There were many attempts at regionalization of climate of Northern Eurasia. The early schemes were based on those individual meteorological variables that control natural vegetation. Thus in the 1920s, Kaminsky used temperature and humidity as a basis for regional division while in the 1930s Voznesensky produced a model based on the principles of Koppen (Borisov, 1965). Later climatic regionalizations were based on generic criteria. Alisov (1956) produced a model based on radiation regime and atmospheric circulation, drawing climatic boundaries in agreement with the distribution of soil and vegetation cover. This model, which has been widely accepted, distinguishes four climatic zones: arctic, subarctic, temperate, and subtropical. These are further subdivided into climatic provinces (Figure 3.3).
The most important criterion in Alisov's scheme is the prevalence of different air masses. For example, the northern boundary of the subtropical zone is determined by the average winter position of the Asiatic branch of the Polar front while the northern boundary of the temperate zone is determined by the average winter position of the Arctic front. The soil and vegetation zones are used as a general background to the climatic scheme. Each zone and many provinces accommodate mountainous regions and local and even macroclimatic effects of the mountains are not incorporated into the scheme.
The two most important features of the air mass climatology of Northern Eurasia is the transformation of air masses from temperate maritime and arctic maritime into temperate continental over the vast land mass and seasonal reversal of the characteristics of temperate continental air. Temperate continental air dominates Northern Eurasia throughout the year. Its frequency varies from 35 per cent in the Baltic region to 65 per cent in Siberia and Kazakhstan (Borisov, 1965). In winter, snow cover plays the main part in the process of transformation. First, snow cover increases reflectivity of the Earth's surface. Albedo changes from 20-30 per cent in July to 60 per cent and 70 per cent north of 50°N in the European territory and Asiatic part respectively, enhancing the seasonal decrease in net radiation (Lydolf, 1977). Second, snow cover inhibits heat flow from the ground. The insulating capacity of snow is important for agriculture: many crops are sown in autumn in order to make full use of the short vegetative season. Third, snow pack looses heat rapidly. Although the outgoing long-wave radiation is low (because of the low temperature of the snow pack), most of it is lost to space under the dry, clear sky conditions whereby there is very little counter-radiation. As a result, a low surface air temperature develops, enhancing the development of high pressure. Calm, clear weather, associated with high pressure, in turn further enhances the loss of heat through this classic positive feedback mechanism which is aided by suppressed turbulence. In January, almost all of Northern Eurasia (apart from the southernmost European territory, Central Asia and Kazakhstan which do not have a stable snow cover), has a negative radiation budget. In summer, the opposite occurs: solar heating of the ground allows for the absorbed energy to be returned to the atmosphere as terrestrial radiation and promotes turbulent heat and moisture exchanges.
In winter, temperate maritime air is of Atlantic origin (Figure 3.4). It is the main warm and humid air mass for Northern Eurasia at this time of year. Associated with it is cloudy weather that prevents rapid loss of heat and slows the transformation process.
On average, the transformation of temperate maritime air occurs by the time it reaches the Ural mountains. However, when depressions transporting the Atlantic air take southerly tracks, maritime air remains distinguishable as far as Lake Baikal. Temperate air of Pacific origin has little influence because of the winter monsoon, affecting only the coastal regions and the islands of the Russian Pacific and occasionally the Chukchi peninsula. Arctic maritime air originates over the Barents and Norwegian Seas and affects mainly the European part of the region. Siberia and the European north-east are affected by arctic continental air which forms over the frozen Siberian seas. Temperate continental air is generally cold and dry although both temperature and humidity vary between different parts of the region declining landwards. In Eastern Siberia, where radiative cooling is extreme, temperate continental air is colder than the arctic air and, paradoxically, the advection from the frozen Arctic Ocean causes temporary temperature increase. Winter precipitation is associated with frontal activity and forms in maritime air masses.
In summer, temperate continental air is also formed of temperate maritime and arctic maritime air but their sources, geographical extent and characteristics are different. Temperate maritime air is of the Atlantic origin in the west and the Pacific in the east. It is cool and humid especially in the northern part of the Russian Pacific where cloudy and foggy weather is associated with it. Arctic maritime air forms over the open water between the Arctic coast in the south and pack ice in the north. It affects the northern part of Eurasia from the Kola peninsula to the Bering Strait, being most frequent in spring and early summer. Fresh arctic air masses are cold and have low moisture contents. Without frequent advection from the north, temperatures would have been 4-7°C higher in the tundra zone and 1-3°C in central East European and West Siberian plains (Zhakov, 1969). The thermal regime of the East Siberian tundra is affected by arctic air particularly strongly because it arrives from the colder seas. However, in the process of transformation over the continent, arctic maritime air masses gain moisture through evaporation enhanced by forests, at the same time becoming less saturated as their temperature increases. The resulting temperate continental air is warm but its humidity varies. While in the northern part of Eurasia it is relatively humid, prolonged transformation over the forest-steppe, steppe, and semi-desert zones results in the loss of moisture and very low humidity. In summer, precipitation develops in both maritime and continental air masses and is of both frontal and convective (air mass) origin.
The southern part of the region, including the southern European territory, Caucasus and Transcaucasia, Central Asia, and the Maritime Province, are influenced by tropical air. Tropical air masses enter Northern Eurasia from the Mediterranean, Middle East, Asia Minor, China, and the Pacific and in summer, they also form over the deserts of Central Asia and Kazakhstan (Figure 3.4). Tropical maritime air reaches the European territory and western Transcaucasia via the Mediterranean and the Black Sea throughout the year in the warm sector of depressions developing on the Polar front. Although these air masses reach Northern Eurasia having been already considerably modified, they still have a very distinct character. Its main characteristics are high temperature, high humidity, and strong instability (although in comparison with other parts of the world, these characteristics are less pronounced as the passage of the Mediterranean air masses over the warm sea surface is limited). Tropical maritime air maintains mild winters in western Transcaucasia. Associated with these air masses are strong precipitation and winter thaws. Even in January, the arrival of tropical maritime air to the southern European territory, which occurs on average 6-8 times per winter, brings about temperature increase to 5-7°C and snow melt (Klimenko, 1994a). Although tropical maritime air masses affect primarily the European south, they can reach as far north-east as the Ob estuary. Tropical continental air mainly affects Transcaucasia and Central Asia, arriving from the Middle East, Iran, and Afghanistan. While Central Asia experiences tropical continental air masses throughout the year, the European south is affected in summer and autumn. In the southern Ukraine, tropical continental air occurs 9 per cent of the time and occasionally it may advance to the European north (Borisov, 1965). In summer, the deserts of the Turanian lowland receive very high insolation of over 20 kcal cm-2 per month. About 70 per cent of net radiation is used for sensible heat exchange, raising mean monthly temperatures to 30°C. In this region, continental temperate air is transformed into tropical continental air. The frequency of this air mass peaks on the Turanian lowland, reaching 28 per cent (Borisov, 1965).
Another region, affected by tropical air, is the southern part of the Far East. Tropical air masses arrive to the Far East only in summer, mainly as tropical maritime air from the western Pacific. It is the main source of precipitation, providing about 70 per cent of the annual total (Myachkova, 1983). Tropical continental air, which also affects southern Transbaikalia, arrives from Mongolia and central China. The main characteristics of these air masses are high temperature and very low humidity.


text:
The Azure and Model validators

``` yaml $(azure-validator)
# default the v2 generator to using the last stable @microsoft.azure/autorest-core
version: ~2.0.4413

use-extension:
  "@microsoft.azure/classic-openapi-validator": "~1.0.9"
  "@microsoft.azure/openapi-validator": "~1.0.2"
```

``` yaml $(model-validator)
# default the v2 generator to using the last stable @microsoft.azure/autorest-core
version: ~2.0.4413

use-extension:
  "oav": "~0.4.20"
```

#### Validation

``` yaml
pipeline:
  swagger-document/model-validator:
    input: swagger-document/identity
    scope: model-validator
  swagger-document/semantic-validator:
    input: swagger-document/identity
    scope: semantic-validator
```

``` yaml $(notnow)
pipeline:
  openapi-document/model-validator:
    input: openapi-document/identity
    scope: model-validator
  openapi-document/semantic-validator:
    input: openapi-document/identity
    scope: semantic-validator
```

# Validation

## Client Side Validation

On by default for backwards compatibility, but see https://github.com/Azure/autorest/issues/2100

``` yaml
client-side-validation: true
```

redpajama_set_name: RedPajamaGithub


text:
Q: How to fix 'preg_match(): Compilation failed: invalid range in character class at offset 1828' error in laravel 'url' validation? when i use 'url' validation in laravel request then give me error.

