Iron intake in relation to ovarian reserve among women seeking infertility treatment.

STUDY QUESTION: Is there an association between iron intake and ovarian reserve among women seeking fertility care? SUMMARY ANSWER: Supplemental iron intake above 45 mg/day is associated with lower ovarian reserve among women seeking fertility care. WHAT IS KNOWN ALREADY: Although the literature regarding iron intake in relation to ovarian reserve is scant and inconsistent, some evidence suggests that iron may have gonadotoxic effects. STUDY DESIGN, SIZE, DURATION: This observational study included 582 female participants attending the Massachusetts General Hospital Fertility Center (2007-2019) enrolled in the Environment and Reproductive Health (EARTH) Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Iron intake was estimated using a validated food frequency questionnaire. Markers of ovarian reserve included antral follicle count (AFC) (assessed via transvaginal ultrasound) and Day 3 FSH, both obtained during the course of an infertility evaluation. MAIN RESULTS AND THE ROLE OF CHANCE: Participants had a median age of 35 years and median total iron intake of 29 mg/day. Total iron intake was inversely related to AFC and this association was driven by intake of supplemental iron. Compared to women with a supplemental iron intake of ≤20 mg/day, women consuming 45-64 mg/day of supplemental iron had a 17% (-35%, 0.3%) lower AFC and women consuming ≥65 mg/day of supplemental iron had a 32% (-54%, -11%) lower AFC after adjusting for potential confounders (P, linear trend = 0.003). Similarly, in a multivariable-adjusted analysis, Day 3 FSH levels were 0.9 (0.5, 1.3) IU/ml higher among women with a supplemental iron intake of ≥65 mg/day when compared to women with a supplemental iron intake of ≤20 mg/day (P, linear trend = 0.02). LIMITATIONS, REASONS FOR CAUTION: Iron intake was estimated using a method that relies on self-report and we had no biomarkers of iron status in our participants; only 36 women consumed ≥45 mg/day of supplemental iron. WIDER IMPLICATIONS OF THE FINDINGS: Since all study participants were seeking fertility treatment, our findings may not apply to women in the general population. Although our findings are consistent with studies of women with iron overload, given the paucity of literature on this topic, it is essential that this question is revisited in studies designed to better understand the dose-response relation of this association across the entire distribution of ovarian reserve and the risk-benefit balance of pre-conceptional iron supplementation given its many positive effects on pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by Grants R01ES022955, R01ES033651, R01ES009718, P30ES000002, and P30DK046200 from the National Institutes of Health. N.J.-C. was supported by a Fulbright Scholarship. N.J.-C., M.M., L.M.-A., E.O.-P., S.W., I.S., and J.E.C. declare no conflict of interest related to the work in the manuscript. R.H. has received grants from the National Institute of Environmental Health Sciences. TRIAL REGISTRATION NUMBER: N/A.

Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction.

