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ABSTRACT: Sex differences have been ascribed mainly to hormonal and life-span factors, while neglecting chromosomal and socio-cultural determinants. Science is now reviewing the disregard for sex and gender as a potential explanation for the lack of expected outcomes in whole populations from clinical research. The medical research process begins with a hypothesis that is applied, generating results that can be disseminated. Many factors impact on this process that can be ascribed to sex, as a biological construct, and gender, as a psychosocial process involving experimental subjects, researchers, funders and the public. Drug trial data analysis and publication of data from women and men have recently been scrutinized and found lacking, because expected clinical outcomes from ‘evidence-based’ guidelines are not being achieved. Hence visibility of sex and gender in all aspects of medical research is considered essential if personalized therapies are to bring benefits to both men and women.
Sexuality & Gender Studies eJournal - Forthcoming. 07/2011;
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ABSTRACT: Adverse drug reactions (ADRs) to local anaesthetic drugs are reported voluntarily through the Adverse Drug Reporting On Line Tracking system (ADROIT). We aimed to determine hazards associated with drugs commonly used in anaesthesia including ropivacaine and levobupivacaine.
The ADROIT database was queried for all ADRs to local anaesthetics used in anaesthesia and surgery between 1967 and 2005. Details of age, sex, suspect drug, date and reaction details were analysed.
There were 985 reports analysed, 797 for lidocaine, 160 for bupivacaine, 16 for ropivacaine and 12 for levobupivacaine. The female to male ratio was 1.6:1 and age was not a factor determining the frequency of reactions. A vasoconstrictor was included in the lidocaine formulation in 27% of reports. When methylprednisolone (Depo-Medrone) or prilocaine (as EMLA cream) were used in combination with lidocaine, the frequency of allergic reports increased significantly (p < 0.0001). Levobupivacaine demonstrated a hazard signal for cardiovascular symptoms. Fatality rate within the reports was higher for bupivacaine (11%) than for lidocaine (3%).
The patient's age and sex were not found to influence the type of reactions reported. Lidocaine with methylprednisolone or prilocaine (as EMLA(TM) cream) generated the largest number of reports of allergic phenomena. Fatalities were most frequently reported in association with bupivacaine.
Pharmacoepidemiology and Drug Safety 08/2009; 18(11):1000-6. · 2.53 Impact Factor
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ABSTRACT: Subtle genetic and psychological variations are increasingly recognized to contribute to pain and analgesic efficacy and safety. The influence of sex on this relationship remains poorly understood, particularly in humans. The issue is complicated by the overlay of gender onto physical sex, and its associated stereotypes and expectations. Women appear to use more pain-relieving medications than men; however, it remains unclear whether these observations represent true differences in analgesic usage patterns, or reporting bias. Differences in analgesic efficacy relating to body composition, metabolism and hormonal profiles have been demonstrated. Psychological and social elements of gender have also been associated with altered pain experiences and analgesic use profiles, albeit with significant individual variations. Intra-group differences may ultimately prove more important than sex differences. Further research may unravel the various threads linking gender and sex effects on analgesia with the aim of individualizing analgesia to optimize pain relief.
Women s Health 02/2009; 5(1):79-90.
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Joel D Greenspan,
Rebecca M Craft,
Linda LeResche,
Lars Arendt-Nielsen,
Karen J Berkley,
Roger B Fillingim,
Michael S Gold, Anita Holdcroft,
Stefan Lautenbacher,
Emeran A Mayer,
Jeffrey S Mogil,
Anne Z Murphy,
Richard J Traub
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ABSTRACT: In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"
Pain 12/2007; 132 Suppl 1:S26-45. · 5.78 Impact Factor
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ABSTRACT: A variety of analgesics are used perioperatively and associated adverse drug reactions (ADRs) may complicate anaesthesia and recovery.
We aimed to measure the demographics of reported suspected ADRs to alfentanil, fentanyl, ketorolac, morphine, nalbuphine, papaveretum, pethidine and remifentanil. We report a retrospective analysis of Yellow Card reports of suspected ADRs from 1965-2004 as classified in the Adverse Drug Reaction On-line Tracking database (ADROIT) of the Medicines and Healthcare products Regulatory Agency (MHRA).
In total, 1312 reactions were retrieved. A single drug was reported in 908, 39 were fatal and 219 categorised as 'allergic'. Allergic phenomenon varied from 2/33 (6%) for remifentanil to 11/53 (21%) for alfentanil. 'Cardiovascular' reactions were reported frequently with remifentanil (18/33, 55%) and alfentanil (19/53, 36%) and these generated a signal for possible hazards from proportional reporting ratios (PRRs). The opioid fentanyl was associated with similar hazard signals for muscular and psychiatric ADRs.