preg_match(): Compilation failed: invalid range in character class at offset 1828

$this->validate($request, [
   'posting_article_url' => 'nullable|url',
]);

it is occurred in php 7.3. in php 7.2 it is working fine.
when i replace 'url' validation with 'regex:pattern' validation then working fine.
$this->validate($request, [
   'posting_article_url' => 'nullable|regex:/^(https?:\/\/)?([\da-z\.-]+)\.([a-z\.]{2,6})([\/\w \.-]*)*\/?$/',
]);

Thanks in advance!

redpajama_set_name: RedPajamaStackExchange


text:
> Articles > L-Dopa: It's more than an anti-Parkinson drug
L-Dopa: It's more than an anti-Parkinson drug
By:- SOUTH, MA, James,
L-dopa, also known as Levodopa and L-3, 4-dihydroxyphenylalanine (1), is best known to the world as a treatment for Parkinson's disease (PD), a neurological disorder. Indeed, as Hauser and Zesiewicz remark: "L-dopa and peripheral decarboxylase inhibitor (PDI) (Sinemet) therapy remains the gold standard for symptomatic treatment for PD. It provides the greatest anti-Parkinsonian benefit with the fewest side effects" (2). Yet even though it is used to treat a disease, L-dopa is not an artificial human-created drug. It is a natural amino acid derivative that occurs in food, (making up 13% of the velvet bean) (1) and is normally present in the human brain (3). L-dopa is the precursor for the neurotransmitter dopamine (DA) (3), and is produced by the action of the enzyme tyrosine hydroxylase on the amino acid tyrosine (3). DA is the precursor of the brain neurotransmitter noradrenalin (NA), yet administration of L-dopa preferentially increases brain DA, while giving tyrosine increases NA more than it increases DA (3).
L-Dopa: Growth hormone releaser
If L-dopa were useful only as a PD treatment, it would be of little interest to most people. Yet L-dopa has uses beyond PD. It has been known for over 30 years that it is an effective stimulant of human growth hormone (HGH) release. In 1970, Boyd and colleagues found that a 500mg oral dose …"caused a significant rise in plasma growth hormone in PD patients, initially starting therapy or on chronic L-dopa therapy for as long as 11 months. The rise in plasma growth hormone persisted for 120 minutes after the administration of the drug." (4). Boden and his co-workers gave 500mg of the drug orally to four male and five female volunteers. "HGH levels rose sharply at 45 minutes from the basal value of 0.8mg/ml, to a maximum of 10.0mg/ml at 90 minutes (p<0.001) and declined thereafter. This rise occurred in eight of the nine subjects." (5). Hayek and Crawford reported that six out of seven "constitutionally short children" responded to oral L-dopa (200-500mg), "…with elevations in HGH concentration above 7mg/ml, peak levels occurring between 30 and 120 minutes after drug administration..". (6).
In 1975, Ajlouni and colleagues reported the effects of 500mg of oral L-dopa on eight normal and 8 non-obese insulin-dependent diabetic subjects. The normal subjects increased their plasma HGH from 1.5mg/ml before L-dopa, to an average 21mg/ml at 90 minutes post L-dopa, with all subjects showing at least a 10 mg/ml increase. The diabetics increased from 2.5mg/ml to 20mg/ml from 60-90 minutes post L-dopa. Giving 100 grams (3 _ ounces) of glucose with, or 30 minutes after the drug totally suppressed the expected HGH increase (7).
Obesity has been shown to blunt HGH release after oral L-dopa. Laurian and his co-workers tested 17 obese, non-diabetic and six normal weight volunteers. All 17 obese subjects failed to respond to L-dopa, while the normal weight subjects had HGH increases of 10-11mg/ml at 90 and 120 minutes after the drug was administered. The 17 obese men and women subsequently lost 12-50kg. After weight loss, 8 people secreted HGH in response to L-dopa, but at levels only 50-60% of the normal weight people. 9 formerly obese people still failed to respond to it (8).
Barbarino and colleagues gave 500mg orally to 12 obese people, with no significant HGH increases. When some of the subjects were given 40mg oral Propranolol, two hours before L-dopa, they then showed HGH response, although at only 50-75% of the level shown by 12 normal weight subjects given L-dopa, whose serum HGH levels reached 7 to 32mg/ml 60-120 minutes after L-dopa (9).
Greenspan et al. compared HGH response to L-dopa in 44 young patients (31-44 years of age) and 42 older patients (64-88 years of age). All were considered "healthy participants". Plasma HGH increased by 221% in the young patients and 167% in the older patients. The post L-dopa HGH levels were similar in young and old (4.5 and 4.8mg/ml) (10).
The preceding studies illustrate some of the studies showing that 500mg oral L-dopa is an effective stimulator of HGH release. Whether a person is male or female, young or old, diabetic or not, thin or obese (possibly with Propranolol), a PD patient or not, L-dopa is a natural HGH-releasing agent when taken on an empty stomach. For those who can't afford HGH injections, or just don't like self-injecting,L-dopa may provide a reasonable alternative.
Dopamine – Neuroregulator of movement
It is common knowledge that bodily movement becomes more difficult with age. Elderly people move at a slower pace, often walking with a shuffling or stooped gait. Hand-eye co-ordination deteriorates and it can become more difficult to get out of a chair. Joints stiffen, muscles weaken and hands tremble. In many ways, the dyskinesia (difficulty performing voluntary movements) of old age resembles a mild form of Parkinson's disease. Marshall and Berrios believe there is a connection. They point out that "The dopamine-containing neurons of the brain have long been known to be essential for normal movement and sensori-motor integration. The movement disturbances of Parkinson's disease, for example, are attributable to a loss of dopamine-containing neurons that innervate forebrain structures, particularly the neostriatum. Damage to these neurons of young adult mammals results in sensorimotor disturbances similar to Parkinsonism. The symptoms of this clinical disorder and its analog in animals are frequently controlled by administration of L-dopa, apomorphine or similar compounds. Our findings suggest that advanced age may represent another link between movement disturbances and the deterioration of dopaminergic neurotransmission.
This conclusion is supported by recent clinical investigations that have noted similarities between the movement disturbances of Parkinsonian and those of non-diseased elderly individuals." (11).
Marshall and Berrios noted that aged rats swim very poorly compared to young rats. In a 15 minute swimming test, young rats swim with vigour for most of the test, with their performance declining gradually. Old rats are significantly impaired after 6 minutes, unable to sustain a horizontal position in the water, frequently sinking below the water. Young rats, whose dopamine neurons are damaged, swim just like the old rats. Giving old rats intraperitoneal L-dopa injections 15 minutes before the test restores their ability to swim just like the healthy young rats (11).
Papavbasiliou and co-workers compared old mice who were fed L-dopa-enriched, with regular mice chow since youth. They noted a profound decrease in motor activity with aging in the regular, chow-fed old mice, but no loss of motor activity in the L-dopa-fed old mice. They concluded: "…motor impairment is an age-related phenomenon in mice associated with selective alterations in brain dopaminergic systems, which may be prevented by dietary Levodopa." (12)
Thus, the animal evidence combined with the effectiveness of L-dopa in PD, and the similarity of the neuromuscular degeneration typical of "normal" aging to PD, all suggest that it may provide a remedy for maintaining more normal "motor activity" throughout middle age into old age. On an anecdotal basis, I have confirmed with various friends and colleagues during the past 20 years that modest L-dopa supplementation (typically 100mg Sinemet ®/day) has increased their sense of neuromuscular co-ordination, strength, vigour and greater "drive to action".
Dopamine : The "warming" neurotransmitter
In their recent book "Balance Your Brain, Balance Your Life", neurologist, Dr. Jay Lombard and preventative medicine specialist Dr. Christian Renna have provided evidence that our health, energy and happiness are significantly affected by our personal brain balance of "warming" and "cooling" neurotransmitters (13). Dopamine, noradrenalin (norepinephrine), acetylcholine and glutamate are the major "warming" neurotransmitters (NTs), while serotonin and GABA are the chief "cooling" NTs (13). They note that "warming" NTs are dominant in the daytime, while the "cooling" counterparts predominate at night, and that "….dopamine is our principal warming neurotransmitter…"(13). A broad array of symptoms may indicate possible warming NT/DA deficiency, including weight gain, drop in energy level, apathy, difficulty concentrating, loss of interest in things that were formerly pleasurable, irritability, not wanting to get out of bed, decreased testosterone in men, depression, spaciness or forgetfulness, reduced speed of information processing and capacity for abstract thought, to name just a few (13). Lombard and Renna provide a 150 question self-test to help assess if one might be suffering a warming or cooling NT deficiency, a modest (100mg Sinemet ®) L-dopa supplement taken at breakfast might reasonably be part of a plan to restore neurological balance to the brain, since L-dopa is more specific to increasing brain DA than the L-dopa precursors phenyl-alanine and tyrosine (3).
L-Dopa : The controversy
It was announced in the American media in early 2004 that actor, Michael J Fox, who has suffered early onset PD for over a decade, recently began a "new" (for him) therapy that brought virtually miraculous relief from his ever-worsening PD. The drug was Sinemet ®. The obvious question is, why had his doctors delayed giving him the "gold standard" PD treatment (2) for so many years? The answer involves some extremely complex biochemistry and brain physiology, and is relevant to L-dopa use by those not suffering the disease.
If one looks at the vast literature on L-dopa, one finds two completely different views about L-dopa and DA. One body of scientific literature says L-dopa and DA are highly toxic to DA – using neurons, while another body of evidence pronounces L-dopa to be not only non-toxic, but claims that it will "….increase reduced glutathione (a critical intra-cellular antioxidant), protect dopamine neurons from oxidants, increase cell survival, and promote neuritic extension, or nerve growth." (2)
What could make L-dopa/DA toxic to dopaminergic neurons? L-dopa/DA both can oxidise to generate toxic free radicals, quinines, hydrogen peroxide and lipid peroxides (14). L-dopa may create excito-toxic metabolites (14). Chronic L-dopa administration may inhibit complex 1 of the mitochondrial electron transport chain, simultaneously reducing mitochondrial ATP energy production and increasing free radical/oxidant levels (15). Indeed, Parris Kidd has argued that PD is the result of "multifactorial oxidative neurodegeneration", brought about by known and unknown environmental insults (such as heavy metal or pesticide poisoning) and metabolic derangements (such as poor antioxidant status). He also argues that the naturally high levels of DA in the substantia nigra (the brain region that "melts down" in PD) plays a key role in promoting such oxidative neurodegeneration (16). It should be noted, however, that "Evidence supporting a toxic action of levodopa or DA on dopaminergic neurons arises largely from in vitro, or test-tube studies." (14).
L-Dopa : Not harmful
As mentioned previously, a large body of evidence finds L-dopa harmless or even beneficial to DA neurons. Thus, Mean et al remark: "The effects of L-dopa on dopamine (DA) neurons are quite different in vivo (living organisms) and in vitro. Whereas, relatively low levels of L-dopa are toxic in culture…, the drug has not been seen to damage DA neurons in healthy animals….or humans…" (17). "It has not been possible to demonstrate a toxic effect of chronic levodopa treatment on dopaminergic neurons of healthy rats and mice." (14) "Treatment for 120 days, (equivalent to roughly 10 human years) with maximally tolerated doses of L-dopa and carbidopa (Sinemet ®)…failed to produce biochemical, histological, or behavioural evidence of damage to the nigrostriatal dopaminergic tract in rats." (18) A 1986 case report found that a 76 year old man who was treated with Sinemet ® L-dopa over 4 years, equivalent to 8-10kg of plain L-dopa. (19). The authors concluded: "Nevertheless, this case report emphasises that the burden of proof for a cytotoxic effect of levodopa in man remains with its proponents." (19).
