Superoxide dismutase and ALS

Superoxide dismutase and ALS

inmates than do the UK, France, Spain, Sweden, and Finland combined.13 Rates are expected to soar under new "three strikes you’re out" legislation (ra...

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inmates than do the UK, France, Spain, Sweden, and Finland combined.13 Rates are expected to soar under new "three strikes you’re out" legislation (ratified in the November, 1994, California election), which locks inmates away for life for third felony arrests. By the year 2000, California will probably house over 230000 inmates, that number requiring an additional twenty-four prisons (data from California Department of Corrections, Office of Communication, Sacramento). We are confronting the AIDS epidemic. Are we ready to confront the new epidemic of prison growth?

Jan Diamond Merrithew Memorial Hospital, Martinez, California, USA Global Programme on AIDS. WHO guidelines on HIV infection and AIDS in prisons. Geneva: World Health Organization, 1993. 2 Hammett TR, Harold L, Gross M, Epstein J. 1992 update: HIV/AIDS in correctional facilities. Washington, DC: US Department of Justice, National Institute of Justice, 1994. 3 Centers for Disease Control and Prevention. Risk behaviors for HIV transmission among intravenous drug users not in drug-treatment— United States, 1987-1989. MMWR 1990; 39: 273-76. 4 Castro K, Shansky R, Scardino V, Narkunas J, Coe J, Hammett T. HIV transmission in correctional facilities. VII International Conference on AIDS, Florence, 1991 (abstr MC 3067). 5 Horsburgh CR, Jones JQ, McArthur T, Ignacio T, Stock P. Seroconversion to HIV in prison inmates. Am J Public Health 1990; 80: 209-10. 6 Centers for Disease Control and Prevention. HIV/AIDS surveillance report; 6(1): 15; October, 1994. 7 Albert P, Eisenberg R, Hansell D, Marcus JK. National Lawyers Guild, AIDS practice manual: a legal guide. 3rd ed, 1992: 14·15-14·23. 8 Greenberg R. Voluntary HIV testing in the San Francisco county jails, an ethical dilemma. In: X International Conference on AIDS, Yokohama, 1994: PD0525 (abstr). 9 Behrendt C, Kendig N, Dambita C, Horman J, Lawlor J, Vlahov D. Voluntary testing for HIV in a prison population with a high prevalence of HIV. Am J Epidemiol 1994; 139: 918-26. 10 Andrus JK, Fleming DW, Knox C, et al. HIV testing in prisoners: is mandatory testing mandatory? Am J Public Health 1989; 79: 840-42. 11 Hoxie NG, Vergeront JM, Frisby HR, Pfiser JR, Golubjatnikov R, Davis JP. HIV seroprevalence and the acceptance of voluntary testing among newly incarcerated male prison inmates in Wisconsin. Am J Public Health 1990; 80: 1129-31. 12 Harding TW, Schaller G. WHO Global Programme on AIDS, HIV/AIDS and prisons: updating and policy review, a survey covering 56 prison systems in 31 countries. Geneva: WHO, 1992: 15-17. 13 Mauer M. Americans behind bars: the international use of incarceration 1992-1993. Washington, DC: Sentencing Project, 1994. 14 Bureau of Justice Statistics. Midyear prisoner statistics. Washington, DC: Bureau of Justice, 1994. 1

Superoxide dismutase and ALS An association between mutations in the gene for copper/zinc superoxide dismutase (SOD-1), and familial amyotrophic lateral sclerosis (FALS, motoneuron disease) was reported last year.’ A meeting in September organised by researchers from the University of Chicago, who were involved in the initial discovery, offered the opportunity to assess subsequent developments. The aims were to assess progress in ascertainment of SOD-1 mutations in FALS families, to determine the relation between SOD-1 mutations and the mechanism of neuronal death in FALS, to discuss the role of free radical toxicity in ALS, and to look forward to the potential treatment approaches raised by these findings. The initial report of SOD-1 mutations was based on large ALS families who were participating in genetic linkage studies. Smaller families were then investigated, and 23 different mutations, in 17 codons of the SOD-1 gene, have now been reported.2-8 Mutations have also