STUDY QUESTION: Are serum polyunsaturated fatty acids (PUFA) concentrations, including omega-3 (ω3-PUFA) and omega-6 (ω6-PUFA), related to ART outcomes? SUMMARY ANSWER: Serum levels of long-chain ω3-PUFA were positively associated with probability of live birth among women undergoing ART. WHAT IS KNOWN ALREADY: Intake of ω3-PUFA improves oocyte and embryo quality in animal and human studies. However, a recent cohort study found no relation between circulating ω3-PUFA levels and pregnancy rates after ART. STUDY DESIGN SIZE, AND DURATION: This analysis included a random sample of 100 women from a prospective cohort study (EARTH) at the Massachusetts General Hospital Fertility Center who underwent 136 ART cycles within one year of blood collection. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum fatty acids (expressed as percentage of total fatty acids) were measured by gas chromatography in samples taken between Days 3 and 9 of a stimulated cycle. Primary outcomes included the probability of implantation, clinical pregnancy and live birth per initiated cycle. Cluster-weighted generalized estimating equation (GEE) models were used to analyze the association of total and specific PUFAs with ART outcomes adjusting for age, body mass index, smoking status, physical activity, use of multivitamins and history of live birth. MAIN RESULTS AND ROLE OF CHANCE: The median [25th, 75th percentile] serum level of ω3-PUFA was 4.7% [3.8%, 5.8%] of total fatty acids. Higher levels of serum long-chain ω3-PUFA were associated with higher probability of clinical pregnancy and live birth. Specifically, after multivariable adjustment, the probability of clinical pregnancy and live birth increased by 8% (4%, 11%) and 8% (95% CI: 1%, 16%), respectively, for every 1% increase in serum long-chain ω3-PUFA levels. Intake of long-chain ω3-PUFA was also associated with a higher probability of life birth in these women, with RR of 2.37 (95% CI: 1.02, 5.51) when replacing 1% energy of long-chain ω3-PUFA for 1% energy of saturated fatty acids. Serum ω6-PUFA, ratios of ω6 and ω3-PUFA, and total PUFA were not associated with ART outcomes. LIMITATIONS REASONS FOR CAUTION: The generalizability of the findings to populations not undergoing infertility treatment may be limited. The use of a single measurement of serum fatty acids to characterize exposure may lead to potential misclassification during follow up. WIDER IMPLICATIONS OF THE FINDINGS: Serum ω3-PUFA are considered biomarkers of dietary intake. The association of higher serum long chain ω3-PUFA levels with improved ART outcomes suggests that increased intake of these fats be may be beneficial for women undergoing infertility treatment with ART. STUDY FUNDING/COMPETING INTERESTS: NIH grants R01-ES009718 from the National Institute of Environmental Health Sciences, P30-DK046200 and T32-DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases, and L50-HD085359 from the National Institute of Child Health and Human Development, and the Early Life Nutrition Fund from Danone Nutricia US. Dr Rueda is involved in a patent 9,295,662, methods for enhancing, improving, or increasing fertility or reproductive function (http://patents.com/us-9295662.html). This patent, however, does not lead to financial gain for Dr Rueda, or for Massachusetts General Hospital. Dr Rueda does not own any part of the company nor does he have any equity in any fertility related company. As Dr Rueda is not a physician, he does not evaluate patients or prescribe medications. All other coauthors have no conflicts of interest to declare.

Muscle-building supplement use and increased risk of testicular germ cell cancer in men from Connecticut and Massachusetts.

BACKGROUND: No analytic epidemiological study has examined the relationship between use of muscle-building supplements (MBSs) and testicular germ cell cancer (TGCC) risk. METHODS: We conducted a population-based case-control study including 356 TGCC cases and 513 controls from Connecticut and Massachusetts. RESULTS: The odds ratio (OR) for ever use of MBSs in relation to risk of TGCC was significantly elevated (OR=1.65, 95% confidence interval (CI): 1.11-2.46). The associations were significantly stronger among early users, men with more types of MBSs used, and longer periods of use. CONCLUSIONS: MBS use is a potentially modifiable risk factor that may be associated with TGCC.

Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology.

BACKGROUND: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use. METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. RESULTS AND CONCLUSIONS: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET.

Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease.

Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Neurosurgery for Parkinson's disease.

Medical therapy for Parkinson's disease (PD) often becomes inadequate over several years. Disability increases despite maximal medical management and many patients develop motor fluctuations and dyskinesia. In addition, medications provide good control of tremor in only 50% of cases. In appropriately selected cases, surgical therapies for PD provide benefit for medically refractory symptoms. Recent advances have provided a greater array of surgical options. Unilateral thalamotomy and thalamic stimulation are considered safe and effective procedures to treat contralateral tremor. Pallidotomy and pallidal stimulation primarily reduce contralateral dyskinesia, with lesser effects on bradykinesia and rigidity. Studies indicate that subthalamic nucleus (STN) stimulation improves "off" period function, decreases "off" time, and lessens dyskinesia. Fetal cell transplantation remains experimental, and studies are underway to evaluate the safety and efficacy of porcine fetal cell and human retinal pigment epithelial cell transplantation. This chapter reviews the history of surgical procedures for PD, describes current procedures, and offers a look into the future of neurosurgical options for PD.

