Experience of India's (Maharashtra) Employment Guarantee Scheme: Lessons for Development PolicyS. Antarctica, and Australia) was present in the southern hemisphere, on or near the South Pole.
Sea levels were fairly high worldwide during the Devonian (indicating that there were no glaciers). Similar red beds of Devonian age are also present in Europe, such as the Old Red Sandstone. In the Williston Basin area (South Dakota, Montana, and adjacent Canada), extensive reefs formed.
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Standardizing minimal residual disease by flow cytometry for precursor B lineage acute lymphoblastic leukemia in a developing country.
Literature from developing countries addressing therapeutic or laboratory practices related to MRD, is largely lacking.
Alcoholic neuropathy involves coasting caused by damage to nerves that results from long term excessive drinking of alcohol and is characterized by spontaneous burning pain, hyperalgesia and allodynia. She talks about how she got involved in working on the ULLMANN’S Encyclopedia, what her most memorable experience as Editor-in-Chief is, and more.
The mechanism behind alcoholic neuropathy is not well understood, but several explanations have been proposed. BCP-ALL samples (n = 42) were characterized at diagnosis to identify a suitable marker for follow-up during mid (D+21) and end of induction (D+33). These include activation of spinal cord microglia after chronic alcohol consumption, oxidative stress leading to free radical damage to nerves, activation of mGlu5 receptors in the spinal cord and activation of the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis.
Treatment is directed towards halting further damage to the peripheral nerves and restoring their normal functioning.
This can be achieved by alcohol abstinence and a nutritionally balanced diet supplemented by all B vitamins.
We hope that this data would encourage more centers in India and other resource constrained health delivery systems to develop MRD assays. However, in the setting of ongoing alcohol use, vitamin supplementation alone has not been convincingly shown to be sufficient for improvement in most patients. Numerous studies in the last two decades have now demonstrated that minimal residual disease (MRD) is an important adjunct in addition to conventional risk factors (4, 6–8).
After ingestion, alcohol distributes throughout body tissues and rapidly crosses the blood-brain barrier.
From ongoing or completed trials which are modifying therapy based on MRD risk, it would appear that MRD directed therapy will become the standard of care for ALL in the coming years (9, 10).However, literature from resource poor developing countries, which addresses therapeutic or laboratory practices related to MRD, is to the best of our knowledge lacking. It is not surprising that ethanol abuse significantly contributes to damage in a variety of tissues including liver, the central and peripheral nervous systems, and skeletal and cardiac muscle. Alcoholic peripheral neuropathy is a potentially incapacitating complication of long-term excessive consumption of alcohol characterized by pain and dysesthesias, primarily in the lower extremities, and is poorly relieved by available therapies [1–3]. Alcohol-related neuropathy is associated with several risk factors, such as malnutrition, thiamine deficiency, direct toxicity of alcohol and a family history of alcoholism [3–6], but it is not clear which of these plays a primary role in inducing neuropathy [7]. Although sensitive, PCR-based methods are labor intensive and more expensive as compared to flow cytometry (9, 11). The factors most directly associated with the development of alcoholic neuropathy include the duration and amount of total lifetime alcohol consumption. Neuropathy is more prevalent in frequent, heavy and continuous drinkers compared with more episodic drinkers [6].
New entrants in this field are left with much uncertainty about the appropriate panel, methodology, and its adaptability to their system.In this manuscript we describe our experience in establishing a flow cytometry-based MRD assay for precursor B lineage ALL (BCP-ALL) in a single tertiary referral center in southern India. Incidence of alcoholic polyneuropathy was found to be higher in women compared with men [9]. We describe in detail the methodology, expenditure, assay standardization, and validation procedures. For controls (n = 10), bone marrow (BM) samples (2 ml of heparinized BM) were obtained from patients undergoing a BM aspiration as a part of routine investigation for nonmalignant hematological disease (for example, idiopathic thrombocytopenia) or lymphoma for staging (proven to be uninvolved on bone marrow biopsy). Painful sensations with or without burning quality represent the initial and major symptom of alcoholic neuropathy [2, 4]. Additionally, patients of T-lineage ALL whose bone marrows were aspirated for end-induction morphological evaluation of residual disease were used as controls (n = 2) for studying B cell development. Under similar conditions, bone marrow samples were obtained in the patient group for establishing the diagnostic leukemia associated immunophenotype (LAIP). Progressively, the sensory and motor symptoms and signs extend proximally into the arms and legs and finally the gait may become impaired [11]. For flow cytometric evaluation of residual disease BM samples were acquired at mid (D+21) and end induction time points (D+33).