been found in apparently sporadic cases of ALS, but further investigation usually revealed a previously unknown family history. Consequently the prevalence of SOD-1 mutations in sporadic ALS is thought to be very small. As more families have been studied, the frequency of mutations of SOD-1 in FALS has declined from about 50%, to around 15-20%.9 FALS accounts for about 5-10% of all ALS, so these mutations are found in less than 2% of all patients with ALS. We do not know whether these patients with FALS have the same disease mechanism as those with the nonfamilial disorders but individuals with SOD-1 mutations cannot be distinguished clinically from those without mutations. An autosomal recessive juvenile onset type of FALS has been linked to a region on chromosome 2,’ and the genetic causes in the remaining 80% of FALS have yet to be elucidated."11 Discovery of SOD-1 mutations has led to a flurry of research into the potential involvement of free radicals in the pathogenesis of ALS. Results accumulated over 20 years have implicated free radicals in many diseases, including other neurodegenerative conditions such as Parkinson’s disease.’2 Copper/zinc SOD is an intracellular enzyme that is present throughout the body but with a differential tissue expression. SOD activity has been studied in erythrocytes and cerebral cortex in ALS," and a reduction of around 50% has been reported in affected members of some families. 14 One suggestion was that replacement of SOD might be curative. However, those with longstanding experience in SOD biochemistry have reservations about some of the techniques and conclusions-for example, the assay might merely be measuring protein instability, which is not important in vivo. Transgenic mice expressing human SOD with the mutations found in FALS have now been produced in several laboratories.9 Some of these mice develop a progressive disease with features of both flaccidity and spasticity. Pathologically there is clear lower motor neuron degeneration, but whether the mouse disorder is a true model of human ALS remains to be determined. Some mice that have developed the disease have normal SOD activity but a striking increase in mutant SOD protein. So, is FALS due to reduced SOD activity, with consequent free-radical-mediated damage to neurons, or to an altered or toxic function of the mutated SOD protein? Some human FALS SOD-1 mutations also seem to have normal SOD activity. 15 Since there is a subtle interrelation between the various enzymes involved in free radical biochemistry-including SOD (SOD-2, mitochondrial SOD), manganese extracellular SOD (SOD-3), glutathione peroxidase, and catalase-correction of a presumed SOD deficiency may not achieve the expected biochemical effect. Moreover, if there is no physiological deficiency of SOD activity, supplementation of SOD may exacerbate the disease through free-radical mechanisms. There are difficulties with the administration of the currently available bovine SOD, and pharmaceutical companies are developing other agents with similar function. Treatment of the specific group of FALS patients with the SOD-1 mutation is complex. Therapy should probably begin before the onset of disease, but within a family the onset may vary widely-eg, from age 20 years to 80 years. Some affected individuals may have a normal life without ever manifesting the disease. Animal models pave the way for


testing various pharmacological agents, including gene therapy strategies. Because of the uncertainty about the functional implications of the SOD-1 gene mutation, there is no consensus as to whether an individual with a SOD-1 mutation should be given SOD supplements or any other specific treatment. Richard W Orrell,

Jacqueline S deBelleroche

Academic Unit of Neuroscience and Department of Biochemistry, Charing Cross and Westminster Medical School, London, UK 1

Rosen DR,


Deng H, Hentati A, Tainer JA, et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 1993; 261:


Matsubara Y, Narisawa K, et al. Mild ALS in Japan associated with novel SOD mutation. Nature Genet 1993; 5: 323-24. Elshafey A, Lanyon WG, Connor JM. Identification of a new missense point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD-1) gene in a family with amyotrophic lateral sclerosis. Hum Mol Genet

Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362: 59-62.










12 13



Ogasawara M,

1994; 3: 363-64. Esteban J, Rosen DR, Bowling AC, et al. Identification of two novel mutations and a new polymorphism in the gene for Cu/Zn superoxide dismutase in patients with amyotrophic lateral sclerosis. Hum Mol Genet 1994; 3: 997-98. Jones CT, Swingler RJ, Brock DJH. Identification of a novel SOD 1 mutation in an apparently sporadic amyotrophic lateral sclerosis patient and the detection of Ile113Thr in three others. Hum Mol Genet 1994; 3: 649-50. Nakano R, Sato S, Inuzuka T, et al. A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. Biochem Biophys Res Commun 1994; 200: 695-703. Rosen DR, Bowling AC, Patterson D. A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis. Hum Mol Genet 1994; 3: 981-87. Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994; 264: 1772-75. Hentati A, Bejaoui K, Pericak-Vance MA, et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nature Genet 1994; 7: 425-28. King AW, Orrell RW, Lane RJM, deBelleroche JS. More than one locus for familial amyotrophic lateral sclerosis: absence of linkage to the SMA locus. Biochem Soc Trans 1994; 22: 149S. Jenner P. Oxidative damage in neurodegenerative disease. Lancet 1994; 344: 796-98. Bowling AC, Schulz JB, Brown RH, Beal MF. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 1993; 61: 2322-25. Robberecht W, Sapp P, Viane MK, et al. Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 1994; 62: 384-87. Borchelt DR, Lee MK, Slunt HS, et al. Superoxide dismutase 1 mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci USA 1994; 91: 8292-96.