L-Dopa to the rescue
Many studies have actually found L-dopa to have a "neurotrophic", or health-promoting effect on DA neurons. Thus Murer and colleagues report: "Our results clearly indicate the absence of toxicity of a pharmacologically effective chronic levodopa treatment on remaining dopaminergic neurons of rats with moderate and severe 6-OHDA-induced lesions. In addition, they clearly suggest that chronic levodopa administration induced a partial recovery of remaining dopaminergic neurons in moderately lesioned rats." (14). Mena et al cultured DA neurons with cortical astrocytes (glial cells), then fed them L-dopa. "This study demonstrates that L-dopa has neurotrophic effects on DA neurons, stimulates elaboration of neuritis, and protects DA neurons from cell death." (17). Han and colleagues found that giving L-dopa or rat mesencephalon (DA neurons) cultures increased levels of the critical antioxidant glutathione. They note: "When mixed mesencephalic cultures were exposed to strong oxidant stress….a loss of viability was seen. Cultures pre-treated with L-dopa….were protected from loss of viability." (20). Uitti and co-workers studies survival data for all Olmsted county PD patients seen at the Mayo Clinic from 1964 to 1978. 61% of the 179 patients were levodopa-treated. They found that the treatment significantly lengthened life of PD patients compared to those not receiving the drug. "We believe our study provides compelling evidence in support of decreased mortality associated with the treatment in PD patients….Levodopa therapy improved survival unconditionally, in that it did not require early institution. We found no evidence for increased mortality in patients treated with levodopa, as one might expect hypothetically, on the basis of levodopa-related oxidative stress mechanisms." (21).
L-Dopa : Resolving the controversy
As Murer and colleagues note, "Evidence supporting a toxic action of levodopa or DA on dopaminergic neurons arises largely from in vitro studies." (14). More precisely, L-dopa toxicity evidence arises from one type of in vitro study – those wherein L-dopa is added to cultures containing DA neurons, but which are without glial/astrocyte cells (17, 20, 23-25). Glial/astrocyte cells are non-nerve cells that support, structurally and nutritionally, the nerve cells of the brain, retina and spinal cord (22). It is generally estimated that there are 10 times the number of glial cells than neurons in the brain. They surround nerve cells, providing mechanical support and nutritional/ antioxidant/ detoxicative/ neurotrophic services to neurons (17, 20, 26).
Mena et al. found that "In……embryonically derived glia-free (DA) neurons, …L-dopa is toxic." (17). Han and colleagues reported that "…pure neuronal cultures (without glia) were exquisitely sensitive to the toxic effects of L-dopa." (20). Michel and Hefti found both DA (formed from L-dopa in DA neurons) and 6-hydroxy DA (potentially formed through oxidation of DA) were potent neurotoxins to DA neurons (23). They also noted that "…our cultures contain a relatively small percentage of non-neuronal (glial) cells, and neurons are not embedded in a matrix of glial cells as in the living brain…." (23). Pardo and co-workers found that "…DA neurons are affected by L-dopa more severely, earlier, and with a lower concentration than non-DA cells." (24). They also reported that "…our cultures….are enriched in neurons and almost (completely) lack glia (1-2% of the total population)." (24). Walkinshaw and Waters found "…that L-dopa induced death of catecholaminergic cells in vitro with an active programme of apoptosis." (25). They also used "pure" neuronal cultures without glial cells.
Glial cells to the rescue
In contrast, many studies have used L-dopa with DA neurons combined with ("co cultured with") glial/astrocyte cells. They have uniformly found different (and positive!) effects when L-dopa is given to DA neuron/glial combinations, which is the way neurons naturally occur in the living brain (23). Thus, Mena and co-workers found that when L-dopa was added to "dopamine neuron/cortical astrocyte (glia) cultures," "L-dopa…protected against dopamine neuronal cell death and increased the number and branching of (neurite) processes." (17). Mean and colleagues reported elsewhere that "L-dopa kills dopamine neurons in culture but is the most effective drug for the treatment of Parkinson's disease, where it exhibits no clear toxicity. While glial cells surround and protect neurons in vivo, neurons are usually cultured in vitro in the absence of glia. We treated fetal mid brain rat neurons with L-dopa mesencephalic glia conditioned medium ….Mesencephalic glia therefore produced soluble factors which are neurotrophic for dopamine neurons, and which protect these neurons from the toxic effects of L-dopa." (27). Han et al. found that "…a mild oxidative stress (generated by L-dopa) is tolerated by primary cultures of rat fetal mesencephalon (which contain both DA neurons and glial cells)….Therefore, it appears that (pure) neuronal cultures do not respond (to L-dopa) in the same way as mixed cultures, which are comprised of both neuronal and glial cells." (20). Desagher and co-workers observed that the "…neurotoxic effect of H2O2 (Hydrogen peroxide) on neurons co-cultured with astrocytes was strongly attenuated compared with that observed on a pure population of neurons…" (26). H2O2 is a neurotoxin generated from L-dopa/DA metabolism, which may be primarily responsible for the L-dopa toxicity observed in pure (without glial cells) neuronal cultures (17, 20).
Thus, the L-dopa controversy is clearly resolved. L-dopa (and its products, DA and 6-Hydroxy DA) toxicity is an artefact. An "artefact" is an artificially produced result, "…any structure of feature produced by the technique used and not occurring naturally." (28). The studies showing L-dopa toxicity required a specific technique: adding L-dopa (or DA/6-hydroxy DA) to neurons without glial cells. Yet in the living brain, DA neurons are naturally surrounded by glial cells, and the number of glial cells surrounding DA neurons actually increases in Parkinson's disease, in an effort to protect the remaining neurons (17). The L-dopa toxicity studies are classic artefacts, and thus of little or no "real world" significance.
The reader is also referred back to the various studies of L-dopa in living animals and humans summarised in the section headed "L-dopa : not harmful" earlier in this article. These in vivo studies, where L-dopa interacts with DA neurons in living brains naturally "conditioned by glia", also found not only no harm, but clear evidence of benefits to DA neurons from L-dopa.
L-Dopa neuroprotection
Although the "pure culture" L-dopa toxicity studies do not have direct application to what does on in the brain, they still have produced some interesting and potentially useful information. Although L-dopa was found toxic to DA neurons without glial protectors in these studies, it was typically found that various nutrients and pharmaceuticals could provide partial or even total protection against "L-dopa toxicity". Thus, Han and co-workers observed that pure DA neuronal cultures were protected from L-dopa toxicity by ascorbate (Vitamin C) (20). Pardo and colleagues also reported, "In the human neuroblastoma cell line NB69, we have previously shown that co-treatment with AA (ascorbic acid) and Deprenyl, totally protected against L-dopa toxicity". (24). Walkinshaw and Waters found that catecholaminergic PC12 cell death induced by L-dopa in glial-free culture was reduced 67% by co-treatment with vitamin E, 99% by vitamin C and 99.5% by reduced glutathione (25). Mena et al. found that both reduced glutathione, and NAC (N-Acetylcysteine), which induces intracellular glutathione production and is a direct antioxidant as well, provided major protection against L-dopa toxicity in glial free DA neuron cultures (17). Levites and colleagues discovered that the green tea polyphenol epigallocatechin-3-gallate (EGCG) provided almost total neuroprotection from 6-hydroxyDA toxicity in neuroblastoma cells (29). What these reports indicate is that any potential toxicity that might, in a worst-case scenario, somehow occur from use of L-dopa, can be prevented by appropriate nutrients and pharmaceuticals.
L-Dopa and mitochondrial activity
One problem that has been shown to be triggered by L-dopa in living rat brain is a diminution of complex 1 activity in the cerebral mitochondrial electron transport chain. This mitochondrial activity involves transferring electrons from complex 1 enzymes through complex 5 enzymes sequentially, to generate ATP energy (15). Przedborski and co-workers did find a drop in complex 1 enzyme activity after feeding test rats L-dopa at doses equivalent to human Parkinson patient doses (15). However, they also found that "Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex 1". (15). They also observed that "Various inhibitors of monoamine oxidase also prevented the effect of dopamine". (15). Of course, deprenyl is a well-known inhibitor of monoamine oxidase metabolism of dopamine (30). Shults and colleagues reported that "The activities of complex 1 and complex 2/3 in platelet mitochondria are reduced in patients with early, untreated Parkinson's disease. Co-enzyme Q10 is the electron acceptor for complex 1 and complex 2. We found that the level of Co-enzyme Q10 was significantly lower in mitochondria from Parkinsonian patients that in mitochondria from age and set-matched control subjects and that the activities of complex 1 and complex 2/3 were significantly correlated". (31) In a later clinical study, Shults and colleagues discovered that CoQ10 supplements could successfully "slow the progressive deterioration of function" in Parkinson's disease compared to placebo, with the greatest benefit coming from the highest dose (1200mg/day) (32). Thus, supplements of Vitamin C, deprenyl and CoQ10 can presumably combat any potential diminution of complex 1 mitochondrial activity that L-dopa might otherwise induce.
L-Dopa plus deprenyl: The controversy
Because L-deprenyl was known to reduce MAO-B activity, and MAO-B creates various toxins from metabolising dopamine, deprenyl was routinely combined with L-dopa in treating Parkinson's disease (PD) patients during the 1980's up to 1995. Then in 1995, A.J. Lees et al. on behalf of the UK-PD Research Group published a "bombshell" paper on L-dopa/deprenyl use in PD patients (33). The Research Group followed 520 PD patients for 5-6 years. Several hundred patients initially received 375mg L-dopa plus a peripheral decarboxylase inhibitor (PDI) daily, while several hundred others received 375mg L-dopa plus PDI along with 10 mg L-deprenyl daily. After 5-6 years, the mortality rate in the L-dopa/deprenyl group was 60% higher than in the L-dopa only group. The study authors therefore recommended that deprenyl not be used in PD treatment, with an implication being drawn by many life extension/deprenyl "enthusiasts" that L-dopa and deprenyl should not be combined in any context, not just in PD treatment.
L-Dopa/ deprenyl : The other side
The UK-PD study is the only one ever to find increased mortality with deprenyl use in PD, and the study has been severely criticised on various methodological grounds by various PD experts. In response to the study, the British Medical Journal published 7 letters in 1996 criticising the study on various methodological, statistical and comparative grounds (34). A 1996 Annals of Neurology article by 4 PD experts provided a detailed analysis of the Lees' UK-PD Group study, raising many questions and criticisms. One key criticism is that the UK-PD study was open label (not blinded), and patients could be withdrawn from their treatment group and changed to other treatments (e.g. Parlodel) during the study. 52% of the L-dopa group and 45% of the L-dopa/deprenyl group changed treatment during the study, yet the allocation of end points (death) was based on patients' original drug assignment, regardless of which drugs the patient was actually taking at the time of death! (This is called an "intent to treat" analysis). When the death rate was compared by Olanow and colleagues only between those remaining on their original drug assignment, there was no statistically significant difference in mortality between the L-dopa and L-dopa/deprenyl groups (35).
