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M.E. (and ICD-CFS) Articles, Research and Books 
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Research topics: General Articles and Research Overviews, Immune System Research, Viral Research, Cardiac Research, Exercise Research, Muscle Research, Metabolic Research, Neurological and Cognitive Research, Genetic Research, Neuroendocrine Research, and Miscellaneous Research.
Article topics: The Definitions of M.E., On 'fatigue', CBT, GET and the unscientific 'behavioural' paradigm of M.E., On 'stress', M.E. Outbreaks, On the Name Myalgic Encephalomyelitis, M.E. and Other Illnesses, Children with M.E., The Severity of M.E., M.E. Fatalities, Activism Articles, Articles sorted by Author, Articles sorted by Country and Historical, Political and Medical Overviews.
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Enteroviral and Post-Polio Research
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*O* PRESS RELEASE: From: The Department of Neurology ,Institute of Neurological Sciences, Glasgow University 1992, Dr Behan
Introduction
The Chronic Fatigue Syndrome (known in the United Kingdom an Myalgic Encephalomyelitis or Postviral Fatigue Syndrome) is a relapsing illness which occurs in epidemics and sporadically.It in now being recognized worldwide and is of apparent increasing prevalence. It's main clinical feature is overwhelming fatigue, made worse by exercise and cited associated with a wide variety of other symptoms including sleep disturbances, muscle aches and pains;, atypical depression, difficulties with concentration and with memory, and symptoms of gastrointestinal upset.
We, in this unit, have had a particular interest in the syndrome and have studied It over the past 15 years or more- We have been able to detect clinically a relationship between the onset of this illness and viral infection, the viral infection being most commonly with Enteroviruses. This possibility that Enteroviruses might be involved
in this disorder has long been suspected particularly because of the relationship of previous epidemics of the syndrome to that of poliomyelitis outbreaks. Recent studies have shown that patients with the syndrome may excrete enterovirus in stool, and preliminary investigations detected enterovirus specific RNA sequence. in samples
of muscle biopsies from patients in which a fifth were found to be positive using a nucleic hybridisation technique. We extended these studies using the highly sensitive polymerase chair reaction and demonstrated that it was possible to examine for low copy numbers of viral nucleic acid sequences in cells and tissues from patients. The technique was applied to muscle biopsies where 53% of patients were found to be positive and their muscle cells to contain enteroviral RNA sequences.
NEW DATA TO BE REPORTED:
We will report at the 1st International Research Conference on Chronic Fatigue Syndrome to be held at Albany, New York, 2 - 4 October 1992, our new findings relating particularly to Enteroviral infection. We have now extended our PCR data to now cover hundreds or patients together with controls and have continued to find a very significant proportion of the patients' muscle biopsies to contain enterovirus on PCR. In addition, we have used several different types of enteroviral primers and have obtained Identical result; in the patients with these primers; the control muscle biopsies from healthy subject; and patient; with other muscle diseases being entirely negative. We furthermore have isolated RNA from patients and probed this with large enterovirus probes which demonstrated that full length 7.4 kilobase virus was present in these patients. Indeed, detailed studies including Northern Blot Analysis showed that the material was true virus, as did specific studies implying antibody to enterovirus as an aid to augmentation to electronmicroscopy. Furthermore, this virus was shown to be replicating normally at the level of transcription. Sequence analysis of this isolated material showed that it had 80% homology with coxsackie B viruses and 76% homology with Poliomyelitis virus, demonstrating beyond any doubt that the material was enterovirus. We were able to extend these studies; in a unique way by being able to study post mortem material from a definite case of Chronic Fatigue Syndrome who died as a result of drug overdose. This showed that Enterovirus was present in skeletal muscle in, heart muscle, but particularly was abundant in brain. Detailed studies of the brain enterovirus revealed that it was most prevalent in diencephalic particularly hypothalamic, regions.
