Prospectively surveying health-related quality of life and symptom relief in a lot-based sample of medical cannabis-using patients in urban Washington State reveals managed chronic illness and debility.

OBJECTIVES: To characterize health-related quality of life (HRQoL) in medical cannabis patients. METHODS: Short Form 36 (SF-36) Physical Health Component Score and Mental Health Component Score (MCS) surveys as well has CDC (Centers for Disease Control) HRQoL-14 surveys were completed by 37 qualified patients. RESULTS: Mean SF-36 PCS and MCS, normalized at 50, were 37.4 and 44.2, respectively. Eighty percent of participants reported activity/functional limitations secondary to impairments or health problems. Patients reported using medical cannabis to treat a wide array of symptoms across multiple body systems with relief ratings consistently in the 7-10/10 range. CONCLUSION: The HRQoL results in this sample of medical cannabis-using patients are comparable with published norms in other chronically ill populations. Data presented provide insight into medical cannabis-using patients' self-rated health, HRQoL, disease incidences, and cannabis-related symptom relief.

Making the most of Papua New Guinea's biodiversity: Establishment of an integrated set of programs that link botanical survey with pharmacological assessment in "The Land of the Unexpected"

An integrated and coordinated set of programs has been established to meet ICBG goals in Papua New Guinea (PNG). Here we give an overview of the PNG ICBG and focus on the key elements and major steps taken to establish a program necessary for the pharmacological assessment of botanicals and traditional medicines in PNG and, by extrapolation, in other developing countries.

Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

BACKGROUND: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP. METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. RESULTS AND CONCLUSIONS: 1. Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine) and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). 2. Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic (EDX) features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U).

Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

BACKGROUND: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy and skin biopsy for the assessment of polyneuropathy. METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. RESULTS AND CONCLUSIONS: 1. Autonomic testing may be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). 2. Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). 3. Skin biopsy is a validated technique for determining intraepidermal nerve fiber (IENF) density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy.

Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation.

BACKGROUND: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP. METHODS: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. RESULTS AND RECOMMENDATIONS: 1) Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). 2) Genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U).

Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation.

BACKGROUND: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy. METHODS: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. RESULTS AND RECOMMENDATIONS: 1) Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). 2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). 3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy.

Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review).

Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP. A literature review using MEDLINE, EMBASE, Science Citation Index, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. (1) Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B(12) with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). (2) Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic (EDX) features and should focus on the most common abnormalities, which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U).

Evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review).

Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy. A literature review using MEDLINE, EMBASE, Science Citation Index, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. (1) Autonomic testing may be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). (2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). (3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber (IENF) density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy.

Late-onset hereditary axonal neuropathies.

BACKGROUND: Hereditary motor-sensory neuropathy or the Charcot-Marie-Tooth syndrome is known to represent considerable genetic heterogeneity. Onset is usually in childhood, adolescence, or young adulthood. The objective of this study was to define late-onset forms of the disorder. METHODS: A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting. RESULTS: Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35-85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative. CONCLUSIONS: There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.

A4V superoxide dismutase mutation in apparently sporadic ALS resembling neuralgic amyotrophy.

We report a case of apparently sporadic amyotrophic lateral sclerosis (ALS) in a young pregnant woman presenting subacutely with severe left shoulder pain followed by progressive weakness and wasting of the left arm, mimicking neuralgic amyotrophy. She was later found electrophysiologically to have widespread denervation involving more than just the arm and an alanine for valine substitution in codon 4 (A4V) in the gene for Cu/Zn superoxide dismutase 1 (SOD1). Her case illustrates that pain on initial presentation, though uncommon, does not exclude a diagnosis of ALS.

Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.

Distal symmetrical polyneuropathy: definition for clinical research.

The objective of this report was to develop a case definition of "distal symmetrical polyneuropathy" to standardize and facilitate clinical research and epidemiological studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetrical polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiological studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach for defining distal symmetrical polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiological research studies will ensure greater consistency of case selection.

Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.