Another criticism raised was that a large number of other studies using deprenyl in PD, many combined with L-dopa, failed to find any difference in mortality between deprenyl groups and control groups (36). Olanow and colleagues also pointed out a glaring difference between the Lees study and other L-dopa with or without L-deprenyl PD studies. The death rate was 200-400% higher in both L-dopa only and L-dopa/deprenyl patients in the Lees study compared to that found in a meta-analysis of 5 previous studies, indicating that something odd was going on in the Lees study, irrespective of deprenyluse or not (35). Clinicians D. MacMahon and R. Bland also pointed out that the deprenyl therapy dose needs to be individually titrated, not just given at one (somewhat high) uniform dose, for maximum benefit and safety. They recounted that a quarter of their patients took less than the 10mg dose, with one elderly gentleman finding a mere 1.25mg deprenyl average daily dose (from taking one half 5mg tablet every other day) as his optimal dose (37). A further "refutation" of the Lees UK-PD study occurred in 2000. Donnan and co-workers published a study showing the results of comparing PD patients treated with L-dopa for seven years, to matched control ("comparators"). They concluded that "subjects with PD had twice the rate of mortality relative to age, and sex-matched comparators. However, those subjects who received selegiline (deprenyl) at any time in combination with co-careldopa or co-beneldopa (i.e. L-dopa plus a peripheral decarboxylase inhibitor) showed no significant difference in mortality compared with comparators". (38). This study thus indicated that the combination of L-dopa plus deprenyl cut the death rate of PD patients dramatically, equalizing (lowering) it to the death rate of age and sex-matched controls without PD and taking neither drug! That is hardly evidence of the toxicity of combined L-dopa/deprenyl treatment.
Already in 1996, Olanow and colleagues had concluded their paper reviewing the UK-PD study with the statement: "It is our opinion that the evidence in support of discontinuing selegiline (deprenyl) in levodopa treated patients, because of fears of early mortality, is not persuasive. Accordingly, we do not recommend that selegiline be withheld in PD patients based solely on the results of the UK study". (35). Given the data cited in this section, and the further detail contained in references 34-38, I can only conclude there is no good reason to avoid combining L-dopa with deprenyl. Indeed, there is positive reason to do so, given Pardo and co-workers success in completely reversing L-dopa toxicity in pure (with protective glial cells) neuroblastoma cell cultures with ascorbate plus deprenyl, in case one's own glial cells should somehow "fall down on the job" in protecting one's own DA neurons when taking supplementary L-dopa.
[Ed.- A report in the British Medical Journal, August 14, 2004 stated that "deprenyl can slow Parkinson's disease safely." They further reported that deprenyl can reduce disability and the need for L-dopa, and that the drugs were not associated with increased mortality. In 17 trials involving 3525 patients wit early Parkinson's disease, the analysis showed no significant differences in mortality, but did find that patients using deprenyl along with L-dopa had better total scores and activity of daily living. In conclusion Professor Keith Wheatley and his colleagues from the University of Birmingham concluded; "Our review provides no evidence that mortality is increased by selegiline (deprenyl) and suggests that this inexpensive drug could be one of the most clinically effective and cost-effective treatments available for early Parkinson's disease." They also believe that the 1995 study that suggested there was increased mortality was a chance finding].
L-Dopa : The form matters
From the data summarised in this paper, it is clear that L-dopa has a safe and useful place in the nutrition/pharmaceutical "life enhancement" strategy. Increasing growth hormone output, preserving healthy, vigorous and well-coordinated movement ability into old age, and gaining anti-depressant/ assertiveness/ increased goal-oriented drive benefits from the chief "warming" neurotransmitter dopamine, whose immediate precursor is L-dopa, are sound reasons for L-dopa use outside a PD content. It should be pointed out, however, that the L-dopa used in the human growth hormone studies was "plain" L-dopa, while the "gold standard" L-dopa (Sinemet ®) used in PD, and which is the most widely used form of L-dopa worldwide, is a combination of L-dopa with a peripheral decarboxylase inhibitor (PDI). The PDI prevents L-dopa from being converted to dopamine outside the brain, thereby reducing side effects (such as nausea) while simultaneously getting more L-dopa to the brain (where the PDI cannot enter). It is generally accepted that 100mg Sinemet ® L-dopa is equal to 400-500mg L-dopa alone (19). Thus 100mg Sinemet ® will approximately provide the typical 500mg L-dopa alone dose used in the human growth hormone studies. However, if the Sinemet ® used is a sustained release variety, it will need to be carefully chewed up (sublingualised) to mimic the fast release L-dopa used in the growth hormone studies. For the movement regulation benefits, as well as for the "warming" neurotransmitter benefits, the sustained-release form is preferable. To maximise the benefit/risk ratio, anyone using L-dopa/ Sinemet ® without medical supervision/monitoring, should probably restrict the dosage to 100mg daily. It is also important to note that dopamine is a stimulating neurotransmitter: Coffee works in part through stimulating dopamine release. Some people will be more sensitive to L-dopa than others. Such effects might look like those from drinking too much coffee, and may include irritability, insomnia, agitation, restlessness, etc. If this occurs, reduce dose to 50mg daily, or take it every other day. If an extreme overreaction occurs, you're dopamine hypersensitive, and its use should be discontinued.
L-Dopa : The program
In addition to taking the 100mg Sinemet ® dose daily (or less if needed), prudence suggests taking one or more of the previously mentioned L-dopa neuro-protectors: vitamin C (ascorbate), vitamin E (d-alpha plus d-gamma tocopherols), glutathione, N-acetylcysteine, CoQ10, EGCG from green tea extract, and L-deprenyl. Two recent studies have shown that a 1.25mg sublingual (buccal) form of deprenyl (selegiline) provides superior results to 10mg of swallowed "conventional" deprenyl (29, 40). There was less of a problem with the so-called "cheese effect" (intestinal MOA-A inhibition) with the 1.25mg sublingual form. There were significantly reduced levels (80% or more reduction) of the toxic deprenyl metabolites amphetamine and methamphetamine with the sublingual form. Blood levels were more stable and uniform. Patients who compared the 1.25mg buccal form to the 10mg conventional dose generally preferred the 1.25mg conventional dose generally preferred the 1.25mg form. A similar degree of MAO-B inhibition occurred with either form. Those wishing to emulate this dosing method can simply take one drop (1mg) of liquid deprenyl citrate under their tongue, (and don't wash it down the liquid immediately afterwards).
This would actually equate to an approximate 8mg conventional dosage. Taking one drop every other day would approximate 4mg conventional dose per day. Taking one drop every third day would approximately be equivalent to 2.67mg conventional dose daily. Reasonable doses for ascorbate are 250-1000mg, four times daily. Vitamin E: 100-400 IU, d-alpha tocopherol plus 100-400mg gamma tocopherol. Glutathione:1000-2000mg daily on empty stomach. N-acetylcysteine (NAC): 600-1200mg daily. CoQ10: 100-400mg daily taken with fat-containing meal. EGCG (green tea polyphenol): 100-200mg daily.
Growth hormone (HGH) release occurs maximally in the first few hours of sleep (around 10pm – 2am).
For most people, taking Sinemet ® at bedtime to release GH will probably not be a viable option, since it will probably be so stimulating they won't get to sleep. An alternative strategy for those into strength training exercises might be to take Sinemet ® (chewed up) 60-90 minutes before exercising since GH release should then peak during the exercise (e.g. weight training), amplifying any GH release/anabolic benefits from the strength training exercise.
Cotzias, G. et al (1974) "Prolongation of the life-span in mice adapted to large amounts of L-dopa" Proc Nat1 Acad Sci USA 71:2466-69.
Hauser, R and Zesiewicz, T. (1999) "Management of early Parkinson's disease" Med Clin N Am 83: 393-414.
Gibson, C. (1983) "Control of monoamine synthesis by amino acid precursors" Adv Biol Psychiat 10: 4-18.
Boyd, A. et al (1970) "Stimulation of human-growth-hormone secretion by L-dopa" New Engl J Med 283: 1425-29.
Boden, G. et al (1971) "The influence of levodopa (L-dopa) on release of anterior pituitary hormones in man" Clin Res 19:716.
Hayek, A & Crawford, J. (1972) "L-dopa and pituitary hormone secretion" J Clin Endocr 34:764-66.
Ajlouni, K. et al (1975) "Effect of glucose on the growth hormone response to L-dopa in normal and diabetic subjects" Diabetes 24:633-36.
Laurian, L. et al (1982) "Growth hormone response to L-dopa in the thinned obese" Isr J Med Sci 18:625-29.
Barbarino, A. et al "Growth hormone response to propranolol and L-dopa in obese subjects" Metabolism 27:275-78.
Greenspan, S. et al (1991) "Dopaminergic regulation of gonadotropin and thyrotropin hormone secretion is altered with age" Horm Res 36:41-46.
Marshall, J. & Berrios, N (1979) "Movement disorders of aged rats: reversal by dopamine receptor stimulation" Science 206:477-79.
Papavasiliou, P. et al (1981) "Age-related motor and catecholamine alterations in mice on levodopa supplemented diet"Life Sci 28:2945-52.
Lombard, J. & Renna, C. Balance Your Brain, Balance Your Life. Hoboken, NJ: John Wiley & Sons, Inc, 2004.
Murer, M. et al (1998) "Chronic levodopa is not toxic for remaining dopamine neurons, but instead promoted their recovery, in rats with moderate nigrostriated neurons" Ann Neurol 43:561-75.
Przedborski, S. et al (1993) "Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity" Ann Neurol 34: 715-23.
Kidd, P. (2000) "Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management" Alt Med Rev 5: 502-45.
Mena, M. et al (1997) "Neurotrophic effects of L-DOPA in postnatal midbrain dopamine neuron/cortical astrocyte cocultures" J Neurochem 69: 1398-1408.
Perry, T. et al (1984) "Nigrostriatal neurons remain undamaged in rats given high doses of L-DOPA and carbidopa chronically" J Neurochem 43: 990-93.
Quinn, N. et al (1986) "Preservation of the substantia nigra and locus coeruleus in a patient receiving levodopa (2kg) plus decarboxylase inhibitor over a four year period" Mov Disord 1: 65-68.
Han, S-K. et al (1996) "L-DOPA up-regulates glutathione and protects mesencephalic cultures against oxidative stress" J Neurochem 66: 501-10.
Uitti, R. et al (1993) "Levodopa therapy and survival in idiopathic Parkinson's disease: Olmsted County project" Neurol 43: 1918-26.
Thomas, C. ed. Taber's ® Cyclopedic Medical Dictionary. Philadelphia: F. A. David Co, 1997, 18th ed. P. 340.
Michel, P & Hefti, F (1990) "Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture" J Neurosci Res 26: 428-35.
Pardo, B. et al (1995) "Tox effects of L-DOPA on mesencephalic cell cultures: protection with antioxidants" Brain Res 682:133-43.
Walkinshaw, G. & Waters, C. (1995) "Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA" j Clin Invest 95: 2458-64.
Desagher, S. et al (1996) "Astrocytes protect neurons from hydrogen peroxide toxicity" J Neurosci 16: 2553-62.
Mena, M. et al (1996) "Glia conditioned medium protects fetal rat midbrain neurones in culture from L-DOPA toxicity" Neuroreport 7: 441-45.
29. Levites, Y. et al (2002) "Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea poly-phenol (-) – epigallocatechin 3-gallate neuroprotective action" J Biol Chem 277: 30574-80.
Thomas, C. ed. Taber's ® Cyclopedic Medical Dictionary. Philadelphia: F. A Davis Co., 1997, 18th ed. P. 156.
31. Shults, C. et al (1997) "Co-enzyme Q10 levels correlate with the activities of complexes 1 and 2/3 in mitochondria from parkinsonian and non-parkinsonian subjects" Ann Neurol 42: 261-64.
Knoll, J. (1983) "Deprenyl (selegiline): the history of its development and pharmacological action" Acta Neurol Scanda (Suppl) 95: 57-80.