Electrophysiologic and pathologic findings mainly indicate axonal neuropathy with reduced nerve fibre densities. Densities of small myelinated fibres and unmyelinated fibres were more severely reduced than the density of large myelinated fibres, except in patients with a long history of neuropathic symptoms and marked axonal sprouting [2]. To block nonspecific binding, these cells were incubated for 5 min with 50 μl of human AB blood group positive serum. It has previously been considered in relationship to nutritional, especially thiamine, deficiencies seen in alcoholics.
Following this the cells were stained with the monoclonal antibody combinations seen in Table 1. Thiamine deficiency is closely related to chronic alcoholism and can induce neuropathy in alcoholic patients. The appropriate concentrations of these antibodies were determined by titration experiments. Ethanol diminishes thiamine absorption in the intestine, reduces hepatic stores of thiamine and affects the phosphorylation of thiamine, which converts it to its active form [12]. Following incubation for 15 min in the dark the samples were washed in PBS and acquired in a four color FACSCalibur flow cytometer (BD Biosciences, USA). In addition to thiamine deficiency, recent studies indicate a direct neurotoxic effect of ethanol or its metabolites. Axonal degeneration has been documented in rats receiving ethanol while maintaining normal thiamine status [5].
Human studies have also suggested a direct toxic effect, since a dose-dependent relationship has been observed between severity of neuropathy and total life time dose of ethanol [6, 13]. The exact mechanism behind alcoholic neuropathy is not well understood, but several explanations have been proposed. These include activation of spinal cord microglia after chronic alcohol consumption [14], activation of mGlu5 receptors in the spinal cord [15], oxidative stress leading to free radical damage to nerves, release of pro-inflammatory cytokines coupled with activation of protein kinase C [16], involvement of extracellular signal-regulated kinases (ERKs) or classical MAP kinases [10], involvement of the opioidergic [14] and hypothalamo-pituitary-adrenal system [17–19].
Some other studies have indicated that chronic alcohol intake can decrease the nociceptive threshold with increased oxidative-nitrosative stress and release of pro-inflammatory cytokines coupled with activation of protein kinase C (Figure 1) [10, 16].
Antigen expression was described as dim, intermediate or overexpressed depending upon their relation to normal counterparts based on standard recommendations (18).Diagnosis of BCP-ALLPatients were diagnosed with BCP-ALL according to the WHO 2008 criteria (3).
Therefore, alcoholic neuropathy may occur by a combination of the direct toxic effects of ethanol or its metabolites and nutritional deficiencies, including thiamine deficiency. The precise mechanisms responsible for toxicity on the peripheral nervous system, however, have not yet been clarified. The initial gates broadly selected the lymphocyte and monocyte regions based on forward and side scatter characteristics.
The demyelination is explained as the result of a slowing down (decceleration) of axoplasmic flow and a degradation of the quality of biological properties of axonal enzymes and proteins. For Tubes 1–3 multiparametric assessment of B cells was done in relationship to various antigens by looking at biaxial plots and comparing them to normal patterns as defined by the templates.
Ethanol and its toxic degradation metabolites affect neuronal metabolism including the metabolic pathways of nucleus, lysosomes, peroxisomes, endoplasmatic reticulum and cytoplasm [21].
The key role in the degradation of ethanol is played by ethanol dehydrogenase and acetaldehyde dehydrogenase-two step enzymatic systems by which ethanol is converted to acetate which is further metabolized in humans. Additionally, the relationship of CD10 positive events with other antigens was also determined. Acetaldehyde dehydrogenase is a mitochondrial enzyme which undergoes a single amino acid substitution (mutation) in about 50% of the Asian population in a way similar to the genetic changes in sickle cell anaemia [21]. For Tube 2 aberrant overexpression of CD22 in CD34 positive B cells with or without under expression of CD45 (20, 21) was determined. Thus, in alcoholics with the mutated dehydrogenase enzyme, acetaldehyde concentrations may reach values about 20 times higher than in individuals without the mutation.