Perioperative vigilance may reduce morbidity and mortality from preventable ADRs to analgesic drugs. Denominator and diagnostic data are essential for prospective studies.
Pharmacoepidemiology and Drug Safety 07/2007; 16(6):687-94. · 2.53 Impact Factor
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Anita Holdcroft
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ABSTRACT: Anaesthetic drugs were selected from the Medicines and Healthcare products Regulatory Agency Drug Analysis Prints in order to determine the number and types of reported reactions and associated mortality.
The chosen drug groups were the intravenous induction agents, the neuromuscular blocking drugs and neostigmine, the inhalational anaesthetic agents and nitrous oxide, local anaesthetic agents and a selection of analgesics agents, naloxone and midazolam and its antagonist flumazenil. From each drug file, the number and type of reactions were analysed. Mortality was calculated as a percentage of the number of deaths against patient reports.
A total of 11,199 reactions were analysed from 6603 patients of whom 620 (9%) died. Few drug records reported reactions from multiple constituent formulations. The majority of reactions were not allergic. The highest mortality was in the inhalational anaesthetic group. Although the greatest number of fatal events was associated with halothane, this drug is no longer used. Nevertheless the percentage remains high because cardiovascular mortality is still being reported. Local anaesthetic use was associated with the smallest percentage mortality (3%). The highest reported number of reactions was associated with the intravenous induction agents and idiosyncratic neurological and peripheral vascular reactions were linked with the use of etomidate.
The reporting of allergic reactions was low. The data demonstrate that induction of anaesthesia presents the highest risk of adverse drug reaction; there is also mortality from newer drugs for example, desflurane, remifentanil as well as from drugs for which there is no alternative, for example, suxamethonium.
Pharmacoepidemiology and Drug Safety 04/2007; 16(3):316-28. · 2.53 Impact Factor
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Anaesthesia 02/2007; 34(3):245 - 249. · 2.96 Impact Factor
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Anita Holdcroft
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ABSTRACT: The research process -- from study design and selecting a species and its husbandry, through the experiment, analysis, peer review, and publication -- is rarely subject to questions about sex or gender differences in mainstream life sciences research. However, the impact of sex and gender on these processes is important in explaining biological variations and presentation of symptoms and diseases.
This review aims to challenge assumptions and to develop opportunities to mainstream sex and gender in basic scientific research.
Questions about the mechanisms of sex and gender effects were reviewed in relation to biological, environmental, social, and psychological interactions. Gender variations, in respect to aging, socializing, and reproduction, that are present in human populations but are rarely featured in laboratory research were considered to more effectively translate animal research into clinical health care.
Methodologic approaches to address the present lack of a gender dimension in research include actively reducing variations through attention to physical factors, biological rhythms, and experimental design. In addition, through genomic and acute nongenomic activity, hormones may compound effects through multiple small sex differences that occur during the course of an acute pathologic event. Furthermore, the many exogenous sex steroid hormones and their congeners used in medicine (eg, in contraception and cancer therapies) may add to these effects.
The studies reviewed provide evidence that sex and gender are determinants of many outcomes in life science research. To embed the gender dimension into basic scientific research, a broad approach -- gender mainstreaming -- is warranted. One example is the use of review boards (eg, animal ethical review boards and journal peer-review boards) in which gender-related standardized questions can be asked about study design and analysis. A more fundamental approach is to question the relevance of present-day laboratory models to design methods to best represent the age-related changes, comorbidity, and variations experienced by each sex in clinical medicine.
Gender Medicine 02/2007; 4 Suppl B:S64-74. · 2.10 Impact Factor
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ABSTRACT: Cannabinoids have dose-related antinociceptive effects in animals. This clinical study aimed to investigate whether a single oral dose of cannabis plant extract (Cannador; Institute for Clinical Research, IKF, Berlin, Germany) could provide pain relief with minimal side effects for postoperative pain.
Patients (aged 18-75 yr) were recruited and consented before surgery if patient-controlled analgesia was planned for provision of postoperative pain relief. Each patient received a single dose of 5, 10, or 15 mg Cannador if he or she had at least moderate pain after stopping patient-controlled analgesia. Starting with 5 mg, dose escalation was based on the number of patients requesting rescue analgesia and adverse effects. Pain relief, pain intensity, and side effects were recorded over 6 h and analyzed using tests for trend with dose.