*O* Three Babuska Clusters of Enteroviral-Associated Myalgic Encephalomyelitis by Byron Hyde MD
Although physicians associated with Nightingale have been studying both M.E. and CFS patients since 1984, it was only in 1995 that we began to include in the investigation of each new Nightingale M.E. patient, an evaluation by PCR for chronic persisting enteroviral infection. The material employed was frozen blood serum that was evaluated by the research team of the viral laboratory of Ruchill Hospital in Glasgow. These patients were re-evaluated approximately once or twice a year for a period of three years. Blood serum from control patients of similar age and sex were submitted with serum from M.E. patients. Blood from other patients with various autoimmune diseases or neurological illnesses were also submitted along with our samples. The names were changed in repeat samples. The serum received at Ruchill Hospital was divided into reserves and two blinded samples of this serum were investigated by PCR in different laboratories. Only when each sample source was found to be positive for the same enteroviral code was the serum accepted as having a specific circulating enterovirus.
Are Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Synonymous Terms? by Byron Hyde MD
Enterovirus infections have an incubation period identical to incubation periods noted in most of the M.E. epidemics, that is, of 4-6 days.
*O* The impact of persistent enteroviral infection by Dr Elizabeth Dowsett
By 1972, a distinguished group of clinicians and scientists had set out to share information, form research groups and hold national and international conferences related to the problems of ME. Following successful vaccination against the three polio viruses during the early 1960s over 60 epidemics of atypical, non paralytic polio had been recorded in the UK alone. It was obvious that (since Nature abhors a vacuum) the non polio enteroviruses were naturally filling the gap(6), and demonstrating their potential for inducing a serious neurological disease of considerable chronicity, mainly affecting school children and middle aged adults in the most important and productive years of their lives. Most of the famous London teaching hospitals were involved, at that time in investigating epidemics and in subsequent research while links were forged with international institutions in USA, Canada, Europe and Australasia, facing the same problems.
*O* Research into ME - 1988-1998 Too much PHILOSPHY and too little BASIC SCIENCE! by Dr Elizabeth Dowsett
Virology finally emerged from the dark ages of technical difficulty in which viral infection could be guessed at but seldom proved. From 1948, when tissue culture permitted some viruses to be grown, electron-microscopy enabled others to be seen and the techniques of molecular biology permitted virtually all microbes to be studied (by the amplification and identification of their genetic fragments, even if hidden in internal body organs) the sequence of events in related diseases such as poliomyelitis and ME became clear. During an outbreak of polio and ME in the 1950s, isolation of a whole range of polio and non polio enteroviruses from clinical and asymptomatic patients, indicated that there were some 69 related viruses in this group associated with a wide range of common acute and chronic infections of children and adults including paralytic poliomyelitis (mainly but not exclusively caused by polioviruses) and with acute viral meningitis, encephalitis, myocarditis, Epidemic Bornholm Disease and Hand Foot and Mouth Disease, infections of the middle ear, skin and eye, to say nothing of chronic myocarditis Juvenile onset diabetes, Myalgic encephalomyelitis and other chronic neurological and motor neurone conditions, caused by a wide range of non polio enteroviruses (Coxsackie, ECHO and enterviruses 68-71)(5). Echo 9 virus was actually isolated from patients during an outbreak of ME in Lancashire during the 1955-56 epidemic years(6.). The rediscovery of the Post-Polio Syndrome (first described in 1870) but brought to the attention of doctors in the USA by patient sufferers one hundred years later, indicated that the polio viruses could persist silently for some 25-40 years after the initial infection.
Enterovirus related metabolic myopathy: a postviral fatigue syndrome. L ane RJ, Soteriou BA, Zhang H, Archard LC.Division of Clinical Neurosciences and Psychological Medicine, Imperial College, London SW7, UK. r.lane@imperial.ac.uk
OBJECTIVE: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients. METHODS: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points. RESULTS: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus. CONCLUSIONS: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.
*O* Are echoviruses still orphans? Hill WM. Deparment of Microbiology, Basildon Hospital, Nether Mayne, England, UK.
A review of some of the outbreaks of disease caused by echoviruses demonstrates their ability to cause significant morbidity and mortality world-wide. There are now 30 recognised echovirus serotypes; several of the original serotypes have been re-classified. More recently, echovirus 22 has been shown to have significant molecular differences from other types and unusual epidemiological features. Echovirus types 7, 11, 19 and 30 have been associated with significant outbreaks in neonatal units and echovirus types 9, 16 and 25 are more frequently associated with exanthem. Echovirus type 3, although relatively uncommon in the UK, was associated with large outbreaks in China. Since the decline in poliomyelitis, the increase in reports of non-polio enteroviruses has revealed a corresponding increase in associated cases of myalgic encephalomyelitis and post-viral fatigue syndrome.
