholamines. Tetrabenazine is a reversible inhibitor; inhibition by reserpine is irreversible and may lead to long-lasting effects. Both drugs may cause hypotension and depression with suicidality; the shorter duration of effect of tetrabenazine greatly simplifies the clinical management. Many HD patients exhibit worsening of involuntary movements as a result of anxiety or stress. In these situations, judicious use of sedative or anxiolytic benzodiazepines can be very helpful. In juvenile-onset cases where rigidity rather than chorea predominates, DA agonists have had variable success in the improvement of rigidity. These individuals also occasionally develop myoclonus and seizures that can be responsive to clonazepam, valproic acid, and other anticonvulsants (see Chapter 21).
ALS (or Lou Gehrig disease) is a disorder of the motor neurons of the ventral horn of the spinal cord (lower motor neurons) and the cortical neurons that provide their afferent input (upper motor neurons). The disorder is characterized by rapidly progressive weakness, muscle atrophy and fasciculations, spasticity, dysarthria, dysphagia, and respiratory compromise. Many ALS patients exhibit behavioral changes and cognitive dysfunction, and there is clinical, genetic, and neuropathological overlap between ALS and frontotemporal dementia spectrum disorders. ALS usually is progressive and fatal. Most patients die of respiratory compromise and pneumonia after 2-3 years, although some survive for many years.
ETIOLOGY. About 10% of ALS cases are familial (FALS), usually with an autosomal dominant pattern of inheritance. An important subset of FALS patients are families with a mutation in the gene for the enzyme SOD1. Mutations in this protein account for about 20% of cases of FALS. Mutations in the TARDBP gene encoding TAR DNA-binding protein (TDP-43) and in the FUS/TLS gene have been identified as causes of FALS. Both TDP-43 and FUS/TLS bind DNA and RNA, and regulate transcription and alternative splicing. More than 90% of ALS cases are sporadic. Of these, a few are caused by de novo mutations in SOD1, TDP-43, FUS/TLS, or other genes, but for the majority of sporadic cases the etiology remains unclear. There is evidence that glutamate reuptake may be abnormal in the disease, leading to accumulation of glutamate and excitotoxic injury. The only currently approved therapy for ALS, riluzole, is based on these observations.
Riluzole. Riluzole (2-amino-6-[trifluoromethoxy] benzothiazole; RILUTEK) is an agent with complex actions in the nervous system.
Riluzole is absorbed orally and is highly protein bound. It undergoes extensive metabolism in the liver by both CYP–mediated hydroxylation and glucuronidation. Its t1/2 is 12 h. In vitro studies have shown that riluzole has both presynaptic and postsynaptic effects. It inhibits glutamate release, but it also blocks postsynaptic NMDA- and kainate-type glutamate receptors and inhibits voltage-dependent Na+channels. The recommended dose is 50 mg twice daily, taken 1 h before or 2 h after a meal. Riluzole usually is well tolerated, although nausea or diarrhea may occur. Rarely, riluzole may produce hepatic injury with elevations of serum transaminases, and periodic monitoring of these is recommended. Meta-analyses of the available clinical trials indicate that riluzole extends survival by 2-3 months. Although the magnitude of the effect of riluzole on ALS is small, it represents a significant therapeutic milestone in the treatment of a disease refractory to all previous treatments.
SYMPTOMATIC THERAPY OF ALS: SPASTICITY. Spasticity is an important component of the clinical features of ALS and the feature most amenable to present forms of treatment. Spasticity is defined as an increase in muscle tone characterized by an initial resistance to passive displacement of a limb at a joint, followed by a sudden relaxation (the so-called clasped-knife phenomenon). Spasticity results from loss of descending inputs to the spinal motor neurons, and the character of the spasticity depends on which nervous system pathways are affected.
Baclofen. The best agent for the symptomatic treatment of spasticity in ALS is baclofen (LIORESAL), a GABAB receptor agonist. Initial doses of 5-10 mg/day are recommended, which can be increased to as much as 200 mg/day if necessary. Alternatively, baclofen can be delivered directly into the space around the spinal cord using a surgically implanted pump and an intrathecal catheter. This approach minimizes the adverse effects of the drug, especially sedation, but it carries the risk of potentially life-threatening CNS depression.
Tizanidine. Tizanidine (ZANAFLEX) is an agonist of α2 adrenergic receptors in the CNS. It reduces muscle spasticity, probably by increasing presynaptic inhibition of motor neurons. Tizanidine is primarily used in the treatment of spasticity in multiple sclerosis or after stroke, but it also may be effective in patients with ALS. Treatment should be initiated at a low dose of 2-4 mg at bedtime and titrated upward gradually. Drowsiness, asthenia, and dizziness may limit the dose that can be administered.
Other Agents. Benzodiazepines (see Chapter 17) such as clonazepam (KLONOPIN) are effective antispasticity agents, but they may contribute to respiratory depression in patients with advanced ALS.
Dantrolene (DANTRIUM), approved in the U.S. for the treatment of muscle spasm, is not used in ALS because it can exacerbate muscular weakness. Dantrolene acts directly on skeletal muscle fibers, impairing Ca2+ release from the sarcoplasmic reticulum. It is effective in treating spasticity associated with stroke or spinal cord injury and in treating malignant hyperthermia (see Chapter 11). Dantrolene may cause hepatotoxicity, so it is important to monitor liver associated enzymes before and during therapy with the drug.