Rescue analgesia was requested by all 11 patients (100%) receiving 5 mg, 15 of 30 patient (50%) receiving 10 mg, and 6 of 24 patients (25%) receiving 15 mg Cannador (log rank test for trend in time to rescue analgesia with dose P < 0.001). There were also significant trends across the escalating dose groups for decreasing pain intensity at rest (P = 0.01), increasing sedation (P = 0.03), and more adverse events (P = 0.002). The number needed to treat to prevent one rescue analgesia request for the 10-mg and 15-mg doses, relative to 5 mg, were 2.0 (95% confidence interval, 1.5-3.1) and 1.3 (95% confidence interval, 1.1-1.7), respectively. The study was terminated because of a serious vasovagal adverse event in a patient receiving 15 mg.
These significant dose-related improvements in rescue analgesia requirements in the 10 mg and 15 mg groups provide a number needed to treat that is equivalent to many routinely used analgesics without frequent adverse effects.
Anesthesiology 06/2006; 104(5):1040-6. · 5.36 Impact Factor
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ABSTRACT: Adverse drug reactions (ADRs) are known to occur during anaesthesia; in the U.K. such ADRs may be reported through the Yellow Card Scheme (YCS). Our aim was to determine the demographics of ADRs to neuromuscular blocking drugs without formal causality assessment.
A retrospective analysis of ADRs to seven neuromuscular blocking drugs reported via the YCS during a greater than 30-year period was performed. Sex and age were analysed in order to identify at risk groups.
Of 998 reports, 969 included gender. Non-allergic suspected reactions occurred with almost the same frequency as those with an allergic component. The majority occurred in females 676 (70%), and significant sex differences were measured between drugs. Males were more likely to have suffered an ADR to atracurium (p = 0.01) whilst females experienced more ADRs to suxamethonium (p = 0.01). ADRs proved fatal in 81 (9%) of the 950 reports for single drugs. Mortality following suxamethonium was significantly higher in males at 22% compared with 9% females (p < 0.001). More women than men were reported to have allergic reactions, 73% (362/499) compared with 27% (137/499) respectively. The female:male ratio for ADRs was reversed for subjects < 10 years compared with peak ADR reports during the decade from 31-40 years.
Sex differences in mortality exist in this analysis. The unexpected high frequency of non-allergic ADRs suggests that morbidity and mortality from reactions to established drugs is twice that expected from allergic reactions alone. Standards and guidance for the reporting of ADRs warrant urgent development.
Pharmacoepidemiology and Drug Safety 03/2006; 15(3):151-60. · 2.53 Impact Factor
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FRCA Karen Patricia Light MBBS,
FRCA Anthony Timothy Lovell MBBS,
Hisham Butt MBChB,
FRCA Nicholas John Fauvel MBBS,
Anita Holdcroft MBChB, MD, FRCA,
Karen Patricia Light,
Anthony Timothy Lovell,
Hisham Butt,
Nicholas John Fauvel, Anita Holdcroft
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ABSTRACT: Background
Adverse drug reactions (ADRs) are known to occur during anaesthesia; in the U.K. such ADRs may be reported through the Yellow Card Scheme (YCS). Our aim was to determine the demographics of ADRs to neuromuscular blocking drugs without formal causality assessment.MethodsA retrospective analysis of ADRs to seven neuromuscular blocking drugs reported via the YCS during a greater than 30-year period was performed. Sex and age were analysed in order to identify at risk groups.ResultsOf 998 reports, 969 included gender. Non-allergic suspected reactions occurred with almost the same frequency as those with an allergic component. The majority occurred in females 676 (70%), and significant sex differences were measured between drugs. Males were more likely to have suffered an ADR to atracurium (p = 0.01) whilst females experienced more ADRs to suxamethonium (p = 0.01). ADRs proved fatal in 81 (9%) of the 950 reports for single drugs. Mortality following suxamethonium was significantly higher in males at 22% compared with 9% females (p < 0.001). More women than men were reported to have allergic reactions, 73% (362/499) compared with 27% (137/499) respectively. The female:male ratio for ADRs was reversed for subjects < 10 years compared with peak ADR reports during the decade from 31–40 years.Conclusions
Sex differences in mortality exist in this analysis. The unexpected high frequency of non-allergic ADRs suggests that morbidity and mortality from reactions to established drugs is twice that expected from allergic reactions alone. Standards and guidance for the reporting of ADRs warrant urgent development. Copyright © 2006 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety 02/2006; 15(3):151 - 160. · 2.53 Impact Factor
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ABSTRACT: Despite the major benefits of antiretroviral therapy on survival during HIV infection, there is an increasing need to manage symptoms and side effects during long-term drug therapy. Cannabis has been reported anecdotally as being beneficial for a number of common symptoms and complications in HIV infections, for example, poor appetite and neuropathy. This study aimed to investigate symptom management with cannabis. Following Ethics Committee approval, HIV-positive individuals attending a large clinic were recruited into an anonymous cross-sectional questionnaire study. Up to one-third (27%, 143/523) reported using cannabis for treating symptoms. Patients reported improved appetite (97%), muscle pain (94%), nausea (93%), anxiety (93%), nerve pain (90%), depression (86%), and paresthesia (85%). Many cannabis users (47%) reported associated memory deterioration. Symptom control using cannabis is widespread in HIV outpatients. A large number of patients reported that cannabis improved symptom control.