Shifting indications for hysterectomy: neither? Most hysterectomies are discretionary rather than life saving. 1,2 Consequently, hysterectomy rates vary widely

nature, nurture,


between countries and over small geographical areas within countries.’-3 This variation has led to accusations that gynaecologists are carrying out large numbers of unnecessary hysterectomies. Some critics attribute differences in rates to patient characteristics (eg, religion or "physician-shopping"), access to medical resources, and the influence of local medical schools; others allege that overzealous male gynaecologists are to blame.1-3 Is there any evidence to substantiate such claims? Male gynaecologists in North Carolina, USA, have significantly higher rates for hysterectomy than do their


female counterparts.4 However, in a multivariate model, only time since residency graduation (ie, completion of formal specialist training) remained predictive of hysterectomy rates, which were lower in recent graduates than in older gynaecologists. Liberal use of the operation in North Carolina may relate more to the prevailing teaching in the 1960s (when most gynaecology residents were men) than to gender. By contrast, male gynaecologists in Switzerland seem to do twice as many hysterectomies as their female colleagues, irrespective of the number of years in practice.’1 Indications for hysterectomy have narrowed in recent decades. Thus symptomless leiomyomas (fibroids) of an arbitrary size (eg, larger than 12 weeks’ gestation) previously justified the operation. This indication lacks merit,2 as does perceived rapid growth in leiomyomas, which does not predict leiomyosarcoma. Hysterectomy is widely regarded as definitive treatment for carcinoma in situ of the cervix, although cervical conisation yields similar cure rates with less risk and cost. "Current indications for hysterectomy have evolved considerably from the time when sterilisation, fear of cancer, and undiagnosed pelvic pain were common reasons for the

procedure. "2 Quality assurance programmess that define minimal criteria for hysterectomy and endorse alternatives will probably lower hysterectomy rates further. By preventing dysfunctional uterine bleeding, oral contraceptives for perimenopausal women can eliminate the need for many endometrial biopsies and hysterectomies. Endometrial ablation is faster, cheaper, and safer than hysterectomy for treatment of heavy menstrual bleeding, although the long-term outcomes may not be as good.6 Ablation of endometriosis by fulguration or laser at laparoscopy, followed by suppressive medical therapy, likewise eliminates the need for some hysterectomies. Growing epidemiological evidence also challenges liberal use of hysterectomy. The uterus may have important systemic effects aside from its role in reproduction. At least five studies7,s suggest that the uterus protects premenopausal women from heart disease. Hysterectomy increases a premenopausal woman’s risk even if her ovaries are retained (although impairment of ovarian blood flow as a result of the procedure may be a factor). There is evidence that the uterus produces prostacyclin (PGI), which both vasodilates and reduces platelet adhesiveness; without prostacyclin from this source women may have an increased risk of myocardial infarction until the age of menopause. For the past forty years, removal of the cervix (for cancer prevention) at abdominal hysterectomy has been a matter of custom, if not surgical honour. However, interest in supracervical (subtotal) hysterectomy is now growing for at least two reasons. Thus the cervix may have an important role in women’s sexual response. In a cohort study,9 total abdominal hysterectomy was associated with a significantly greater reduction in was than orgasms subsequently supracervical Moreover removal of the cervix adds both hysterectomy. time and morbidity to the operation by converting the case from a clean, to a clean-contaminated procedure." In Sweden, rates of supracervical hysterectomy are as high as 2 1 %; " in the USA they are about 1%. While overall hysterectomy rates are declining, rates of

laparoscopy-assisted hysterectomy


growing, partly