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Meet the Author
Heather Kirchhoff lives in Missouri where she works at a nursing home and has one dog and a betta. She became a bookworm back in sixth grade when her teacher suggested the Phantom Stallion series by Terri Farley and instantly fell in love. Heather loves reading paranormal stories, plus some love ones here and there. Writing is her passion--it helps her escape the world for a while, as well as reading--she doesn't know what she'd do without it. When Heather isn't writing, she is reading, taking walks, taking pictures, or spending time with her two best friends, animals, and family. Richelle Mead, Alyson Noel, and Stephenie Meyer inspired Heather to write.
Twitter: https://twitter.com/HeatherKirc
Facebook: https://www.facebook.com/AuthorHeatherKirchhoff/
Goodreads: https://www.goodreads.com/.../show/6579604.Heather_Kirchhoff
Amazon: https://www.amazon.com/Heather-Kirchhoff/e/B00ED77LEY
Newsletter: http://weebly.us11.list-manage.com/subscribe?u=3fc558069baa1a4f84df498f6&id=9d5c2f25c4
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Josette Reuel has been an avid reader her entire life, many wonder if she was born with a book in her hand. She is currently on a journey to share her love of books and has published her own paranormal romance full-length novels and short stories.
May 2017
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Category: Stock Vector
GraphicRiver Sugar Canes 9500742
Stock Vector \ Conceptual \ Seasons \ Holidays \ Christmas
Vector \ Editable \ Illustration \ Hanging \ YearChristmas \ Winter \ Branch
Stock Vector - Sugar Canes 9500742 by Prikhnenko @ GraphicRiver
Stock Vector \ Conceptual \ Seasons \ Holidays \ Christmas
Christmas sugar canes hanging on branch of fir-tree.
Vector illustration, fully editable, vector objects separated and grouped.
Editable EPS 10 Vector illustrations.
Layered: No; Graphics Files Included: JPG Image, Vector EPS; Minimum Adobe CS Version: CS.
Vintage Royal Card; Flowers; Flowers Background; Tree Branches Border ; Tree Branches Frame ; Tree Branches Frame ; Tree Branches Frame.
Keywords: background, bow, candy, cane, celebration, christmas, decoration, design, fir, food, gift, green, hang, hanging, holiday, illustration, isolated, new, ribbon, season, striped, sugar, sweet, traditional, tree, vector, white, winter, xmas, year.
Create GraphicRiver Sugar Canes 9500742 style with After Effect, Cinema 4D, 3DS Max, Apple Motion or PhotoShop. GraphicRiver Sugar Canes 9500742 from creative professional designers. Full details of GraphicRiver Sugar Canes 9500742 for digital design and education. GraphicRiver Sugar Canes 9500742 desigen style information or anything related.