Journal of Pain and Symptom Management 05/2005; 29(4):358-67. · 2.50 Impact Factor
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ABSTRACT: BACKGROUND: Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. METHODS: Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF). RESULTS: TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] - no pain group, n = 8, 0.69 [0-1.27]; pain group, n = 10, 2.15 [0.77-4.38]; p = 0.0009). Nerve Growth Factor, which up-regulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] - no pain group, n = 6, 0.75 [0-2]; pain group, n = 11, 2 123, p = 0.008; TRPV4, median [range] - no pain group, n = 6, [0-1]; pain group, n = 11, 1 [0.5-2], p = 0.014). CONCLUSION: Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1-blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study.
BMC Women s Health 04/2005; 5(1):2.
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ABSTRACT: A reversible decrease in brain size has been demonstrated during normal pregnancy that is maximal at term and returns to normal after many months. The purpose of this longitudinal study was to use phosphorus-31 MR spectroscopy to determine if metabolic changes explain this physiologic event.
Pregnant women (n = 12) were examined at term and up to 6 months after delivery. Nonpregnant control subjects (n = 7) were imaged twice (a month apart) to exclude hormone effects. Brain (31)P MR spectra were acquired at 1.5 T, and intracellular pH was calculated from the chemical shift between phosphocreatine and inorganic phosphate resonances. Statistical analysis was performed by using an analysis of variance.
We found no statistically significant differences in the relative levels of metabolite associated with cerebral bioenergetics and cell membrane metabolism between pregnant women and nonpregnant women. However, a significant increase in cerebral pH was observed in pregnant women at 6 weeks after delivery compared with control subjects (7.074 +/- 0.063 vs 7.017 +/- 0.041; P < .05). pH returned to normal by 6 months after delivery (7.014 +/- 0.010).
Changes in brain size associated with pregnancy appear to be associated with an increase in intracellular pH after delivery. The observed alkalosis may reflect altered cellular metabolism. These persistent brain perturbations associated with pregnancy indicate that, when postpartum physiologic and pharmacologic changes are measured, long-term effects may be expected in central nervous system processing.
American Journal of Neuroradiology 03/2005; 26(2):352-6. · 2.93 Impact Factor
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ABSTRACT: Previous research has shown that post-partum abdominal pain is greater in multiparous than primiparous women (Murray and Holdcroft, 1989). Although breast feeding in the immediate post-partum period induces uterine contractions and abdominal pain, it is unknown how parity influences the contractions. Here, a structured questionnaire that included the McGill Pain Questionnaire (total pain intensity index, TPI) and visual analog scales (VAS) was used to evaluate the intensity, location, referred tenderness (hyperalgesia), descriptor, and temporal characteristics of pain during breast feeding up to three days after uncomplicated vaginal delivery. Three groups of women were studied: primiparous (n=25); low parity (1-2 prior births; n=14); high parity (3-5 prior births; n=11). Uterine contractions during breast feeding were recorded using tocodynamometry in some women from each group (n=17, 6, 7, respectively). For comparison, an identical questionnaire was used to evaluate pains the women remembered experiencing during menstruation in the year immediately preceding the current pregnancy. During breast feeding, nearly all women (96%) reported deep pain primarily at three sites: lower abdomen, low back, and breast, with associated referred hyperalgesia in 62% of them. The intensity of these pains increased significantly with parity (P<0.001), along with an increase in the number of pain sites (P=0.03), mainly in lower abdomen and back, but not breast. Similarly, both the mean duration and number of uterine contractions increased significantly with parity (P<0.001). Furthermore, the mean duration of contractions correlated significantly with the pain scores (P=0.03 [VAS] and P=0.006 [TPI]). In contrast with pain during breast feeding, the intensity of pain during menstruation did not change with parity. These results demonstrate that pain, referred pain, and uterine contractions during breast feeding in the immediate post-partum period increase with parity, suggesting that childbirth can induce central neural changes that increase predisposition for pain during the post-partum period.
