Aims/hypothesis
Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental studies. However, whether circulating concentrations of ...prolactin are associated with risk of type 2 diabetes remains uncertain.
Methods
We analysed the prospective relationship between circulating prolactin concentrations and type 2 diabetes risk in the Nurses’ Health Study (NHS) and NHSII with up to 22 years of follow-up. Total plasma prolactin was measured using immunoassay in 8615 women free of type 2 diabetes and cardiovascular disease at baseline blood collection (NHS 1989–1990; NHSII 1996–1999) and a subset of 998 NHS women providing a second blood sample during 2000–2002. Baseline bioactive prolactin was measured in a subset of 2478 women using the Nb2 bioassay. HRs were estimated using Cox regression.
Results
A total of 699 incident type 2 diabetes cases were documented during 156,140 person-years of follow-up. Total plasma prolactin levels were inversely associated with type 2 diabetes risk; the multivariable HR comparing the highest with the lowest quartile was 0.73 (95% CI 0.55, 0.95;
p
trend
= 0.02). The associations were similar by menopausal status and other risk factors (
p
interaction
> 0.70). Additional adjustment for sex and growth hormones, adiponectin, and inflammatory and insulin markers did not significantly alter the results. The association of plasma bioactive prolactin with type 2 diabetes risk was non-significantly stronger than that of total prolactin (HR comparing extreme quartiles, 0.53 vs 0.81 among the subset of 2478 women,
p
difference
= 0.11). The inverse association of total prolactin with type 2 diabetes was significant during the first 9 years after blood draw but waned linearly with time, whereas for bioactive prolactin, the inverse relationship persisted for a longer follow-up time after blood draw.
Conclusions/interpretation
A normally high circulating total prolactin concentration was associated with a lower type 2 diabetes risk within 9–10 years of follow-up since blood draw in US women. Our findings are consistent with experimental evidence, suggesting that among healthy women, prolactin within the biologically normal range may play a protective role in the pathogenesis of type 2 diabetes.
Abstract About 20% of patients with diabetes suffer from chronic pain with neuropathic characteristics. We investigated the multivariate associations between 92 neurology-related proteins measured in ...serum from 190 patients with painful and painless diabetic neuropathy. Participants were recruited from the Pain in Neuropathy Study, an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the exploration cohort, two groups were defined by hierarchical cluster analyses of protein data. The proportion of painless vs painful neuropathy did not differ between the two groups, but one group had a significantly higher grade of neuropathy as measured by the Toronto Clinical Scoring System (TCSS). This finding was replicated in the replication cohort. Analyzing both groups together, we found that a group of 11 inter-correlated proteins (TNFRSF12A, SCARB2, N2DL-2, SKR3, EFNA4, LAYN, CLM-1, CD38, UNC5C, GFR-alpha-1, and JAM-B) were positively associated with TCSS values. Notably, EFNA4 and UNC5C are known to be part of axon guidance pathways. To conclude, although cluster analysis of 92 neurology-related proteins did not distinguish painful from painless diabetic neuropathy, we identified 11 proteins which positively correlated to neuropathy severity and warrant further investigation as potential biomarkers.
A new summation method model of the reactor antineutrino energy spectrum is presented. It is updated with the most recent evaluated decay databases and with our total absorption gamma-ray ...spectroscopy measurements performed during the last decade. For the first time, the spectral measurements from the Daya Bay experiment are compared with the antineutrino energy spectrum computed with the updated summation method without any renormalization. The results exhibit a better agreement than is obtained with the Huber-Mueller model in the 2-5 MeV range, the region that dominates the detected flux. A systematic trend is found in which the antineutrino flux computed with the summation model decreases with the inclusion of more pandemonium-free data. The calculated flux obtained now lies only 1.9% above that detected in the Daya Bay experiment, a value that may be reduced with forthcoming new pandemonium-free data, leaving less room for a reactor anomaly. Eventually, the new predictions of individual antineutrino spectra for the ^{235}U, ^{239}Pu, ^{241}Pu, and ^{238}U are used to compute the dependence of the reactor antineutrino spectral shape on the fission fractions.