Pulmonary responses to oil fly ash particles in the rat differ by virtue of their specific soluble metals.

Occupational exposure to residual oil fly ash (ROFA) particulate has been associated with adverse respiratory health effects in humans. We hypothesized that ROFA collected at different sites within an oil burning power plant, by virtue of its differing metal and sulfate composition, will induce differential lung injury. Ten ROFA samples collected at various sites within a power plant were analyzed for water- and 1.0 M HCl-leachable arsenic (As), beryllium (Be), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), vanadium (V), zinc (Zn), and sulfur by inductively coupled plasma-atomic emission spectroscopy. All ROFA samples contained variable amounts of leachable (water-extractable) and 1.0 M HCl-extractable Fe, V, and/or Ni. All other metals, except Zn (ROFA No. 1 contained 3.43 and No. 3, 6.35 micrograms/mg Zn), were present in negligible quantities (< 1.0 microgram/mg) in the water extract. In vivo pulmonary injury from exposure to whole saline suspensions of these ROFA was evaluated. Male, SD rats (60 days old) were intratracheally instilled with either saline or saline suspension of whole ROFA (< 3.0 mass median aerodynamic diameter) at three concentrations (0.833, 3.33, or 8.33 mg/kg). After 24 h, lungs were lavaged and bronchoalveolar lavage fluid (BALF) was analyzed for cellular influx and protein content as well as lactate dehydrogenase (LDH) and N-acetyl glucosaminidase (NAG) activity and total hemoglobin as indicators of lung injury. ROFA-induced increases in BALF protein and LDH, but not neutrophilic inflammation, were associated with its water-leachable total metal, Ni, Fe, and sulfate content. However, the neutrophilic response following ROFA exposure was positively correlated with its water-leachable V content. Modest lung injury was observed with the ROFA samples which contained the smallest amounts of water-leachable metals. The ability of ROFA to induce oxidative burst in alveolar macrophage (AM) was determined in vitro using a chemiluminescence (CL) assay. AM CL signals in vitro were greatest with ROFA containing primarily soluble V and were less with ROFA containing Ni plus V. In summary, ROFA-induced in vivo acute pulmonary inflammation appears to be associated with its water-leachable V content; however, protein leakage appears to be associated with its water-leachable Ni content. ROFA-induced in vitro activation of AM was highest with ROFA containing leachable V but not with Ni plus V, suggesting that the potency and the mechanism of pulmonary injury will differ between emissions containing V and Ni.

High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor.

Pharmacologic treatment for essential tremor and the tremor of Parkinson's disease is often inadequate. Stereotaxic surgery, such as thalamotomy, can effectively reduce tremors. We performed a multicenter trial of unilateral high-frequency stimulation of the ventral intermedius nucleus of the thalamus in 29 patients with essential tremor and 24 patients with Parkinson's disease, using a blinded assessment at 3 months after surgery to compare clinical rating of tremor with stimulation ON with stimulation OFF and baseline and a 1-year follow-up. Six patients were not implanted because of lack of intraoperative tremor suppression (2 patients), hemorrhage (2 patients), withdrawal of consent (1 patient), and persistent microthalamotomy effect (1 patient). A significant reduction in both essential and parkinsonian tremor occurred contralaterally with stimulation. Patients reported a significant reduction in disability. Measures of function were significantly improved in patients with essential tremor. Complications related to surgery in implanted patients were few. Stimulation was commonly associated with transient paresthesias. Other adverse effects were mild and well tolerated. Efficacy was not reduced at 1 year. Chronic high-frequency stimulation is safe and highly effective in ameliorating essential and parkinsonian tremor.