A certain amount of acetaldehyde is not metabolized by the usual pathways (Figure 2) and binds irreversibly to proteins which results in the creation of cytotoxic proteins which adversely affect the function of nervous system cells. These abnormal proteins influence other cell populations especially the hepatocytes where the damage to hepatic mitochondria results in hepatic cirrhosis with reduction of energetic substrates in the liver. These individuals draw the majority of calories from calorie rich alcoholic beverages with low nutritive value.
Chronic abuse of alcohol depletes the pool of liver proteins which are consumed for energy production and insufficient intake of proteins only worsens this imbalance.
Resulting disturbances in protein and lipid metabolism lead to undernourishment which adversely influences other metabolic pathways, including those influencing the function of the nervous system.
The relationships between alcoholic neuropathy and commonly associated nutritional deficiencies, especially thiamine deficiency have been discussed in terms of the apparent clinical and pathologic presentations [24, 25]. In case two markers were abnormal for that tube for example underexpression of CD45 and overexpressed CD58, then the LAIP was 2. However it was decided that if a case did not have a useful LAIP in any of the combinations, an overlap with <50% of the normal template would be considered as useful. Although clinical manifestations varied widely between patients with either type of thiamine deficiency neuropathy, overall clinicopathologic features, including the spectrum of clinical variability, did not differ significantly by cause.
For Tubes 1 and 2, a multiparametric immunophenotype was evaluated whereas for the rest only single marker abnormalities were analyzed.


Thus, clinicopathologic features of post gastrectomy polyneuropathy with thiamine deficiency are identical to those of beriberi neuropathy, and the results further confirmed that thiamine deficiency can be a major cause of postgastrectomy polyneuropathy [27]. Serial dilutions were done to a maximum of 1:10,000 for CD45 (n = 2), CD38 (n = 2), CD123 (n = 1), CD22 (n = 1), and CD58 (n = 1). Mock dilution of leukemic cells was done (1:10,000) into normal bone marrow to establish the assay sensitivity. In both patients, the upper and lower extremities showed a rapidly progressive weakness over the course of 1 month. Muscle weakness in the first patient progressed even after admission to hospital and urinary retention, Wernicke's encephalopathy, lactic acidosis, paralytic ileus and heart failure appeared subsequently.
This analysis was limited only to the cost of the reagents and did not include additional expenses such as cost of the equipment, depreciation of the equipment, annual maintenance contract, salaries for medical and technical personnel. Clinical symptoms in both patients showed improvement after initiation of thiamine administration, although some residual deficit remained.
Clinically, sensory disturbance and weakness, especially in the distal part of the lower extremities, are common features of both alcoholic and thiamine deficiency neuropathies [24, 29].
Electrophysiologic and histopathologic findings of axonal neuropathy have also been considered as common features [2, 5, 29, 30]. Depending upon the tittered volume for each antibody and the combination per tube, expenditure involved in a 4 or 5 tube assays was generated.
These similarities have led to a belief that these two neuropathies are identical, and that polyneuropathy associated with chronic alcoholism most likely is caused by thiamine deficiency [24, 25]. On summing up these numbers the total reagent cost that occurred per MRD time point was accomplished.
Thus, the concept of alcoholic neuropathy encompasses both direct neurotoxicity of ethanol or its metabolites and the concomitant effects of nutritional status, especially thiamine deficiency.In one clinical study, aimed at studying distinct clinicopathologic features of alcoholic neuropathy, 64 patients were assessed. Combinations of these tubes were evaluated on the original dataset to minimize the panel so as to make it cost effective (Table 2). In 47 of these patients sural nerve biopsy was performed, with discrimination in terms of their thiamine status [3]. The subgroup without thiamine deficiency consisted of 36 patients, while the subgroup with thiamine deficiency consisted of 28 patients. In addition, 32 patients with nonalcoholic thiamine deficiency neuropathy were also evaluated for comparison. In 95.2% (n = 40) at least two LAIPs could be obtained, in the remaining two only a single LAIP was possible. The subgroup without thiamine deficiency, considered to be a pure form of alcoholic neuropathy, uniformly showed slowly progressive, sensory dominant symptoms. The types of aberrancies and their relative frequencies can be appreciated in Table 3, whereas the utility of each of the six tubes can be seen in Table 1.