Abstract Pain influences many aspects of daily living and effective analgesics should reinstate normal spontaneous daily behaviours. Experiments are described herein which show that the innate, ...spontaneous behaviour of burrowing by rats, which can be simply and objectively assessed by measuring the amount of gravel left in a hollow tube 1 h after presentation to the rat, is reduced by peripheral nerve injury (tibial nerve transection (TNT), L5 spinal nerve transection (SNT) and partial sciatic nerve ligation (PSNL)) and also following inflammation induced by intra-plantar injection of Complete Freund’s Adjuvant (CFA). Gabapentin (100 mg/kg sc) but not at 30 mg/kg sc significantly reduced burrowing activity in naive rats. All peripheral nerve injuries and CFA reduced burrowing compared with shams and rats naive to surgery. The level of mechanical hypersensitivity in rats with peripheral nerve injury did not correlate with the deficit in burrowing indicating that different parameters of the holistic pain experience are measured in these paradigms. Gabapentin at 30 mg/kg sc, but not 100 mg/kg sc, reversed the deficit in burrowing induced by TNT and ibuprofen (30 mg/kg sc) reversed the effect of CFA on burrowing. These experiments show that measurement of burrowing is a simple, objective assay of innate rodent behaviour affected by pain that is ethologically relevant to the rat, does not rely wholly on evoking a reflex and can dissociate a selective analgesic dose of gabapentin from one inducing motor impairment in the same animal.
A distal symmetrical sensory peripheral neuropathy is frequently observed in people living with Human Immunodeficiency Virus Type 1 (HIV-1). This neuropathy can be associated with viral infection ...alone, probably involving a role for the envelope glycoprotein gp120; or a drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors as a component of highly active anti-retroviral therapy. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). Systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity (33% decrease in limb withdrawal threshold) that when combined with perineural HIV-gp120 is exacerbated (48% decrease in threshold) and both treatments result in thigmotactic (anxiety-like) behaviour. Immunohistochemical studies revealed little ddC-associated alteration in DRG phenotype, as compared with known changes following perineural HIV-gp120. However, the chemokine CCL2 is significantly expressed in the DRG of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fibre density, comparable to that seen in herpes zoster infection. Moreover, a spinal gliosis is apparent at times of peak behavioural sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone. Treatment with the microglial inhibitor, minocycline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120+ddC model and reversal of some measures of thigmotaxis. Finally, the hypersensitivity to mechanical stimuli was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. These data suggests that both neuropathic pain models display many features of HIV- and anti-retroviral-related peripheral neuropathy. They therefore merit further investigation for the elucidation of underlying mechanisms and may prove useful for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain.
High mammographic density (MD) is a strong risk factor for breast cancer. However, it is unclear whether high MD is an intermediate phenotype or whether breast cancer risk factors influence breast ...cancer risk and MD independently.
Our study population included 1290 invasive breast cancer cases and 3422 controls from the Nurses' Health Studies. We estimated the percent of the total association between the risk factor and breast cancer that was mediated by MD.
In both pre- and postmenopausal women, the association between history of biopsy-confirmed benign breast disease and risk was partially mediated by percent MD (percent mediated (PM) = 17 %, p < 0.01 and PM = 33 %, p = 0.04, respectively). In premenopausal women, the associations between early life body size (adolescent somatotype and BMI at age 18) and breast cancer risk were substantially mediated by percent MD (PM = 73 %, p = 0.05 and PM = 82 %, p = 0.04, respectively). In postmenopausal women, the proportion of the associations of childhood somatotype and adolescent somatotype that were mediated by percent MD were lower (PM = 26 %, p = 0.01 for both measures). Hormone therapy use at mammogram was significantly mediated by percent MD in postmenopausal women (PM = 22 %, p < 0.01). Associations with other risk factors, such as age at menarche or family history of breast cancer, were not mediated by percent MD.
Percent MD partially mediated some of the associations between risk factors and breast cancer, though the magnitude varied by risk factor and menopausal status. These findings suggest that high MD may be an intermediate in some biological pathways for breast cancer development.
Live plants are increasingly used in hydraulic laboratories to investigate flow‐vegetation interactions. In such experiments, they are often exposed to stressful handling and storage that can cause ...strong physiological responses and modifications in plant biomechanics. Little is known about the potential effect of these impacts on the performance of plants during hydraulic experiments. In this multidisciplinary study with a freshwater macrophyte (Potamogeton natans) we assess whether the duration and the conditions in which plants are stored in a laboratory prior to testing can impact plant stress, biomechanics and hydrodynamics, and quantify this impact. Plant stress was evaluated using chlorophyll fluorescence analysis (and the maximum quantum yield of photosystem II as specific indicator). Plant hydrodynamics were assessed using the drag coefficient calculated from drag force measurements at two flow scenarios. The results show that different plant handling/storage procedures can have a significant impact on plant hydrodynamics even within a short time frame, with a variation of the mean drag coefficient of approximately 30% across groups, which is comparable to the variation found across different species of freshwater macrophytes in previous studies. Plants with the highest level of stress were also characterized by the lowest drag coefficient across the groups considered, suggesting a potential link between plant stress and hydrodynamics.