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Monthly Archives: May 2011
More Recursion–Removing Multiple Spaces
My last post about recursive CTEs reminded me of a recursive SQL Server function I wrote a while back for removing multiple spaces from strings. By removing multiple spaces, I mean replacing all consecutive repeating spaces with a single space. … Continue reading
Posted in Uncategorized Leave a comment
The Missing UNGROUP BY Clause (T-SQL Tuesday #18)
For May 2011, T-SQL Tuesday is brought to us by Chicago's own Bob Pusateri (blog | @SQLBob). Bob chose common table expressions, otherwise know as CTEs as the topic of the month. Thanks for hosting Bob, and for the great … Continue reading
Posted in Uncategorized 6 Comments


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Mon, 2 March 2009
Tuscaloosa News insider Cecil Hurt is the special guest this week. Also, Keith Sisson is joined by Chase Goodbread of BamaOnline.com, as well as SEC insiders Michael Draper and Bart Holt, to talk about Bama's three game winning streak on the hardwood; plus the Bama baseball team.
Direct download: BRC_030209.MP3
Category:podcasts -- posted at: 1:34pm CST


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NEW FOR 2017! ThunderVolt Speedway GoKarts!
Featuring button-activated TURBO BOOST technology to give your race an extra dimension of fun! You only get two TURBO BOOSTS per race, so use them wisely!
The new ThunderVolt Speedway GoKarts are electric cars, which provide a much quicker acceleration than gas cars along with being being better for the environment with no carbon emmisions.
New safety features include full speed control for each GoKart, so unsafe drivers can be penalized by reducing their individual speed - keep it clean and you have nothing to worry about! Speed is also reduced to a slow speed when pulling into the pit to help ensure safe parking. Full working headlights and brake lights on each car add an extra element of safety.
Don't let the rain dampen your need for speed. The track will be converted back to indoor-only during bad weather.
Footwear and a shirt or top is required to participate in this attraction. Bare feet are not allowed.
Minimum solo driver height: 56"
Minimum passenger height, with an adult or person with a driver's license: 36"
Shoes and shirt are required.


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About this Business
From Our Editors
The secret behind Carmine Street NY Pizza & Mussels' New York–style slices is the restaurant's stone-brick oven, which sears dough until it attains the style's signature crispy, thin-crusted crunch. However, Carmine Street knows that a great pizza relies on more than its base, so they top dough with gourmet ingredients such as chicken marsala, meatballs, and fresh baby spinach.
Like a graphic novel about pearls, the restaurant also features a few oceanic alter egos. Mussels, shrimp, and calamari are delivered to the kitchen daily, allowing chefs to toss them with wine, herbs, and pasta, or quickly fry them for fresh appetizers. Calzones, paninis, and entrees of chicken piccata are among the menu's classic Italian meals. Diners may pair meals with wines and cocktails procured at the full liquor bar, or take in the soothing streams of live music while feasting indoors or on the patio.


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Go HERE and play for your chance to get a burger timer or .50/1 beef coupon. You can play up to five times per day. Use code A23568 to play.
This coupon states "ANY beef", and if your store doubles, it makes this $1/1 beef.
For those of you starting out- This is where you think like a couponer. Instead of buying your normal several dollar package of beef, find the SMALLEST package and get free beef!!
Or, if you find really cheap packs, possibly even overage??
Thursday, October 22, 2009
$.50/1 Beef coupon
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Plus-size Ashley Graham nabs spread in Sports Illustrated's most diverse Swimsuit Issue ever
Ashley Graham is officially a Sports Illustrated model.
The plus-size fashion star has been making waves in the style industry for the past 12 months, topping off a successful year with this latest accolade. She'll be appearing in the publication's famous Swimsuit Issue, and she has already shared some bikini snaps on her Instagram account.
"It's official - I'm a @si_swimsuit model!!" she exclaimed. "This is a dream come true. Thank you to everyone who stood up for curves- our voices were heard and together we can help me win Rookie of the Year (prize for model newcomer). Stay tuned for voting instructions #beautybeyondsize #siswim (sic)."
The shot she captioned sees 28-year-old Ashley reclining on a beach in a purple two-piece swimming outfit, looking relaxed as she gazes into the camera. Last year the US size 16 model appeared in Sports Illustrated Swimsuit Issue in an advert, while size 12 star Robyn Lawley broke stereotypes with her inclusion in the magazine.
Read more: 10 times Ashley Graham wrote the book on body confidence
Ashley also uploaded a gold bikini shot, telling her followers that having confidence is all a girl really needs.
"Confidence is my golden rule. Have you seen my new #SwimSexy campaign with @swimsuitsforall in @SI_Swimsuit?" she wrote.
Ashley has other reasons to celebrate too; she's now hit one million followers on the photo sharing site. To mark the occasion she uploaded a third swimsuit snap, this time wearing a white bikini.
"1 MILLION FOLLOWERS!!!!! Thank you so much!!! #beautybeyondsize #sexystateofmind," she gushed.
The model has never been afraid to talk about her size, but in a recent chat with elle.com she did admit to hating the term "real women".
"I like to use the word woman," she said. "And I say that because there are so many women out there who are naturally thin, or are naturally curvy, and I think when we start putting a label on the type of woman it gets misconstrued and starts to offend people. At the end of the day we just all want to be known as women or models or actresses or whatever."
Online Editors
Promoted Links
Related Content
- Plus-size model Ashley Graham on her NYFW debut: 'It showed women we haven't forgotten about them'
- 'I am Size Sexy' - Plus size model Ashley Graham's debut at NYFW is finally sending the right message
- Size 10 'curve' model Emma Waldron weighs in on the plus-size model debate
- YouTube star Loey Lane hits back at body shamers: 'Bigger girls aren't asking for your feedback'
- 9 inspiring Mindy Kaling quotes to live by