Shults, C. et al (1997) "Effects of Co-Enzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline" Arch Neurol 59: 1541-50.
Lees, A. (1995) "Comparison of therapeutic effects and mortality data of levodopa and levodopa with selegiline in patients with early, mild Parkinson's disease" Br Med J 311:1602-07.
Br Med J 312: 702-05, 7 letters criticizing Lees study.
Olanow, C. et al (1996) "Selegiline and mortality in Parkinson's disease " Ann Neurol 40:841-45.
Maki-Ikola, O. et al (1996) "Other studies have not shown increased mortality" Br Med J 312:702.
MacMahon, D. & Bland, R. (1996) "Selegiline is effective and safe in early stages" Br Med J 312:703.
Donnan, P. et al (2000) "Selegiline and mortality in subjects with Parkinson's disease" Neurol 55: 1785-89.
Clarke, A. et al (2003) "A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition" J Neural Transm 110:1241-55.
Clarke, A. et al (2003) "A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition" J Neural Transm 110: 1257-71.
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In preparation of the Trance.nu Summer Dance 2.0, we have managed to catch up with some of the DJs spinning at the party to do some interviews, read the first one here!
Swedish based Mike Shiver has been impressing people with his melodic trance for quite a while now, as some of you might know he is also labelmanager of Captured Music, a sublabel of the renowned Above The Sky Recordings, and an aspiring DJ that we will here a lot about in the future, read on to find out what interesting questions Mike answered for Trance.nu!
Hello Mike! For the readers that haven't heard of you before, can you tell us a little bit about yourself?
Hi! Sure, I grew up in a place called Härnösand in Sweden (where I actually still live) with almost one thing on my mind: Music!
I started my musical career for about 1½ year ago and things have been really turning rapidly since I released my debut track "Mike Shiver – Feelings" on the very well established UK label Lost Language last summer. The track went really well and received plays from almost every world top DJ at that time, which I was very satisfied with as I didn't have much expectations on my very first track.
In December 2003 I started my own record label "Captured Music" which was initially set up to release new material from me, as well as signing upcoming artists to help bringing the scene forward a bit. Thru Captured Music I released "Sonicvibe & Mike Shiver – Lunation" in January this year which came to be a very well supported track.
Benno De Goeij (½ of Rank 1), Mat Silver & Tony Burt to mention a few.
Besides producing, my DJing has really taken off and I'm currently spinning throughout Europe as well as on various well knowned radio stations like " "Global DJ Broadcast", Digitally Imported (Di.fm) and Tranceairwaves UK.
If you haven't heard me playing near where you live, you could always catch any of my broadcast sets throughout the internet. Information about my radio show "Capturized" on Tranceairwaves UK and other radio performances as well as forthcoming gigs are easily found on my official website.
You can also read more about me and hear my productions on the site, so point your browsers to www.mikeshiver.com and enjoy the visit!
What do you like the best about being a musician?
To be doing this as my full time job and really enjoy it as I love music so much and also seeing the listeners reactions of my creations.
What do you dislike about being a musician?
To be seeing illegal downloading of your own tracks/remixes you work so hard for completing, which increases the possibilities of actually trying to make a living on it. Otherwise I see no negative aspects on being a musician so far in my musical career.
Living in Sweden, how would you describe the Trance scene in Scandinavia at the moment, and what are your expectations for the future?
The scene is really growing as far as I've noticed, especially in Sweden. I've been playing a couple of times now for the Swedish crowd which really seems to be enjoying the type of music I play, which is melodic, uplifting and vocal rance mixed with some harder tech trance as well.
Big trance parties are now more often arranged were they bring over the biggest trance artists/DJ's such as Armin Van Buuren, Ferry Corsten, Paul Van Dyk, Marco V, Paul Oakenfold, DJ Tiesto among all others which I believe is very good for developing the Swedish scene, and I hope that it will continue growing!
I've been playing twice in Finland as well which gave me a pretty good average look with well educated audience which really enjoyed my sets.
So all in all I think the Scandinavian scene is still growing, but mostly I think Sweden is the number one in Scandinavia atm if you relate to the parties arranged, and Finland close to our heels with their lovely producers and DJ's such as Super8, Magellan Project / Avanto, Cosmicman, Orkidea, Miika Kuisma and Faraway Project!
Hehe…you Dutch people !!!!! Can u never leave the Swedish girls alone?
Well….OK!! Ill tell you what I think!
I think the Swedish girls are the most gorgeous girls on earth!
What are your expectations for the trance scene in general, do you expect it to continue relying on names like Tiesto, Armin, Paul van Dyk and Ferry Corsten, or do you think it will take a different turn?
I don't know actually what to expect, but I do believe the up comers will find a way up there to help the scene grow even more and make it wider.
You see a lot of upcoming DJ's / artists already now going strong like for example Markus Shultz, Perry O Neil, Menno De Jong, Özgür Can, Envio, Lange, Thrillseekers, Ronski Speed, Airbase, John Askew, Filo & Peri, Goldenscan and Signum to be naming some of them.
So I guess we just have to wait and see what the time will bring!
But to be honest, I think the scene would actually need the up comers cause most big parties today have too less variation in the choice of DJ's.
What is the best party you have ever visited yourself as a guest, and why?
The best party I've ever visited was actually the Monday Bar Summer Cruise with Armin Van Buuren, Markus Shultz, Tall Paul and Özgur Can.
Monday bar held the party together with Ministry Of Sound and the night turned out wonderfully with loads of great music as well as many people showing up!
What would you say is the most memorable moment of your career so far?
My actual first foreign gig that was held in Berne, Switzerland at DJ Mind-X's famous "Club Gate One". The place and the audience were really nice and fun to be performing for. I was also well treated by the Gate One crew which ill never forget! Big ups to you guys!
You are currently running the quality trance label Captured Music, how did you get into doing that, and how have your experiences with it been so far?
As I mentioned earlier, I decided to start an own label with two of my best friends Johan Bergström and Andreas Hjorth. I got in contact with Tony Burt, the owner of the UK based Above The Sky Records, which is actually the London's biggest online vinyl record shop as well as one of the best labels in London in my opinion.
After speaking to Tony about my ideas for this label, he simply offered me to come over to London in October 2003 with Johan and Andreas at his offices to have a real discussion about might setting Captured Music up as a subdivision of his Above The Sky label.
So after a weekend spent in England, learning to know Tony in person whom I need to mention is a very nice fellow, we finally decided to join forces with him, and put the idea into reality.
The label has really helped me further into the scene, making contacts with other labels, DJ's and most of all…producers.
How do you tackle the production of a song, and what sort of equipment do you use?
Usually a melody comes up in my mind which I try to write down and there from I work around it and make a chorus for it. After creating the chorus I start working with tweaking the right sounds and melodies that should compose the actual main part of the track.
To produce my track I use hardware synthesizers with an ordinary midi sequenser to control the synthesizers.
You will be playing at the Trance.nu Summer Dance Event 2.0 in September… excited about it?
I'm very excited about it as it actually is my Dutch debut as well as I'm really excited to meet all the producers and DJ's who will be there as well as meeting the Dutch crowd!!!
Lets say you are rocking a crowd of thousands, people are going mad to your music, and the party is nearing its ending, what track would you close with?
Hard to say, but it would definitely be a track that really stands close to my heart I believe. It all kind of depends on which tracks I've played previously during the set and what kind of music the crowd seems to be enjoying best as well.
Are there any exciting things coming up in your music career? Anything we need to keep an eye out for?
Madeira – Is a new solo melodic project I've created for a forthcoming release later this autumn on a newly established UK label called Motion Recordings. The first track for this project will be called "Solaris" and will include a remix from the hot UK duo "Smith & Pledger" on the flip. To be reading more about this release, go to www.motion-musicuk.com , samples of this track will soon be found on www.mikeshiver.com as well.
Brock Colee – Newly started harder styled project with some tribal influences together with my label colleague Andreas Hjorth which actually will be debuted with a Brock Colee Remix of Mat Silver & Tony Burt – Waimea along with a Mike Shiver Remix on Above The Sky Records. More productions of this duo project are in sight!
A.M. – Is a collaboration between me and Ashkan Fardost pka. Envio. The debut single will be released on Alphazone's "Skywarp Records" and its due for September / October. The track feature vocals from the very talented singer "Tiff Lacey" which recently performed for ATB's latest single "Marrakesh" on Kontor Records in Germany. Tiff has also been responsible for great vocal work of Paul Oakenfold – Hypnotized, Red Square – In Your Hands and Neo & Farina – The Eternal.
"Sun Decade – Follow You [Euphonic Records].
The first track will be named "Catching Sun – Sumatra" .
More info is to be announced very soon.
Besides the side projects above mentioned, I'm also working on the long awaited follow up to the very successful "Mike Shiver – Feelings".
The track will hopefully see a release later this year as "Mike Shiver – On The Surface". I expect finishing this track in about 1 month from now.
Also worth mentioning is that I'm making a follow up with Daniel Grigore pka as Sonicvibe to our first release we had on Captured Music (Soncvibe & Mike Shiver – Lunation). This track will be entitled "Sonicvibe & Mike Shiver - Synodic Month" and will probably see a release on Captured Music early 2005 if everything goes like planned.
Our track has been co-written with The absolutely gorgeous UK leading singer Carrie Skipper who previously written Smith & Pledger – Forever on Anjunabeats earlier this year among others.
"Mike Shiver Mix" and "Elevation Mix "where the Mike Shiver Mix shows the uplifting side of the record, while the Elevation Mix goes a lot deeper and proggy.
Expect this release in a short future as Captured Music's 004 release, is ready to keep your feet's moving.
Finally rounding things of with keeping you updated on my remix works.
What are your aims/goals as a DJ and as a producer?
To be developing my skills as a producer and DJ as well as keeping all the listeners out there enjoyed with new material!
What do you think it takes to become a good DJ/Producer nowadays, any hot tips for the talented people out there?
You have to keep your head high no matter what, and never give up if you want to reach your goals! What I always try to keep in mind is also to just be yourself and keep a "down to earth"- profile no matter where the future takes you.
And to finish off the interview… what wise words can you leave us with?
I'm not really a person with a lot of wise words on stock, but I really want to take the opportunity to say a big THANKS to everyone who has been supporting me and my label and I'm really really looking forward to take on Holland with a great big smile and hopefully contribute the Trance.nu Summer Dance event with a great show!
I'm counting to see all of you there! Already longing!
Thanks for taking the time to answer our questions, see you at the Trance.nu Summer Dance 2.0!
Thanks for inviting me! See you all there!