Charcot-Marie-Tooth Hereditary Neuropathy is a heterogeneous syndrome associated with mutations in several different genes including peripheral myelin protein 22, myelin P0, connexin 32, and early growth response 2. There is considerable variability in the phenotypic expression of this syndrome and the relationship of this variability to mutation genotypes requires extensive analysis. Here we describe the phenotypes and genotypes of four new mutations underlying the Charcot-Marie-Tooth syndrome and document segregation with disease. Four families with Charcot-Marie-Tooth were ascertained, examined, and evaluated electrophysiologically. Each family had peripheral blood DNA screened for mutations in myelin protein 22, myelin P0, and connexin 32. Two families were found with new mutations in the myelin P0 gene: S140T in the extracellular domain and K236del in the cytoplasmic domain. All families showed segregation of the mutations with the Charcot-Marie-Tooth phenotype as did a new family with the rare G163R mutation in the membrane domain. A 49-year-old man with the S140T mutation demonstrated conduction block on electrophysiological testing. A family with a novel S49P mutation in the connexin 32 gene had a neuropathy with very slow nerve conduction. These new mutations in the myelin P0 and connexin 32 genes help to clarify the pathophysiology of the clinical Charcot-Marie-Tooth syndrome. The S140T mutation in myelin P0 can be associated with conduction block and Charcot-Marie-Tooth should be part of the differential diagnosis of that phenomenon. Mutations in the cytoplasmic domain of myelin P0 can cause clinical neuropathy. The S49P mutation in the connexin 32 gene can produce aspects of a demyelinating type of X-linked hereditary neuropathy.

Immobilized artificial membrane chromatography with mass spectrometric detection: a rapid method for screening drug-membrane interactions.

A high-performance liquid chromatography (HPLC)/electrospray ionization mass spectrometry method for measuring drug-membrane interactions was developed using immobilized artificial membrane (IAM) fast-screening mini-columns. The HPLC mobile phase consisted of phosphate-buffered saline (i.e., 5.0 mM phosphate buffer at pH 7.4, 1.35 mM KCl, and 68.5 mM NaCl) and acetonitrile. This method facilitated the measurement of IAM retention time of over ten compounds in one experiment, significantly reducing analysis time compared with the earlier IAM-HPLC method. The particular electrospray source used demonstrated the ability to tolerate the high salt-containing nonvolatile buffer used for retention time measurement.

Marijuana in the management of amyotrophic lateral sclerosis.

Marijuana has been proposed as treatment for a widening spectrum of medical conditions. Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted.

Advances in the management of neuropathic pain.

Much progress has been made in the assessment and management of neuropathic pain over the past 5 years. Assessment has improved with the Neuropathic Pain Scale, a new, easily administered, diagnostic tool. Mechanistically, recent studies indicate that peripheral neuropathic pain is generated through a focal inflammatory process rather than axonal destruction. This process also appears to involve mRNA regulation of fast sodium channels, which produce ectopic discharges and are presumably responsible for pain generation. In addition the entire neuraxis undergoes neuroplastic changes as a result of peripheral nerve injury. The available clinical trial data indicate that newer antiepileptic drugs (AEDs), most notably gabapentin, are better alternatives to older medications such as carbamazepine or phenytoin in the treatment of neuropathic pain. Gabapentin is at least as good with respect to actual pain relief as the antidepressants, including amitriptyline, but has a much better safety profile with minimal drug-drug interactions and side effects. Mexiletine is a reasonable alternative agent in patients who have not had a satisfactory response to, or cannot tolerate, the AEDs or antidepressants. Long-acting opioids should be considered in patients refractory to these adjunctive agents. With the advent of the topical lidocaine patch, the first drug with an FDA-approved indication for postherpetic neuralgia, a revolutionary new agent is now available for the treatment of neuropathic pain that does not have any systemic side effects.

Health-related quality of life in peripheral neuropathy.

It is now possible for the clinician to use multidimensional measures to assess the quality of life of their patients. Some of the more widely used instruments to measure HRQOL are the Medical Outcomes Study Short Form 36, the Nottingham Health Profile, the Sickness Impact Profile, and the World Health Organization Quality of Life instrument. Potential uses of quality of life assessment tools include: (1) monitoring the health and social status of a given population, (2) evaluating health care policy, (3) conducting clinical trials, (4) assessing the effectiveness of rehabilitation services, (5) justifying the allocation of limited social and health care resources, and (6) tailoring management to the needs of the patient.

New biotransformation products of nemadectins.

Selected nemadectins (formerly LL-F28249 series) have been fed to a panel of microorganisms with the aim of generating new derivatives. In addition to products resulting from the oxidation of the terminal methyl group (C-29), a unique phosphorylated nemadectin was isolated. The phosphate group was determined to be at C-23 by HMBC between phosphorus and H-23. Milbemycin or nemadectin derivatives with natural substituents involving the 23-hydroxyl group were hitherto unknown.