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Round Trip to Heaven Trailer (1992)
"Heaven could never be this HOT!" 02 September 1992 97 mins
Since Larry works at a garage, he gets to use one of the Rolls Royces. There is only one problem, there is a briefcase full of money in the trunk. So when Larry and his cousin Steve decide to go to Palm Springs to look for Ms. Right at a popular beauty pageant, the owner of the briefcase will do the impossible to get it back.
Watch the official Round Trip to Heaven 1992 trailer in HD below or find more Round Trip to Heaven videos on Vidimovie.


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ICC World Cup: Pakistan failed as a batting unit, says Misbah-Ul-Haq
Adelaide: Disappointed Pakistan captain Misbah-Ul-Haq blamed batting failure for his team's ouster from the World Cup following a six-wicket defeat against Australia in the quarter-final in Adelaide yesterday.
Pakistan were bowled out for a below-par 213 in the final over after being well set at 97-2 — a trend Misbah said had prevailed throughout the World Cup. "I think we failed as a batting unit in the whole tournament," said Misbah, whose dismissal after scoring 34 derailed Pakistan's innings.
Josh Hazlewood took 4-35 while Mitchell Starc and Glenn Maxwell took two wickets apiece as Pakistan never recovered on a batting-friendly Adelaide Oval pitch.
"Batting has been a problem for the last two, three years as we are not up to the international standards. Fielding is another aspect we need to improve to compete at international level but it comes with fitness and we are not there. If we don't get there we will suffer in future."


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Listing Courtesy of Alan Iverson of Castle Realty, Llc
Listing information
- Beds: 3
- Stories: 0
- New Construction: No
- Above Ground Sq. Feet: 2,900
- Lot Size: 868
- School District: Lacresent-Hokah #300
- Style: Single Family
- Baths: 3 (Full: 2 3/4: 0 1/2: 1 Other: 0)
- Fireplaces: 1
- Foreclosure: No
- Below Ground Sq. Feet: 1,488
- Estimated Annual Taxes: $4,964
- Year Built: 2002
- Status: Sold on 8/31/2016
- Parking Type Description: Attached 2 cars
- Total Square Footage: 4,388 ($80.33 per sq. foot)
- Lot Area: 1.09
- County: Houston
3 Bdrms on One Flr Yes
Air Conditioning Central
Amenities - Exterior Brick/Stone Accent, Cul-de-Sac, Deck, Driveway - Concrete, Garage Door Opener, Patio, Tile Floors
Amenities - Interior Cable, Ceiling Fan(s), Ceramic Tile, Ethernet Wired, Formal Dining Room, Foyer, French Doors, Hardwood Floors, Kitchen Center Islnd, Kitchen Vent, Kitchen Window, Master Bathroom, Master BR W/I Closet, Mud Room, Natural Woodwork, Open Staircase, Paneled Doors, Vaulted Ceilings, Washer/Dryer Hkups
Appliances Dishwasher, Disposal, Dryer, Exhaust Fan/Hood, Microwave, Range/Stove, Refrigerator, Washer
Basement Features Daylight/Lookout Wnd, Unfinished
Basement Material Poured Concrete
Basement Style Full, Walk-out
Bath Description Full Master, Jetted Tub, Main Floor 1/2 Bath, Private Master, Separate Tub & Shwr
Construction Type Frame/Wood
Dining Eat-in Kitchen, Formal Dining Room, Open Floor Plan
Exterior Brick, Vinyl
Financing Conventional
Fireplace Yes
Fireplace Type Gas
Fuel Natural Gas
Garage Type Attached
Heat Forced Air
Miscellaneous: DPR Eligible No
Other Finished Above Grade - 2900.00, Finished Below Grade - 0.00, Garage Type: Garage SqFt - 868, Square Feet: Above Ground SqFt - 2900, Square Feet: Below Ground SqFt - 1488, Square Feet: Main Floor SqFt - 1718, Square Feet: Total SqFt - 4388, Tax Year - 2015
Rental License No
Road Frontage City, Dead End/No Outlet, Paved
Roof Asphalt Shingles
Sewer City
Stories 2 Story
Water City
Waterfront No
Waterfront Name None
Bathroom U x
Bedroom 2 U 13x14
Bedroom 3 U 13x14
Master Bedroom U 19x17
Den M 13x13
Dining Room M 12x12
Family Room M 15x16
Foyer M 10x7
Kitchen M 15x20
Laundry Room M 7x13
Living Room M 11x12
Listing Courtesy of Alan Iverson of Castle Realty, Llc