Superficial sensation, especially nociception, was predominantly impaired and painful symptoms were the primary complaint in most patients in this group.
In contrast, the neuropathic symptoms of nonalcoholic thiamine deficiency neuropathy, considered to be identical to beriberi neuropathy [26], were variable, but typically were motor dominant and acutely progressive, affecting both superficial and deep sensation. We evaluated the utility of other markers and resulting combinations when CD45 was not contributory to the LAIP (n = 17). The histologic features of sural nerve biopsy specimens demonstrated small fibre predominant axonal loss as characteristic of the pure form of alcoholic neuropathy.Role of nutritional status other than thiamine deficiencyDeficiency of vitamins other than thiamine may also contribute to clinical features of alcoholic neuropathy.
Chronic alcoholism can alter the intake, absorption and utilization of various nutrients (nicotinic acid, vitamin B2, vitamin B6, vitamin B12, folate or vitamin E).
Deficiencies of B vitamins other than thiamine also may contribute to variation in clinical features, but characteristic symptoms of multiple vitamin deficiency were not seen in patients with thiamine deficiency neuropathies due to gastrectomy and dietary imbalance [26]. The remainder could not be obtained due to numerous reasons (not opted for treatment, institutional attrition, induction deaths, missed by investigator, or patient unwilling for an invasive procedure). These clinical features include anorexia, diarrhoea, erythematous and hyperkeratotic dermatitis, and mental changes in pellagra (nicotinic acid deficiency), cheilosis, glossitis, keratoconjunctivitis and dermatitis in vitamin B2 deficiency and myelopathy in vitamin B12 and folate deficiencies. The authors noted that Danish beer at the time of the study contained thiamine and vitamin B6. Thus, deficiency of these vitamins was felt to be unlikely in Danish beer drinkers at that time and, indeed, measured vitamin concentrations were mostly normal. The most useful tubes to establish a positive MRD were 1 (84%), 4 (56%), 5 (44%), and 2 (16%). Clinical features of neuropathies in the alcoholic and post gastrectomy patients were similar. These two groups, however, were distinct from the standpoint that nerve conduction velocities were slower and sural nerve biopsy specimens revealed more segmental demyelination in the post gastrectomy group. The upper panel (left to right) shows the initial gates based on scatter characteristics and CD19 positive events. The authors concluded that malnutrition, including low blood concentrations of B vitamins, is not a prerequisite for the development of alcoholic neuropathy, and ethanol per se plays a role in the pathogenesis of alcoholic neuropathy. The middle panel (left to right) shows normal pattern of CD45 and CD34 and a representative example of BCP-ALL (MRD-46) at diagnosis. The lower panel (left to right) shows detectable residual disease at mid (D+21) and end induction time points (D+33) for the same patient. One possible mediator of the direct neurotoxic effect of ethanol is acetaldehyde, a highly toxic metabolite of ethanol with extraordinary reactivity.
The first three tubes utilize multiparametric immunophenotyping and the rest look for single marker LAIPs in early and late developing B cells.
The mechanisms of the toxicity for liver include production of acetaldehyde-protein adduct formation, depletion of glutathione, microtubular impairment, inhibition of DNA repair, impairment of mitochondrial electron transport chain and stimulation of immunologic reactivity. Numerous groups across Europe and North America have used either of these principles and have shown that their panels can detect LAIP in ∼ 90% of BCP-ALL (Table 5).
There is evidence that acetaldehyde-protein adducts are present even in organs that do not seem to produce acetaldehyde efficiently themselves, due to lack of ADH expression [33]. Most of these have been validated to yield clinically useful information (4, 7, 15, 23, 24). In such cases, acetaldehyde may be formed by induction of the microsomal ethanol oxidizing system [34]. Given these possibilities, the mechanisms by which acetaldehyde has toxic effects on peripheral nerves may be similar to those in the liver and other organs. Dose-dependent increases in neuronal cell death were demonstrated by incubation of neuronal cell cultures with acetaldehyde-derived advanced glycation end-products (AA-AGE), and the neurotoxicity of AA-AGE is attenuated by the addition of an anti-AAAG-specific antibody [35]. These results suggest that the neurotoxicity due to accumulation of acetaldehyde may be associated with the pathogenesis of alcoholic neuropathy.Oxidative-nitrosative stress and alcoholic neuropathyOxidative stress is known to play a very important role in experimental animal models of neuropathic pain. Endoneural oxidative stress leads to nerve dysfunction in rats with chronic constriction injury [39]. A significant decrease in the activity of anti-oxidant enzymes (superoxide dismutase and catalase) and an increase in lipid peroxidation were observed in sciatic nerves of diabetic rats with established neuropathic pain [40].