*O* Myalgic encephalomyelitis--a persistent enteroviral infection? Dowsett EG, Ramsay AM, McCartney RA, Bell EJ. Basildon Hospital, Essex, UK.
Myalgic encephalomyelitis is a common disability but frequently misinterpreted. Amongst 6,000 patients referred for general microbiological diagnosis between 1975 and 1987, 420 cases were recognized. Coxsackie B neutralization tests, in 205 of these, demonstrated significant titres in 103/205 (50%), while of 124 additionally investigated for enteroviral IgM, 38/124 (31%) were positive. This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory. Routine diagnosis, specific therapy and prevention, await further technical advances.
*O* Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Department of Biochemistry, Charing Cross and Westminster Medical School, London.
Enterovirus-specific probes have been prepared by reverse transcription of conserved sequences in purified Coxsackie B2 virus genomic RNA and molecular cloning techniques. These probes were used in quantitative slot blot hybridizations to test for the presence of enterovirus-specific RNA in skeletal muscle biopsy specimens from 96 patients who had suffered from the postviral fatigue syndrome myalgic encephalomyelitis for up to 20 years. Biopsy specimens from 20 patients were positive for the presence of virus-specific RNA with hybridization signals more than three standard deviations greater than the mean of the normal muscle controls. Biopsies from the remaining 76 patients were indistinguishable from the controls. These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that a persistent virus infection has an aetiological role.
Evidence for enteroviral persistence in humans. Galbraith DN, Nairn C, Clements GB. Journal of Genenal Virology 1997; 78(2): 307-12.
Abstract: We have sought evidence of enteroviral persistence in humans. Eight individuals with chronic fatigue syndrome (CFS) were positive for enteroviral sequences, detected by PCR in two serum samples taken at least 5 months apart. The nucleotide sequence of the 5' non-translated region (bases 174-423) was determined for each amplicon. Four individuals had virtually identical nucleotide sequences ( > 97%) in both samples. The sequence pairs also each had a unique shared pattern indicating that the virus had persisted. In one individual (HO), it was clear that there had been infection with two different enteroviruses. In the remaining three individuals, the lack of unique shared features suggested that re-infection had occurred, rather than persistence. With the exception of HO, the sequences fell into a subgroup that is related to the Coxsackie B-like viruses.
Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. Galbraith DN, Nairn C, Clements GB. Journal of General Virology 1995; 76: 1701-1707.
Abstract: This study used phylogenetic analysis based on a region of the 5' non-translated region (5'NTR) of a variety of enteroviral sequences to compare sequences associated with chronic fatigue syndrome (CFS) and those from enteroviruses causing acute infections. Direct sequencing of PCR products was used to obtain the nucleic acid sequences from CFS patients. The inferred phylogenetic tree identified three groupings, one correlating with the diagnosis of CFS. The analysis identified a close relationship between the chronic fatigue enteroviral sequences, and showed that 19/20 were distinct from previously described enteroviruses. These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences.
Enteroviral RNA sequences in muscle in patients with chronic fatigue syndrome. Gow RJ, Behan PO. British Medical Journal 1991; 302: 692-6.
Abstract: OBJECTIVE-To determine the presence of enteroviral sequences in muscle of patients with the postviral fatigue syndrome. DESIGN-Detection of sequences with the polymerase chain reaction in a well defined group of patients with the syndrome and controls over the same period. SETTING-Institute of Neurological Sciences, Glasgow. SUBJECTS-60 consecutive patients admitted to the institute with the postviral fatigue syndrome who had undergone extensive investigation to exclude other conditions. 41 controls from the same catchment area without evidence of fatigue, all undergoing routine surgery. MAIN OUTCOME MEASURES-Routine investigations, serological screen for antibodies to a range of viruses, and presence of enteroviral RNA sequences in muscle biopsy specimens. RESULTS-15 (25%) patients and 10 (24.4%) controls had important serological findings. 12 patients had neutralising antibody titres of greater than or equal to 256 to coxsackieviruses B1-5 (six positive for enteroviral RNA sequences, six negative); three were positive for Epstein-Barr virus specific IgM (two positive, one negative). Six controls had similar neutralising antibody titres to coxsackieviruses (all negative); one was positive for Epstein-Barr virus specific IgM (negative); and three had titres of complement fixing antibody greater than or equal to 256 to cytomegalovirus (all negative). Overall, significantly more patients than controls had enteroviral RNA sequences in muscle (32/60, 53% v 6/41, 15%; odds ratio 6.7, 95% confidence interval 2.4 to 18.2). This was not correlated with duration of disease, patient and age, or to raised titres of antibodies to coxsackieviruses B1-5. CONCLUSIONS-Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role.