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It was only two years ago that Rolf Harris toasted yet another honour from the Queen when he was made an Officer of the Order of Australia.
The award was the latest of several to have been bestowed upon the entertainer, who was already an MBE, OBE and CBE as well as having been afforded the rare privilege of being invited to paint the Queen's portrait in 2006.
But in Harris's eyes, it was this last honour, coming as it did days after he took centre stage at the Diamond Jubilee celebrations, which meant that 2012 was shaping up to be the pinnacle of his career. "This has been an amazing year for me. And it's just getting better and better," he said at the time.
However, that November, five months after his moment of triumph, Harris was being interviewed by police as a suspected sex offender after coming under the gaze of Scotland Yard's Operation Yewtree, the sex abuse inquiry stemming from the Jimmy Savile scandal.
Unlike with Savile, about whom suggestions of impropriety had long lingered, there was little to suggest until his arrest that Harris was a sex offender.
When the reputation of any great public figure is sullied, there are certain stories from their past that take on a haunting new meaning. For when someone enjoys the great zeal of national affection, there are certain things — the occasional indiscretion, an unintended slip-up — that we are willing to forgive. But when they fall from grace, these memories are often twisted. For Rolf Harris, a reputation not so much sullied as blackened beyond repair after he was yesterday found guilty of child sex abuse, there is one in particular that comes to mind.
Nearly 30 years ago, in 1985, Harris — a universally loved presenter and entertainer — approached the production company Skippon Video Associates with an idea for an educational film. It was to be Britain's first programme warning children about sex abuse, entitled "Kids Can Say No!" and aimed at five to eight-year-olds. Harris was, he claimed, inspired by the experience of a teacher friend, who, on giving a talk to her pupils about abuse, had seen one run out of the classroom and reveal decades of torment at the hands of a family member. He was, he said, naïve; he didn't realise such things happened, and he wanted to be the first to address the subject on television.
The 20-minute film appeared later that year, and featured Harris discussing the dangers of paedophiles with a group of primary-age schoolchildren. Made in association with the NSPCC, the video was shown in schools and youth clubs. Harris, ever the entertainer, wrote a song for the final scenes: "My body's no body's body but mine," it went. "You take care of your body; I'll look after mine."
He was, in the eyes of generations of devoted fans, whiter than white. Innocence was Harris's hallmark, from his early days as a children's entertainer, to his stint on the hugely popular Animal Hospital, to his latter career as portrait painter, festival headliner and friend of the Royal family. Nobody, not one person who had ever met him, ever doubted his motives; his love for children; for animals; his utter devotion to the public who made him a star.
"I'm a big kid," he once professed. "I remember very vividly what it's like to be a child. The adults you liked were the ones who listened to you when you spoke and gave you time to say what you wanted … My job with kids is to say: 'Listen, here's an idea. Have you seen it?'"
Yet according to witness statements given at Harris's trial, which yesterday found him guilty of 12 counts of indecent assault, when he made that educational video, he had already acted out the evils he claimed to be protecting children against.
Evidence presented before the trial but deemed inadmissible by the judge was given by a woman who claimed to have met Harris in 1977, when she was 14. The woman claimed that she met Harris when he stayed at a motel near Sydney, and that he had touched her bottom and waist, before pushing her up against a door and saying "Rolfie deserves a cuddle". He then allegedly followed her to the lift and touched her breasts.
Few could have believed what was being alleged against a public figure once described by his biographer as "the most talented man in the world". Yet what has emerged most poignantly throughout Harris's trial at Southwark Crown Court, amid the slew of allegations, the victims, horrific abuse spanning 18 years, is the devastating sense of duplicity.