Plain Language Summary
Aquatic plants are used in laboratory experiments designed to understand how they affect water velocity, sediment movement and the distribution of substances in the water. Plants are moved from the field or nursery to the laboratory, where the light conditions are often insufficient for photosynthesis and the water quality can be poor; this can lead to deterioration in plant health and cause plants to physically change. Here we use a common aquatic plant to investigate how such changes can affect the force associated with the water flow that pulls the plant downstream (drag force). To measure plant health, we used an indicator of photosynthesis efficiency, to measure plant rigidity we conducted bending tests on plant stems, and to measure the drag force on the plant we carried out tests in a channel equipped with a force sensor. The results show that the drag force experienced by plants depends on how, and for how long, they have been stored and that stressed plants are better at avoiding some of the drag force. This has implications for scientists who use live plants in laboratory experiments, indicating that storage and handling prior to experiments can have a significant effect on the results.
Key Points
The hydrodynamics of freshwater macrophytes can be affected by the conditions in the field and storage procedure used prior to experiments
This impact is quantified as up to 30% of the drag coefficient, similar to the impact associated with using different macrophyte species
Higher levels of plant stress are associated with lower drag forces
Disabling neuropathic pain (NeuP) is a common sequel of diabetic peripheral neuropathy (DPN). We aimed to characterise the sensory phenotype of patients with and without NeuP, assess screening tools ...for NeuP, and relate DPN severity to NeuP. The Pain in Neuropathy Study (PiNS) is an observational cross-sectional multicentre study. A total of 191 patients with DPN underwent neurological examination, quantitative sensory testing, nerve conduction studies, and skin biopsy for intraepidermal nerve fibre density assessment. A set of questionnaires assessed the presence of pain, pain intensity, pain distribution, and the psychological and functional impact of pain. Patients were divided according to the presence of DPN, and thereafter according to the presence and severity of NeuP. The DN4 questionnaire demonstrated excellent sensitivity (88%) and specificity (93%) in screening for NeuP. There was a positive correlation between greater neuropathy severity (r = 0.39, P < 0.01), higher HbA1c (r = 0.21, P < 0.01), and the presence (and severity) of NeuP. Diabetic peripheral neuropathy sensory phenotype is characterised by hyposensitivity to applied stimuli that was more marked in the moderate/severe NeuP group than in the mild NeuP or no NeuP groups. Brush-evoked allodynia was present in only those with NeuP (15%); the paradoxical heat sensation did not discriminate between those with (40%) and without (41.3%) NeuP. The "irritable nociceptor" subgroup could only be applied to a minority of patients (6.3%) with NeuP. This study provides a firm basis to rationalise further phenotyping of painful DPN, for instance, stratification of patients with DPN for analgesic drug trials.
Ovarian cancer is the fifth most common cause of cancer death among women in the USA. In this study, our objective was to determine whether modifiable exposures to common analgesics outside of ...standard treatment influence prognosis in patients with ovarian cancer.
The Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) are ongoing prospective studies of 121 700 and 116 429 US nurses who have completed biennial questionnaires since 1976 and 1989, respectively. We retrieved information from medical records, death certificates, or linkage to a state or Surveillance, Epidemiology, and End Results (SEER) cancer registry on ovarian cancer cases. Eligible participants had confirmed invasive, stage I–III epithelial ovarian cancer, and had data available on analgesic use. The primary objective was to determine whether self-reported regular use (≥2 days per week) of aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), or paracetamol before and after ovarian cancer diagnosis, was associated with ovarian cancer-specific survival. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for these associations, adjusting for age and year of diagnosis, disease stage, and histology.