ROS triggers second messengers involved in central sensitization of dorsal horn cells [41] or they activate spinal glial cells which in turn play an important role in chronic pain [42].
In our series, we found that Tube 1 was applicable to 71.4% of BCP-ALL at diagnosis and contributed maximally to the detection of MRD. Reduced glutathione is a major low molecular weight scavenger of free radicals in cytoplasm.
Depletion of glutathione increases the susceptibility of neurones to oxidative stress and hyperalgesia [43, 44].Nitric oxide is also implicated in neuropathic pain [45, 46].
It sensitizes spinal neurones and contributes to sensitization of central neurones by disinhibition [47].
Moreover, unfettered production of nitric oxide coupled with deficient superoxide dismutase leads to production of peroxynitrite, which is several times more potent than its parents in terms of tissue toxicity.
Ethanol is oxidized to acetaldehyde by cytochrome P450, which increases reactive oxygen species, with concomitant changes in redox balance [48, 49]. Rats given chronic ethanol show enhanced production of oxidative markers, such as thiobarbituric acid reactive substances, hydrogen peroxide and OH- like species [50]. Studies have suggested that chronic ethanol increases oxidative damage to proteins, lipids and DNA [51, 52]. As a part of multiparametric analysis, however, this tube was found to be applicable to 57% of our cases. CD22 when seen solely as a marker of aberrant expression seems to be of limited utility as shown by Campana et al. The amount of malondialdehyde, a lipid peroxidation product, increases in the sciatic nerves of rats fed an ethanol-containing diet, when compared with pair-fed animals. Moreover, glutathione content and glutathione peroxidase activity in this same tissue decrease in ethanol-fed vs. PKC is involved in receptor desensitization, modulating membrane structure events, regulating transcription, mediating immune responses, regulating cell growth and in learning and memory.
On doing so, the applicability of these tubes dropped, the lowest being Tube 3 indicating that at least in some of the cases under-expression of CD45 influenced the use of that tube.
Apart from above function, over-activation of epsilon form of protein kinase C (PKCε) is known to be involved in mediating neuropathic pain, such as pain induced by cancer chemotherapy (vincristine) [56] and diabetes [57]. However, it must be mentioned that the fluorochrome and antigens (CD45 instead of CD45-RA, and CD10PE instead of CD10FITC) used in Tube 3 differ from those used originally by Dworzak et al.
PKC and protein kinase A (PKA) are both known to be important in nociceptor function [57–59]. There are several studies suggesting the involvement of protein kinases in alcoholic neuropathy. Thermal hyperalgesia and mechanical allodynia were also present with decreased mechanical threshold of C-fibres. The hyperalgesia was acutely attenuated by intradermal injection of nonselective PKC or selective PKCε inhibitors injected at the site of nociceptive testing. Recently using gene expression profiling for recognizing candidate markers in BCP-ALL followed by flow cytometry, the overexpression of this antigen as compared to nonleukemic samples was seen in 50.7% of ALLs (32). Our preliminary analysis seems to suggest that this seems to be a useful marker for MRD studies.Using a very innovative approach, Pedreira et al.