Pain 09/2003; 104(3):589-96. · 5.78 Impact Factor
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ABSTRACT: The management of pain differs if pain is self limiting or persistent; for example, if pain is prolonged then treatment will be managed by a multidisciplinary team in a pain clinic. Pain is not just from physical disorders but also from combinations of physiological, pathological, emotional, psychological, cognitive, environmental, and social factors (fig 1). The keys to successful pain control are the mechanisms that initiate and maintain pain. Major advances in neurobiology, from molecular studies to imaging the cortex of the brain, show the complex integration of nerve cell activity and have generated a fundamental change in attitude and expectation about the control of pain.1 Now, the public and health professionals expect to control pain by using preventive and active strategies, including drugs and physical and psychosocial interventions.Fig 1 Biopsychosocial factors that interact and modulate the experience of pain
Methods
The topics we have chosen result from discussions with all grades of staff involved in the management of acute and chronic pain and range from new drug development based on scientific evidence that may impact on future pain management to a holistic approach to patient care. Our searches focused on the key words “pain,” “systematic review,” “management,” and “neuropathic.” We searched Medline, the Cochrane Library, and Health Technology Assessments, and we scrutinised the BMJ and the National Institutes of Health websites as well as professionally based websites for pain, such as that of the International Association for the Study of Pain and scientific websites such as that of the National Academy of Sciences. We identified systematic reviews from the past three years from these sources and leading scientific papers.
Recent developments
A major change in pain management is a move from empirical therapies to a mechanism based approach
New drug developments are targeting specific receptor subtypes
Pain assessment includes qualitative sensory affective and …
BMJ (Clinical research ed.). 04/2003; 326(7390):635-9.
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ABSTRACT: Qualitative decreases in maternal brain size have been observed late in pregnancy. The aim of this study was to quantitatively evaluate changes to the maternal brain during and after healthy pregnancy and to compare these changes with those observed in cases of preeclampsia.
Three-dimensional T1-weighted MR volume images were obtained in nine healthy participants before and after delivery. Additional images were obtained in some of these participants before pregnancy, during pregnancy, and within 52 weeks after delivery. Five women with preeclampsia were examined before delivery and 6 weeks after delivery. Three of these patients were examined within 52 weeks after delivery. Images were registered, and both brain and ventricular volumes were calculated by using a semiautomated computer program.
Both the healthy and preeclamptic groups had a reduction in brain size during pregnancy that was maximal at term and that reversed by 6 months after delivery. The ventricular size showed a corresponding increase in size during pregnancy and a decrease in size after delivery. In the preeclamptic patients, brain size was significantly smaller (P =.05) than in healthy participants, both before and after delivery.
The brain decreases in size during pregnancy and increases in size after delivery. The changes follow a consistent time course in each woman. The mechanism and physiologic importance of these findings are speculative at the present time.
American Journal of Neuroradiology 02/2002; 23(1):19-26. · 2.93 Impact Factor
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ABSTRACT: Etomidate, (R-(+) ethyl-1-(phenylethyl) 1H-imidazole-5-carboxylate), when administered as drops to the eyes of normal New Zealand white rabbits in concentrations of 2%, 4% and 8% in arachis oil has been shown to significantly lower the intraocular pressure in these animals. The intraocular pressure was measured with the Perkins handheld applanation tonometer.The intraocular pressure reducing effect of the 2% and 4% were better than that of 1% pilocarpine; the two per cent etomidate solution reduced intraocular pressure from a pretreatment mean of 13.6mm Hg to a new mean of 7.7mm Hg after three weeks treatment, while the 4% etomidate solution lowered the intraocular pressure from a pretreatment mean of 14.4mm Hg to a new mean of 7.3mm Hg also after three weeks treatment. Pilocarpine (1%) reduced the intraocular pressure from a pretreatment mean of 13.7mm Hg to 10.7mmHg after three weeks treatment in the same group of rabbits. Etomidate (8%) solution also showed a more significant reduction of intraocular pressure than the 2% solution of pilocarpine. The eight percent etomidate reduced the pretreatment mean intraocular pressure of 14.0mm Hg to a new mean of 6.5mm Hg after three weeks treatment while 2% pilocarpine lowered a pretreatment mean of 13.9mm Hg to 9.0mm Hg after three weeks treatment in the same group of rabbits.There was a persistence of the low intraocular pressure produced by the various concentrations of etomidate in arachis oil after treatment with these drops was stopped. However, this feature was also shown by the two concentrations of pilocarpine used but not in as marked an extent as the etomidate solutions with regard to duration of effect and height of reduction of the intraocular pressure.During a three week period of topical application of drops to the rabbits eyes, the etomidate solutions were found to have no effect in the iris sphincter.
International Ophthalmology 04/1980; 2(2):71-76.