one piece episode 850: i'll be back! luffy, deadly departure! by : After huge explosion came from Pedro's Suicide Perospero's Devil Fruit ability was melted, The explosion make Carrot shocked cause Pedro sacrifies himself to escape Straw Hat crew from hard candy and finally the Sunny escape through the Coup de Burst. But Katakuri is still on the ship, and Luffy is having a hard time holding him back. and bring him into MirrorWorld. The two men started to battle again, but the result is the same the former. Luffy can't really hit Katakuri with his Gomu Gomu Gattling. He is still puzzled on why Haki is not working against Katakuri's body. So he made a decision that will put himself in danger: he will leave the crew to let them escape. First, he made a Gomu Gomu Elephant Gun, not to hit Katakuri, but to hold and restrain him. It is effective and can stop Katakuri from escaping his attack. He then made a brief promise to his crew that he will come back and that he's leaving everything to them before throwing himself and Katakuri in the Mirror World. With this, a battle will begin.
One Piece Episode 208: The Foxy Pirate Crew and the Davy Back!


text:
Meet The Word-Based Battle Royale You Never Knew You Needed
in Gaming News
Although the world of battle royale games tends to be dominated by big titles like Fortnite or COD: Warzone, that hasn't stopped smaller games from popping up with offbeat, genre-mashing takes on the format. New game Babble Royale might just have one of the most unique interpretations of the genre, mashing up wordplay games with the fast-paced and competitive nature of battle royale. As the game's tagline says, it's "words with enemies."
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Babble Royale borrows a lot of the design elements popularised in games like PUBG and Fortnite, with players parachuting into the game map, and having to stay within an ever-contracting ring of death. The big difference, however, is that Babble Royale's map is essentially a Scrabble board, with players having to spell out words to move across the board and attack their enemies.
The game supports 16 players on one map, with the eventual winner taking home the honor of having the "last word." Players can choose to either lean into pure word-making play, or stick to short words and dominate the game board tactically. Like more conventional battle royales, Babble Royale also offers loot and power-ups that can be collected cross the map, as well as an in-game currency that can be used to level up.
If this fast-paced and cutthroat version of Scrabble sounds like your kind of battle royale, you can check out the game now, for free. Developer Everybody House Games is currently running an early access Season Zero, with the aim of gathering plenty of player feedback to improve and evolve the unique game.
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OKLAHOMA CITY - Governor Mary Fallin vetoed "most of the revised budget bill approved by legislators in special session."
Governor Fallin said in a press release Friday evening that she kept part of the bill intact that temporarily "preserves funding for key health and human services until lawmakers return in another special session to approve long-term funding solutions."
"House Bill 1019X does not provide a long-term solution to the re-occurring budget deficits, and within three months we will come back facing an estimated $600 million shortfall," she said. "My action avoids immediate health and human services cuts and provides time for legislators to come back and approve revenue proposals that can provide a permanent fix."
She vetoed all but five of the 170 sections contained in the House Bill 1019X, that was passed by the Senate Friday morning by a vote of 29 to 14.
House Bill 1019X included $60 million worth of cuts across various state agencies while also using $23 million in Rainy Day funds, $23 million in carryover cash from last year, and $60 million through revolving money to bridge the $215 million gap. The overall plan also included a recently passed measure to raise the gross production tax ('GPT') on legacy wells.
There would have also been cuts to the three agencies that would have received $215 million from the cigarette fee, which was deemed unconstitutional by the Oklahoma Supreme Court.
Those agencies include the Department of Human Services, the Oklahoma Healthcare Authority, and the Department of Mental Health and Substance Abuse Services.
"Fallin's action keeps intact a $30 million emergency appropriation to the Department of Health, which will allow the agency to make its next payroll and be funded without cuts through the remainder of this fiscal year, which ends June 30," a press release states.
Her veto will do away with $60 million in cuts to state agencies and use $60 million from revolving funds. The use of more than half of the state's $83 million in cash reserves will be reduced because of her line-item veto.
It is unclear when Governor Fallin will call a second special session, but News 4 is being told is will be before the start of the next regular session in February.