It would be most interesting to analyze the normal B cell populations and phenotypic aberrations that we observed in our dataset using this technique. Moreover, phosphorylated PKC was significantly increased in the spinal cord following chronic ethanol consumption. Such an approach would allow MRD analysis at diagnosis and two follow-up time points to be done in $100–150. In gonad-intact female rats, Walsh inhibitor peptide (WIPTIDE), both a PKCε inhibitor as well as a PKA inhibitor, injected intradermally at the site of nociceptive testing after establishing alcohol induced hyperalgesia, significantly inhibited hyperalgesia. Following ovariectomy, alcohol failed to induce hyperalgesia in female rats while oestrogen replacement reinstated alcoholic neuropathy in the female rats. These costs vary from one institute to another and are only meant to be a general guideline for developing countries. The PKA inhibitor, WIPTIDE, also attenuated alcohol-induced hyperalgesia in oestrogen-replaced female rats. To the best of our knowledge, this is the first data from India on standardization of flow-based MRD for BCP-ALL. In addition, the magnitude of analgesia induced by a PKCε inhibitor was greater in female as compared with male rats. The clinical and genetic correlation for these cases is pending and data are being accrued for the same. However, in male rats, a PKCε inhibitor, but not a PKA inhibitor, attenuated alcohol-induced hyperalgesia [10]. We hope that this data would encourage more centers in India and other developing countries to develop a cost effective technique.LITERATURE CITEDTop of pageAbstractMETHODSRESULTSDISCUSSIONLITERATURE CITED1 Pui CH, Relling MV, Downing JR. Many different stimuli, including growth factors, cytokines, viral infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway. It has been recognized that spinal cord glial cells, astrocytes and microglia are activated by neuropathic pain or peripheral inflammation [42]. Furthermore, astrocytes and microglia are activated by such pain relevant substances as substance P, calcitonin-gene related peptide (CGRP), ATP and excitatory amino acids from primary afferent terminals, in addition to viruses and bacteria [67, 68]. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. Translocation of NFkβ to the nucleus has been reported to result in activation of the endogenous proteolytic enzyme system caspases [69]. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Joseph & Levine [71] suggested that activity in signaling pathways that ultimately lead to apoptosis plays a critical role in the generation of neuropathic pain, before death of sensory neurones becomes apparent. Activator and effector caspases, defining components of programmed cell death signalling pathways, also contribute to pain-related behaviour in animals with small fibre peripheral neuropathies.
Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: A Children's Oncology Group study.
The death receptor ligand, tumour necrosis factor α, and its downstream second messenger, ceramide, also produce pain-related behaviour via this mechanism. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: Results in 3184 patients of the AIEOP-BFM ALL 2000 study.
Several mGluR subtypes have been identified in the superficial dorsal horn of the spinal cord [76, 77] and on primary afferent fibres [78]. Glutamate concentrations are elevated in the superficial dorsal horn of rats after chronic ligature of the sciatic nerve [79]. Practical application of minimal residual disease assessment in childhood acute lymphoblastic leukaemia annotation.
BIOMED-I concerted action report: Flow cytometric immunophenotyping of precursor B-ALL with standardized triple-stainings. As supported by immunostaining, the membrane fraction showed that spinal mGluR5 concentrations in ethanol-treated rats were significantly increased compared with those in the control diet group. BIOMED-1 concerted action investigation of minimal residual disease in acute leukemia: International standardization and clinical evaluation. These findings support the idea that the increased number of membrane-bound mGluR5 following chronic ethanol consumption may lead to a long lasting activation of neuronal protein kinase C in the dorsal horn of the spinal cord.
This phenomenon may be responsible for the induction of the neuropathic pain like behaviour following chronic ethanol consumption.
Not only mGluRs but ionotropic glutamate (NMDA) receptors are also involved in alcoholic-induced neuropathic pain. Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. These findings suggest that chronic ethanol treatment causes the specific dysfunction of MOR. Thus, up-regulation of cPKC activity may, at least in part, be involved in MOR dysfunction (may be an increase in MOR phosphorylation) following chronic ethanol treatment. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting.
Increased activity in the sympathetic nervous system has been implicated in some forms of neuropathic pain [81, 82] and glucocorticoids have been reported to exacerbate pain in some animal models of peripheral neuropathy [83]. Moreover, they found that the hyperalgesic phenotype in rats which had undergone adrenal medullectomy by administering stress levels of epinephrine was reconstituted. A limited antibody panel can distinguish B-precursor acute lymphoblastic leukemia from normal B precursors with four color flow cytometry: Implications for residual disease detection. The critical contribution of stress hormones to the pain associated with alcohol-induced peripheral neuropathy, combined with the demonstration of stress-induced hyperalgesia, dependent on neuroendocrine stress axes [85, 86], suggests that the mechanisms described in the study of Dina et al. The combined actions of catecholamines and glucocorticoids, via their receptors on sensory neurones, demonstrate a novel mechanism by which painful alcoholic neuropathy is induced and maintained.Effects on axonal transport and cytoskeletal propertiesAxonal transport and cytoskeletal properties are impaired by ethanol exposure [4].