Clinical monitoring using otoacoustic emissions.

Damaging influences to the cochlea are a leading cause of sensorineural hearing loss. Examples include acute or chronic noise exposure and cochleotoxic drugs such as aminoglycosides. Typically, once damage has occurred, the cochlea cannot recover. Therefore, prevention is critical. If damaging influences cannot be avoided, then secondary prevention or early detection of cochlear hearing loss becomes important. Ideally, methods for the detection of cochlear damage should be as specific and as sensitive as possible. Otoacoustic emissions satisfy these criteria and offer a means of testing aspects of cochlear function in a non-invasive and objective way. Evoked otoacoustic emissions measured either after transient stimuli or during two-tone stimulation (distortion-product otoacoustic emissions) are the types most commonly used for clinical purposes. They are stable over time within individual ears and their repeatability has been established under conditions of clinical testing using commercial equipment. Thus, they are well suited as an effective means of monitoring subtle changes in cochlear status. The possibility of making non-invasive repeated measures of cochlear function has led to the widespread use of otoacoustic emissions in animal experiments. Influences of development, anoxia, anaesthesia, noise, and drugs have been monitored. Preliminary studies in humans demonstrate that cochlear damage due to ototoxic drugs such as aminoglycosides or cisplatin and due to noise exposure can be detected using otoacoustic emissions. Comparison of such results to those available using pure-tone audiometry indicates a greater sensitivity of otoacoustic emissions for detecting early cochlear damage.(ABSTRACT TRUNCATED AT 250 WORDS)

[The clinical use of oto-acoustic emissions of cochlear distortion products]. / Die klinische Anwendung otoakustischer Emissionen kochleärer Distorsionsprodukte.

Otoacoustic emissions of cochlear distortion products (DPOAEs) were measured in normally hearing and hearing-impaired human ears. A total of 133 subjects (231 ears) were tested. Two puretone stimuli f1 and f2 were delivered to a sound probe fixed in the outer ear canal. The frequencies of the two primaries were chosen so that their geometric mean represented pure-tone audiometric frequencies. The otoacoustic emission was measured at the distortion product frequency 2f1-f2 by spectral averaging. For 199 ears, the levels of the primaries were 73 dBHL for L1 and 67 dBHL for L2. Statistical analysis was carried out in 77 ears of 46 subjects with normal hearing (average hearing levels at pure-tone audiometric thresholds less than or equal to 10 dBHL) and 36 ears of 25 subjects exhibiting near-normal hearing (average hearing levels at pure-tone audiometric thresholds less than or equal to 20 dBHL). The mean DPOAE amplitudes were similar in these two groups of ears. In 111 of these 113 ears (98.2%), DPOAEs were detected at three or more of the six tested frequencies between 1 and 6 kHz. DPOAEs were measured in more than 75% of ears at each frequency between 1-6 kHz and in more than 86% between 1-4 kHz. Eighty-six hearing-impaired ears of 44 subjects with sensorineural hearing loss formed the patient group. A highly significant correlation between pure-tone audiometric thresholds and DPOAE amplitudes was demonstrated in the frequency range of 1-4 kHz. Percentiles of DPOAE amplitudes were calculated in 22 ears with a mean pure-tone threshold less than or equal to 5 dBHL and in 12 specially selected pathological ears.(ABSTRACT TRUNCATED AT 250 WORDS)

Click- and tone-burst-evoked otoacoustic emissions in normally hearing ears and in ears with high-frequency sensorineural hearing loss.