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U2 frontman's Mercedes 450 SEL for sale at auction
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This copy of the Mercedes 450 SEL, whose interior has received an unusual "cow" theme, belongs to the frontman of the U2 group. One of the features of the car is the $ 64,925 stereo system. The car is being auctioned.
The frontman of the famous group U2 Bono decided to sell his Mercedes-Benz. The rock singer is about to auction his 1980 Mercedes-Benz 450 SEL. This Merc is a modern classic in its own right, but Bono has made several modifications that set this 450 SEL apart from all other examples of this model.
Bono, who also owns exotic cars such as the Maserati Quattroporte, bought this 450 SEL from 1980 to celebrate the release of U2's first album, Boy.
When Bono bought the car in 1980, he immediately made some changes to suit his needs. The most notable of these should be the cowhide-patterned upholstery. The car is also equipped with a very cool Alpine audio system, which includes several amplifiers and subwoofers.
The system is so powerful that Bono kept a fire extinguisher in the back of one of the seats in case it "gets too hot in the cabin." According to sources, he paid the equivalent of $ 64,925 to install the stereo. This gray 450 SEL has already traveled 262,323 kilometers and is powered by the original 6.9-liter cast-iron V8 engine with around 290 horsepower.
"The Mercedes-Benz S-Class is known for its luxurious aesthetics, and this particular car shows it like nowhere else, but if you really want to grab the attention of everyone passing by with its custom interior and sound system, this is what you need." according to the official press release of the auction at which the car is on display. "This isn't just your typical classic Mercedes from the eighties, it's a piece of modern rock music history." The car is expected to sell for around $ 20,730.
Not so long ago, AutoTimesNews wrote that one of the rare and valuable Porsche 911 2.8 RSR was put up for auction. A radical and rare Porsche 911 2.8 RSR in perfect condition with a long history is set to be auctioned by the French house Artcurial in Monaco. This is not only one of the few copies of the almost unknown version, but also one of two that were made in black and have a sporting history.
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Home » Tag » Latest News & Updates for: Cricket Australia
Latest News & Updates for: Cricket Australia
January 13, 2023 in Afghanistan
Afghanistan players express anger over Cricket Australia's decision to cancel their ODI series
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February 5, 2022 in Australia
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Running a profitable, efficient automotive service department is like dieting. There is no quick fix, and trendy "hacks" will only last so long. Your efforts need to be a way of life to remain successful, and it takes ongoing commitment from everyone involved.
That being said, there are some things you can do right now to jump start performance and get your team motivated to improve! Here are three things you can do TODAY to make a difference in your service lane.
Pull two dozen repair orders from the past few weeks and review them for missed opportunities.
Does every single repair order have a multi-point inspection entered as a line item, with a copy of findings attached?
Ensuring that a multi-point inspection is conducted every time (and communicated to the customer) is a simple way to catch sales opportunities and build relationships with your customers.
Look for customers coming in for a repair who might be due for scheduled maintenance (e.g. 30K, 60K or 90K) or a common service that their car might need at their current mileage.
If your repair order is only for their repair request, and recommendations weren't made, you might have a missed sales opportunity.
Put these repair orders aside and take a quick look at service history to see if other services may have already been performed.
Charging for shop fees helps you recoup the costs of fluids, seat covers, rags, floor mats, special tools and equipment, technology and tech subscriptions.
If you already have shop fees set up, make sure they're on every repair order (including internal work).
If you don't charge for shop fees, do some market comparisons to see what your competitors are charging. I recommend going with a % of P&L with a cap based on your market.
Should you discover missing multi-points, maintenance recommendations that should have been made, forgotten shop fees or other issues: take these repairs directly to the advisor or tech and discuss missed opportunities, along with what you'd like to see next time.
Observing the action in your service drive is a perfect opportunity for coaching. You don't need to park yourself there all day, but make an effort to spend 10 minutes or so during key times when best practices can lapse: morning drop off, during lunch and at the end of the day.
Walk around inspections for every vehicle.
Consistency in the processes you and your team have developed.
Missed opportunities for sales or relationship-building.
Opportunities to praise your team.
Making time to see your team in action will give you a glimpse into what customer experience is like in your shop, and provide great opportunities to manage your team side-by-side.
We recommend regular one-on-ones with your service advisors to offer personalized coaching and support, but you can get the ball rolling right away with a daily all-shop meeting.
Start scheduling a brief all-shop meeting before business starts for the day. Use this time to touch on work coming in that day, ask if anyone needs help with issues (that you can address after the meeting), recognize your team's accomplishments and reinforce your expectations.
Aim to wrap it up after 5 minutes, and have everyone standing throughout the meeting to keep it moving along.
These practices can help you jump start performance in your shop. But for ongoing, sustained success you'll need to examine all of your processes, focus on profitability and follow through on your goals.
If you're ready to start maximizing performance in your service department, contact me today to learn more!