Some long term sequelae of Coxsackie B virus. Gray JA. Journal of the Royal College of General Practitioners 1984; 34: 3-6.
Are echoviruses still orphans? Hill WM. British Journal of Biomedicine Science 1996; 53(3): 221-6.
Abstract: A review of some of the outbreaks of disease caused by echoviruses demonstrates their ability to cause significant morbidity and mortality world-wide. There are now 30 recognised echovirus serotypes; several of the original serotypes have been re-classified. More recently, echovirus 22 has been shown to have significant molecular differences from other types and unusual epidemiological features. Echovirus types 7, 11, 19 and 30 have been associated with significant outbreaks in neonatal units and echovirus types 9, 16 and 25 are more frequently associated with exanthem. Echovirus type 3, although relatively uncommon in the UK, was associated with large outbreaks in China. Since the decline in poliomyelitis, the increase in reports of non-polio enteroviruses has revealed a corresponding increase in associated cases of myalgic encephalomyelitis and post-viral fatigue syndrome.
Disturbance of hypothalamic function and evidence for persistent enteroviral infection in patients with chronic fatigue syndrome. Richardson J. Journal of Chronic Fatigue Syndrome 1995; 1(2): 59-66.
Abstract: It has been suggested that one of the major effects of persistent virus infections in the production of disorders such as the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is on the hypothalamus (1). Buspirone, which is one of the anxiolytic drugs of the azapyrone group, causes a release of prolactin by stimulation of serotonin 5-hydroxytryptamine (5-HT) receptors. The buspirone-prolactin response was studied in a subgroup of patients with CFS/ME and evidence of persistent enteroviral infection, as shown by the repeated detection of the group-specific protein of enteroviruses, VP1, in the blood. Family controls who were asymptomatic were studied at the same time. In addition to the response to buspirone, diurnal variations in cortisol and prolactin levels were studied. It was found that the patients with CFS/ME had much greater rises in prolactin levels one hour after buspirone compared to controls. Cortisol levels were elevated in the patients, but the rise was not significantly different between the two groups. There was a significant association between the pattern of sleep disturbance, which we speak of as the OWL syndrome, and the ratio of pre- and post-buspirone prolactin levels. This study shows that there is a hypothalamic disturbance in the patients who also had evidence of enteroviral infection as part of the disorder of CFS/ME. It represents a quantifiable biochemical alteration to be found in this group of patients.
Chronic enterovirus infection in patients with postviral fatigue syndrome. Yousef G, Bell E, Mann G, et al. Lancet 1988; 1: 146-50.
Abstract: 76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were no (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive from VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients.
Enteroviruses and postviral fatigue syndrome. Behan PO, Behan WM, Gow JW, Cavanagh H, Gillespie S. Ciba Foundation Symposium 1993; 173: 146-54.
Abstract: Postviral fatigue syndrome (PFS) occurs both in epidemics and sporadically. Many of the original epidemics were related to poliomyelitis outbreaks which either preceded or followed them. The core clinical symptoms are always the same: severe fatigue made worse by exercise, myalgia, night sweats, atypical depression and excessive sleep. The other common symptoms include dysequilibrium disorders and irritable bowel syndrome. We have detected enteroviral genome sequences in muscle biopsies from cases of PFS, using specific enteroviral oligonucleotide primers in the polymerase chain reaction (PCR). In addition, whole virus particles can be demonstrated in PCR-positive muscle, using solid-phase immuno-electron microscopy. An increase in the number and size of muscle mitochondria was found in 70% of PFS cases, suggesting an abnormality in metabolic function. Evidence of hypothalamic dysfunction was present, particularly involving 5-hydroxytryptamine metabolism. A putative model of PFS, based on persistent enteroviral infection in laboratory mice, revealed resolving inflammatory lesions in muscle with, however, a marked increase in the production of certain cytokines in the brain. This model may help to explain the pathogenesis of PFS.
Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome. Gow JW, Behan WM, Clements GB, Woodall C, Riding M, Behan PO. Department of Neurology, University of Glasgow.
OBJECTIVE--To determine the presence of enteroviral sequences in muscle of patients with the postviral fatigue syndrome. DESIGN--Detection of sequences with the polymerase chain reaction in a well defined group of patients with the syndrome and controls over the same period. SETTING--Institute of Neurological Sciences, Glasgow. SUBJECTS--60 consecutive patients admitted to the institute with the postviral fatigue syndrome who had undergone extensive investigation to exclude other conditions. 41 controls from the same catchment area without evidence of fatigue, all undergoing routine surgery. MAIN OUTCOME MEASURES--Routine investigations, serological screen for antibodies to a range of viruses, and presence of enteroviral RNA sequences in muscle biopsy specimens. RESULTS--15 (25%) patients and 10 (24.4%) controls had important serological findings. 12 patients had neutralising antibody titres of greater than or equal to 256 to coxsackieviruses B1-5 (six positive for enteroviral RNA sequences, six negative); three were positive for Epstein-Barr virus specific IgM (two positive, one negative). Six controls had similar neutralising antibody titres to coxsackieviruses (all negative); one was positive for Epstein-Barr virus specific IgM (negative); and three had titres of complement fixing antibody greater than or equal to 256 to cytomegalovirus (all negative). Overall, significantly more patients than controls had enteroviral RNA sequences in muscle (32/60, 53% v 6/41, 15%; odds ratio 6.7, 95% confidence interval 2.4 to 18.2). This was not correlated with duration of disease, patient and age, or to raised titres of antibodies to coxsackieviruses B1-5. CONCLUSIONS--Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role.
A study of Coxsackie B virus infections, 1972-1983. Bell EJ, McCartney RA.
The results of a twelve-year study of Coxsackie B virus (CBV) infections in patients with a variety of acute and chronic illnesses are reported. CBVs were isolated from only 123 patients most of whom were children with respiratory illness. Virus diagnosis in adults was based mainly on the detection of significant rising or static high neutralizing antibody titres. Between 1972 and 1979 most investigations centred on patients with suspected viral heart disease, 12% of whom were found to have diagnostically significant CBV titres. In studies on patients with definite myo-pericarditis the number positive increased to 33%. In 1980 clinical interest switched to the possible role of CBV in myalgic encephalomyelitis (ME), an illness of diverse symptomatology. Investigation of suspected cases of ME in 1983 showed that 16% were serologically positive compared to 4% of normal adults in the West of Scotland. In patients with well-documented ME this figure rose to 41%. The demand by clinicians for CBV neutralizing antibody tests has increased over the past twelve years and continues to escalate annually, especially in patients with chronic relapsing illness.
*O* Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. Galbraith DN, Nairn C, Clements GB. Regional Virus Laboratory, Ruchill Hospital, Glasgow, UK.
This study used phylogenetic analysis based on a region of the 5' non-translated region (5'NTR) of a variety of enteroviral sequences to compare sequences associated with chronic fatigue syndrome (CFS) and those from enteroviruses causing acute infections. Direct sequencing of PCR products was used to obtain the nucleic acid sequences from CFS patients. The inferred phylogenetic tree identified three groupings, one correlating with the diagnosis of CFS. The analysis identified a close relationship between the chronic fatigue enteroviral sequences, and showed that 19/20 were distinct from previously described enteroviruses. These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences.
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Viral Research - continued
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Page 2: Enteroviral and Post-polio Research (continued)
Page 3: Enteroviral and Post-polio Research (continued)
Page 4: HHV6 Research
Page 5: Stealth Virus Research, General Virus Research and Relevant Books
Page 1: Enteroviral and Post-polio Research
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