Otoacoustic emissions (OAEs) evoked by clicks and tone bursts (TBs) were measured using a minor modification of the 1987 Bray and Kemp system in normal and hearing-impaired ears with high-frequency sensorineural hearing loss. Sixty ears of 60 subjects were tested. The average behavioral hearing threshold of 20 normally hearing ears was measured for the different "nonlinear" stimulus groups and defined as 0 dBnHL. Emissions were recorded in another 20 normally hearing ears and in 20 ears with steep high-frequency sensorineural hearing loss above 2kHz. An unfiltered click of 80 microseconds duration and TBs at frequencies of 0.5, 1, 2, 3, 4, 5, and 6 kHz served as stimuli. The ears with high-frequency hearing loss were clearly distinguished from the normal ears in that emission energy decreased with higher frequency stimuli above 2 kHz. The mean slopes of the response-growth functions were significantly higher at lower audiometric thresholds. The normal ears showed a slope of 0.21-0.35 dB/dBnHL above 2 kHz while the slope of the pathological ears was 0.04-0.13 dB/dBnHL. These differences in TBOAEs could possibly be used clinically to carry out hearing tests that are more frequency-specific than those measuring solely click-evoked OAEs. Pathological ears had emissions in the lower frequency range, where they had a normal audiometric threshold. However, these emissions had significantly far lower amplitudes at frequencies around 0.5 and 1 kHz when compared to normal ears. This reduced emission energy may indicate a cochlear impairment of the pathological ears in frequency ranges where they still had normal audiometric thresholds.

Distortion product otoacoustic emissions in normal and hearing-impaired ears.

Otoacoustic emissions of distortion products (DPOAE's) were recorded in normal and hearing-impaired human ears using relatively straightforward methods. Two pure-tone stimuli at fixed frequency levels of 73 dB HL for f1 and of 67 dB HL for f2 were used. The frequencies of the two primaries were chosen so that their geometric mean represented standard audiometric frequencies. Measurements of the emission amplitudes at 2f1-f2 and the adjacent noise floor were achieved by spectral averaging. A total of 101 subjects (199 ears) were tested. Seventy-seven ears in 46 subjects had normal hearing (hearing levels less than or equal to 20 dB at standard audiometric frequencies; average hearing levels, less than or equal to 10 dB). Thirty-six ears in 25 subjects had near-normal hearing (no hearing complaints, hearing levels less than or equal to 40 dB; average hearing levels, less than or equal to 20 dB). No significant differences in mean DPOAE values were apparent between these two groups of ears. All but two of these 113 ears (98%) showed emissions at three or more of the six frequencies tested between 1 and 6 kHz. Emissions were detected in more than 75% at each frequency between 1 and 6 kHz and in more than 85% between 1 and 4 kHz. A further 86 ears in 44 subjects exhibited varying degrees of sensorineural hearing loss caused by different pathologies. In general, emission amplitudes approximated the shapes of the audiograms, and a highly significant correlation between hearing thresholds and emission amplitudes was demonstrated in the frequency range of 1 to 4 kHz.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical use of click evoked oto-acoustic emissions at the Freiburg ENT clinic]. / Zur klinischen Anwendung Click-Evozierter Otoakustischer Emissionen an der Freiburger HNO-Klinik.

Click-evoked otoacoustic emissions appear to be an efficient way to assess cochlear function in infants and neonates. A new technique developed by Bray and Kemp (1987) enables data to be gathered under clinical conditions. A total of 310 children aged between one day and five years were examined in a realistic clinical situation: 204 of them were admitted to the authors' outpatient department for evaluation of a hearing impairment and 106 were special-care babies or normal newborns. Otoacoustic emissions were successfully tested in 244 of these 310 children at the first attempt after performing behavioural tests. A classification of the emissions by the coefficient of the cross-correlation function and the frequency response spectrum was used. Emissions were observed in 95% (n = 181 ears) of the three- to five-year-old children with a mean behavioural threshold better than 20 dB. In 82% (40/49) of the special-care babies and in 89% (51/57) of the normal newborns a successful emission recording was be obtained. Such findings suggest that this technique for detecting emissions may be useful in early diagnosis of hearing impairments, especially when combined with simple behavioural tests.