Indeed, a year after Harris was awarded his first honour by the Queen — an MBE in 1968 — he attacked his first and youngest known victim, a seven-year-old girl who had asked the singer for his autograph. But it would be 45 years before he was finally brought to justice.
In contrast to his half-century as a national hero, Harris's descent to disgraced paedophile was unnervingly fast. Born in the suburb of Bassendean in Perth, Western Australia, to parents of Welsh origin, the young Harris had hopes of sporting stardom and was a swimming champion by age 16. After dropping out of a psychology degree, he was on course to become a teacher, but an interest in art began when an infection left him hospitalised. He moved to London and started a course at the City and Guilds Art School, but, bored by the syllabus, quit. After seeing an advertisement for presenters at the BBC, Harris soon found himself hosting a 10-minute cartoon-drawing slot alongside a puppet called Fuzz in 1952.
Unlike the staid and buttoned-up demeanour of many other broadcasters at the time, Harris's easy-going manner proved an instant hit. He went on to present a series of children's shows before making an unlikely departure into the musical world after accidentally inventing the "wobbleboard" while drying a piece of wood. He had his first British chart hit with Tie Me Kangaroo Down Sport in 1960, and in the decades to follow, even Margaret Thatcher declared herself a fan of his song Two little Boys. In 1967, The Rolf Harris Show propelled him to A-list status in Britain, running for seven years on prime-time television. With his catch-phrase, "Can you tell what it is yet?" he charmed a generation of children. By the Eighties he was a global star, regularly travelling the world, and later branched out from art programmes and music to present highbrow documentaries.
Harris was married to Alwen Hughes, a sculptor he had met at art school. They had a daughter, Bindi, and lived in large bohemian house in Sydenham, south-east London. But his trial would later hear how family life was marred by his bouts of depression. He had a sexual relationship with the housekeeper and on a family holiday in Hawaii and Australia in 1978 his wandering eye first fell on his daughter's 13-year-old friend. The relationship which followed sent his victim into a spiral of depression and alcoholism. When she confided to her family in the mid-Nineties, it prompted Harris to write to her father, asking for forgiveness and saying he felt "sickened" by the misery he had caused.
All the while, however, the shadow in Harris's private life did nothing to distract from his ascent to the status of national treasure. Naivety and virtue were his trademarks. How he is guilty of such contemptible acts is, still, somewhat unutterable.
Harris's name, too, stands out among the roll-call of once-lauded public figures whose names have been tarnished by the Operation Yewtree investigation: Dave Lee Travis, Stewart Hall, Gary Glitter, Freddie Starr, Jim Davidson. For unlike his contemporaries, Harris had not fallen out of the spotlight. His paintings still drew crowds at exhibitions; his performances at festivals were still selling out. This week, four years ago, Harris's name was in the paper for very different reasons — he had just won over a new generation of fans at the 40th anniversary of Glastonbury Festival, in what ticket-holders deemed one of the festival's best-ever performances.
Now, a convicted sexual offender, Harris faces the ignominy of spending his twilight years behind bars. He is likely to be stripped of his honours — the British Academy of Film and Television Arts has already removed the fellowship it bestowed on him in 2012 — and will never again enjoy the affection of the nation which made him its adopted son. And, as the shock of his conviction sinks in, thoughts of surprise are likely to turn to questions: who knew what this monster was truly capable of; how was he allowed to continue; and why, during those long 18 years, was nothing done to stop him?
In time, answers may emerge. For now, it seems, we were to the bitter end convinced by Harris the great performer. In the words of Det Chief Insp Mick Orchard of the Metropolitan Police, he, like Savile, operated in "plain sight", using his celebrity as a cover. True to form, just two months after his arrest in March 2013, Harris won a standing ovation after a performance at the Bristol Hippodrome. He told the 1,800-strong crowd: "You've no idea what this means, for you all to turn up with such support and enthusiasm," adding: "It's not about waiting for the storm to pass, it's about learning to dance in the rain."
How those words would return to haunt him. For Rolf Harris, the storm is only beginning.