The Lavandière is made to reunite people! Full of natural light, this house has a huge living room on th egorund floor. Ideal for the family and friends to gather! There are 3 bedrooms with ensuite bathroom, shower room, one laundry room and a small living room for the kids. A balcony is linking the Lavandière to the provencale.


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Home Contributing code
You are welcome to change ViSP and are invited to contribute your improvements back for the benefit of the community.
Important before submitting a contribution
Before contributing to any ViSP folder in https://github.com/lagadic/visp, the contributor must transfer the rights of the work to Inria (France) by providing a copyright transfer agreement. If you intend to do this, download the transfer form, fill it, and send us back a scan.
The work must follow the ViSP coding standards.
We also propose to the community a dedicated contrib repository https://github.com/lagadic/visp_contrib to collect modules from contributors. For contribution in this repository, the contributor don't have to transfer the rights of the work to Inria. The license associated to the contribution should be explicit.
In all cases, the contributor will be considered as the author of the contributed work, and be acknowledged for it in the release notes, web documentation, and other places that may apply (such as source code for contributed modules). Note that all contributions are individually considered for inclusion by the ViSP dev team and may be rejected. If you have any questions about making a contribution, please do not hesitate to contact us.


Again... in your nose, out your mouth.
Now, smile. The kind where your top row of teeth are visible.
Keep breathing (in your nose, out your mouth) while holding the smile... breathing out through that beautiful smile.
You should feel a substantial and palpable shift of energy. Peace, satisfaction, joy and love should be welling up from inside of you... localized in the chest area. STAY THERE.
Now, get this-- not only are you feeling better right now, you've shifted realties! Shifted. Worlds.
This is exactly how 'You Version2.0' feels-- the you that already has the freedom, the success, the fame, the new car, the happy marriage, the vacations, the healthy baby, the sprawling estate, the penthouse loft, the racks on racks, etc.
You are feeling exactly how she feels, right here, right now! You're already everything you want to be, living all of the experiences you want to experience and the only proof you need is the good feels you're feeling right now. Every time you feel it, you shift. Stay there. It's the bridge to 'You Version2.0'.
p.s. the more you rest in the good feels, the faster your outer reality will change, dissolving long standing issues and reflecting circumstances that'll cause you to smile even bigger. Choose the good feels (the new reality), in every moment, no matter the circumstances. That's the key.
And when you lose it (and you will, repeatedly), go right back to it. Return your attention to the good feels that are always there, waiting for you to stop overlooking them (it's actually a reflection of who you really are at a deeper level). They're your birthright.


The User Engagement Dashboard displays information about users and resources. You can see who is signed in, which applications are being used, and how often the applications are being accessed. You can create reports to track users and group activities and resources usage.
The time that displays on the User Engagement Dashboard is based on the time zone set for the browser. The dashboard updates every one minute.
The header displays the number of unique users that logged in on that day and displays a timeline that shows the number of daily login events over a seven day period. The Users Logged in Today number is surrounded by a circle that displays the percentage of users that is signed in. The Logins sliding graph displays login events during the week. Point to one of the points in the graph to see the number of logins on that day.
The Users and Groups section shows the number of user accounts and groups set up in VMware Identity Manager. The most recent users that logged in are displayed first. You can click See Full Reports to create an Audit Events report that shows the users who logged in over a range of days.
The App popularity section displays a bar graph grouped by app type of the number of times that apps were launched over a seven day period. Point to a specific day to see a tool tip showing which type of apps were being used and how many were launched on that day. The list below the graph displays the number of times the specific apps were launched. Expand the arrow on the right to select to view this information over a day, a week, a month or 12 weeks. You can click See Full Reports to create a Resource Usage report that shows app, resource type and number of users' activity over a range of time.
The App adoption section displays a bar graph that shows the percentage of people who opened the apps they are entitled to. Point to the app to see the tool tip that shows the actual number of adoptions and entitlements.
The Apps launched pie chart displays resources that have been launched as a percentage of the whole. Point to a specific section in the pie chart to see the actual number by type of resources. Expand the arrow on the right to select to view this information over a day, a week, a month or 12 weeks.
The Clients section shows the number of Identity Manager Desktops being used.


text:
import numpy
try:
    from scipy.stats import nanmean as mean
except ImportError:
    from numpy import mean

def downsample(myarr,factor,estimator=mean):
    """
    Downsample a 2D array by averaging over *factor* pixels in each axis.
    Crops upper edge if the shape is not a multiple of factor.

    This code is pure numpy and should be fast.

    keywords:
        estimator - default to mean.  You can downsample by summing or
            something else if you want a different estimator
            (e.g., downsampling error: you want to sum & divide by sqrt(n))
    """
    ys,xs = myarr.shape
    crarr = myarr[:ys-(ys % int(factor)),:xs-(xs % int(factor))]
    dsarr = estimator( numpy.concatenate([[crarr[i::factor,j::factor]
        for i in range(factor)]
        for j in range(factor)]), axis=0)
    return dsarr

def downsample_cube(myarr,factor,ignoredim=0):
    """
    Downsample a 3D array by averaging over *factor* pixels on the last two
    axes.
    """
    if ignoredim > 0: myarr = myarr.swapaxes(0,ignoredim)
    zs,ys,xs = myarr.shape
    crarr = myarr[:,:ys-(ys % int(factor)),:xs-(xs % int(factor))]
    dsarr = mean(numpy.concatenate([[crarr[:,i::factor,j::factor]
        for i in range(factor)]
        for j in range(factor)]), axis=0)
    if ignoredim > 0: dsarr = dsarr.swapaxes(0,ignoredim)
    return dsarr

def downsample_1d(myarr,factor,estimator=mean):
    """
    Downsample a 1D array by averaging over *factor* pixels.
    Crops right side if the shape is not a multiple of factor.

    This code is pure numpy and should be fast.

    keywords:
        estimator - default to mean.  You can downsample by summing or
            something else if you want a different estimator
            (e.g., downsampling error: you want to sum & divide by sqrt(n))
    """
    xs = myarr.shape
    crarr = myarr[:xs-(xs % int(factor))]
    dsarr = estimator( numpy.concatenate([[crarr[i::factor]
        for i in range(factor)] ]),axis=0)
    return dsarr