Between June 1, 1976, and May 31, 2012, for the NHS and between June 1, 1989, and May 31, 2013, for NHSII, 1789 participants of the NHS and NHSII studies were diagnosed with epithelial ovarian cancer and 1143 (64%) were eligible to be included in this study; 1031 (90%) of 1143 cases were included in the pre-diagnosis exposure analysis and 964 cases (84%) in the post-diagnosis exposure analysis. Compared with never-users, participants who reported recent (current use in the past 2 years) post-diagnosis use of aspirin (HR 0·68 95% CI 0·52–0·89) and non-aspirin NSAIDs (HR 0·67 95% CI 0·51–0·87) had an improved ovarian cancer-specific survival. Any type of analgesic use pre-diagnosis, and post-diagnosis use of paracetamol, were not positively associated with ovarian cancer-specific survival. In analyses of change in analgesic use from pre-diagnosis to post-diagnosis, those participants who became recent users of aspirin (HR 0·44 95% CI 0·26–0·74) or became recent users of non-aspirin NSAIDs (HR 0·46 95% CI 0·29–0·73) post-diagnosis had a lower risk of ovarian cancer-specific death than never-users.
Recent use of aspirin or non-aspirin NSAIDs, defined as current use in the past 2 years, after diagnosis appears to improve ovarian cancer-specific survival. If these results are confirmed in further studies, further research should explore potential synergistic effects of anti-inflammatory medications used in combination with standard ovarian cancer therapies to improve the prognosis for patients diagnosed with ovarian cancer.
National Institutes of Health, National Cancer Institute, The Marsha Rivkin Center for Ovarian Cancer Research.
This review is an update of a review published in 2011, itself a major update of previous reviews published in 2005 and 2000, investigating the effects of gabapentin in chronic neuropathic pain (pain ...due to nerve damage). Antiepileptic drugs are used to manage chronic neuropathic pain and fibromyalgia.
To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain and fibromyalgia.
We identified randomised trials of gabapentin for chronic neuropathic pain or fibromyalgia by searching the databases MEDLINE (1966 to March 2014), EMBASE (1980 to 2014 week 10), and CENTRAL in The Cochrane Library (Issue 3 of 12, 2014). We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched Clinicaltrials.gov. Searches were run originally in 2011 and the date of the most recent search was 17 March 2014.
Randomised, double-blind studies reporting the analgesic and adverse effects of gabapentin in neuropathic pain or fibromyalgia with assessment of pain intensity, pain relief, or both, using validated scales. Participants were adults.
Three review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.For efficacy, we calculated the number needed to treat to benefit (NNT), concentrating on at least 50% pain intensity reduction, and Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) definitions of at least moderate and substantial benefit. For harm we calculated number needed to treat for harm (NNH) for adverse effects and withdrawal. Meta-analysis was undertaken using a fixed-effect model. We emphasised differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, complex regional painsyndrome type 1 (CRPS-1), and fibromyalgia.
Seven new studies with 1919 participants were added. Another report (147 participants) provided results for a study already included, but which previously had no usable data. A further report (170 participants) used an experimental formulation of intrathecal gabapentin. Thirty-seven studies (5633 participants) studied oral gabapentin at daily doses of 1200 mg or more in 12 chronic pain conditions; 84% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy or mixed neuropathic pain. There was no first tier evidence.Second tier evidence for the outcome of at least 50% pain intensity reduction, considered valuable by patients with chronic pain, showed that gabapentin was significantly better than placebo in postherpetic neuralgia (34% gabapentin versus 21% placebo; NNT 8.0, 95% CI 6.0 to 12) and painful diabetic neuropathy (38% versus 21%, NNT 5.9, 95% CI 4.6 to 8.3). There was insufficient information in other pain conditions to reach any reliable conclusion. There was no obvious difference between standard gabapentin formulations and recently-introduced extended-release or gastro-retentive formulations, or between different doses of gabapentin.Adverse events occurred significantly more often with gabapentin. Persons taking gabapentin could expect to have at least one adverse event (62%), withdraw because of an adverse event (11%), suffer dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (9%). Serious adverse events (3%) were no more common than with placebo.There were insufficient data for direct comparisons with other active treatments, and only third tier evidence for other painful conditions.
There was no top tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with some painful neuropathic pain conditions. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. About 35% achieved this degree of pain relief with gabapentin, compared with 21% for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in neuropathic pain conditions except postherpetic neuralgia and painful diabetic neuropathy, and in fibromyalgia, is very limited.The levels of efficacy found for gabapentin are consistent with those found for other drug therapies in postherpetic neuralgia and painful diabetic neuropathy.
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