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Read and Write a Post
Peep blog and vlog posts created by girls like YOU
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Monmouth University communications/music industry major. Singer/guitarist/songwriter. Avid writer who knows way too much about pop culture. Official member of Taylor Swift's friend group. 5th member of One Direction.


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Jillian Michaels : Beginner Shred Trailer (2014)
02 September 2014 75 mins
Whether you're looking to start exercising for the first time ever or get back into it, Jillian Michaels Beginner Shred has you covered! Jillian Michaels Beginner Shred is a comprehensive 30-day exercise plan to help you kickstart your weight loss journey, dramatically transforming not just your physique but also your level of fitness and self-confidence. Comprised of three 20-minute workouts over a 30-day period, this program will burn calories to melt off the fat, build strong lean muscles, and push you to find your true strength and inner power. Complete Workout 1 for the first ten days, rock out Workout 2 for the second set of 10 days, and finish strong with Workout 3 in the last ten days. There are both basic and advanced modifications for each move, so once you've mastered the moves with proper form you can progress your workout to match your fitness level.
Watch the official Jillian Michaels : Beginner Shred 2014 trailer in HD below or find more Jillian Michaels : Beginner Shred videos on Vidimovie.


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4 Bedroom Craftsman Style home73 2ND AV -
Craftsman style four bedroom home on a charming corner lot with a fenced in backyard, complete with brick patio and fenced garden area. Large 28 x 28 detached car garage with storage above. Hardwood floors throughout with a quaint front porch. New windows and exterior recently painted. This home offers so much character. Generously sized bedrooms. This fully restored home is decorated in neutral colors and just 1.5 miles from Lake Luzerne beach. Easy commute to Lake George, Queensbury or Saratoga. Even has mountain views!
Listing information
- Year Built: 1928
- Status: Sold on 2/17/2015
- Parking Type Description: Detached 2 cars
- Total Square Footage: 1,500 ($99.93 per sq. foot)
- County: Saratoga
- Property ID: 103444125
- Beds: 4
- Total Rooms: 7
- New Construction: No
- Lot Area: 0.34
- School District: Hadley Luzerne
- Style: Cottage
- Baths: 2 (Full: 1 3/4: 0 1/2: 1 Other: 0)
- Stories: 2
- Foreclosure: No
- Estimated Annual Taxes: $1,779
Age Description Estimated
Amenities Built In Cabinets, Ceramic Tile, Chair Rail, Country Kitchen, Walk In Closet, Wood Floors
Appliances Dishwasher, Range W Oven, Refrigerator, Washer Dryer
Attic Eaves, Part, Storage
Basement Full
Condition Excellent
Exterior Cedar, Clapboard
Exterior Features Fenced Yard, Garden, Lighting, Patio, Porch Enclosed, Privacy Fence
Garage Description Detached
General Taxes Description Estimated
Heat Fuel Oil
Heat System Hot Air
Interior Features Cable Hook Up, Garage Door Opener
Lot Description Corner, Landscaped, Level, Privacy, View
Master Bedroom First Floor
Other General Taxes - 1039, Model - Craftsman, School Taxes - 740, Tax Id Section - 27.18, Tax Identification Block - 6, Tax Identification Lot - 25, Village - Hadley
Roof Metal
School Taxes Description Estimated
Sewer Public
Sign Yes
Total Taxes Description Estimated
Water Public
Bedroom Main Level
Dining Room Main Level
Encl Porch Main Level
Kitchen Main Level
Living Room Main Level
Bedroom 2nd Level
Listed by Lisa McTygue of Coldwell Banker Prime Properties 518-587-3400


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