Since alcoholic neuropathy manifests with length-dependent axonal degeneration, the axonal transport system, which supplies essential proteins and other cellular components, may be the primary site exhibiting vulnerability to the toxicity of ethanol. Immunophenotype-defined sub-populations are common at diagnosis in childhood B-cell precursor acute lymphoblastic leukemia. Detection of residual disease in pediatric B-cell precursor acute lymphoblastic leukemia by comparative phenotype mapping: A study of five cases controlled by genetic methods.
An in vitro study of axonal transport using dorsal root ganglion-sciatic nerve preparations from the rat showed that transport was reduced following long term ethanol feeding [88]. In vivo studies using rats have demonstrated impairment of retrograde axonal transport [89, 90].
Ethanol exposure reduces neurofilament protein concentrations in primary cultured hippocampal neurones [91].
Studies using the rat spinal cord indicate that chronic ethanol exposure causes a reduction in neurofilament-associated phosphatase activity and an increase in phosphate content of neurofilament proteins [92].
An in vitro study using rat brain has demonstrated that phosphorylation of microtubule-associated proteins, which modulate the functional properties of microtubules, is altered by ethanol exposure [93]. A study using hepatoma-derived cells has shown altered integrity of proteins associated with microtubules following ethanol exposure [94].
Altered expression of neuronal protein 22, which interacts with microfilament and microtubule matrices, may also be involved in the pathogenesis of alcoholic neuropathy [95]. This can be achieved by alcohol abstinence, a nutritionally balanced diet supplemented by all B vitamins, and rehabilitation.
However, in the setting of ongoing ethanol use, vitamin supplementation alone has not been convincingly shown to be sufficient for improvement in most patients.
Painful dysesthesias associated with alcoholic neuropathy can be treated using gabapentin or amitriptyline with other over the counter pain medications, such as aspirin or acetaminophen.
A deficiency of vitamin B1 in chronic alcoholics can be due to inadequate dietary intake, reduced capacity for hepatic storage, inhibition of intestinal transport and absorption or decreased formation of the active coenzyme form. In an animal study, it has been found that chronic alcohol consumption in rats resulted in a significant depletion in thiamine diphosphate (TDP), the active coenzyme form of thiamine. Supplementation with benfotiamine significantly increased concentrations of TDP and total thiamine compared with supplementation with thiamine HCl [96]. An 8 week, randomized, multicentre, placebo-controlled, double-blind study compared the effect of benfotiamine alone with a benfotiamine complex (Milgamma-N) or placebo in 84 alcoholic patients. Parameters measured included vibration perception in the great toe, ankle and tibia, neural pain intensity, motor function and paralysis, sensory function and overall neuropathy score and clinical assessment.
Although benfotiamine therapy was superior to Milgamma-N or placebo for all parameters, results reached statistical significance only for motor function, paralysis and overall neuropathy score.
The reason for better results in the benfotiamine alone group than in the Milgamma-N group, despite the fact that the benfotiamine dosage was equivalent, is not completely understood. The authors hypothesized that vitamins B6 and B12 might have competed with the effects of vitamin B1 in the Milgamma-N group [97]. During the treatment the regression of neuropathy symptoms, other sensor and movement disorders were observed.
The evidence of positive dynamics at peripheral and segmental nerve system level was supported by neurophysiological data. Benfotiamine was found to be beneficial in patients with alcoholic polyneuropathy [98].Alpha-lipoic acidAlpha-lipoic acid, the most well-researched nutrient for peripheral neuropathy, has been used as a treatment for peripheral neuropathy in Europe for decades. Several studies examining the mechanism of alpha-lipoic acid have been conducted on streptozotocin-diabetic rats with neuropathy.
The decreases in nerve conduction velocity were significantly less in groups supplemented with acetyl-L-carnitine. Treatment with vitamin E was found to be beneficial in the treatment of patients with diabetic peripheral neuropathy [104] and neuropathic pain in streptozotocin-induced diabetic rats [105]. Recently findings from our laboratory also suggest the benefecial effects of both α-tocopherol and tocotrienol, isoforms of vitamin E, in the prevention of hyperalgesia and allodynia in rats administered ethanol for 10 weeks [55].



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