Automated estrous detection using multiple commercial precision dairy monitoring technologies in synchronized dairy cows.

Estrus in dairy cattle varies in duration and intensity, highlighting the need for accurate and continuous monitoring to determine optimal breeding time. The objective of this study was to evaluate precision dairy monitoring technologies (PDMT) for detecting estrus. Estrus was synchronized in lactating Holstein cows (n = 109) using a modified G7G-Ovsynch protocol (last GnRH injection withheld to permit expression of estrus) beginning at 45 to 85 d in milk. Resumption of ovarian cyclicity at enrollment was verified by transrectal ultrasonography for presence of a corpus luteum. Cows were observed visually during 30 min (4 times per day) for behavioral estrus on d -1 to 2 (d 0 = day of estrus). Periods peri-estrus were defined by the temporal blood plasma progesterone patterns on d -5, -4, -3, -2, -1, 0, 2, 4, 6, and 8. Estrous detection by PDMT, an estrous behavior scoring system, and by visual observation of standing estrus were compared with the reference (gold) standard. Only 56% of cows that ovulated were observed standing by visual observation. Sensitivity and specificity for estrous detection were not different among all PDMT. Devices in this study measuring activity in steps, neck movement, high activity of head movement, or a proprietary motion index increased on the day of estrus 69 to 170% from the baseline before estrus. The change in rumination time on the day of estrus decreased for both neck and ear-based technologies (-2 to -16%). Temperature of the reticulorumen, vagina, and ear skin were not different on the day of estrus than day peri-estrus. Daily lying times decreased on average to 24.6% on the day of estrus for IceQube (IceRobotics Ltd., Edinburgh, Scotland). In contrast, lying time increased 15.5 and 33.1% for AfiAct Pedometer Plus (Afimilk, Kibbutz Afikim, Israel) and Track a Cow (ENGS Systems Innovative Dairy Solutions, Rosh Pina, Israel), respectively. All PDMT tested were capable of detecting estrus at least as effectively as visual observation. Four of the 6 PDMT that reported estrous alerts correctly detected 15 to 35% more cows than visual observation 4 times per day. Use of temporal progesterone patterns correctly identified more cows than visual observation alone. Dairy producers considering PDMT should focus on (1) the reference (gold) standard used to test efficacy of a device's alerts and (2) the device that will have the fewest false readings in their operations.

The inflammasome as a target for pain therapy.

The interleukin-1 family of cytokines are potent inducers of inflammation and pain. Proteolytic activation of this family of cytokines is under the control of several innate immune receptors that coordinate to form large multiprotein signalling platforms, termed inflammasomes. Recent evidence suggests that a wide range of inflammatory diseases, cancers, and metabolic and autoimmune disorders, in which pain is a common complaint, may be coordinated by inflammasomes. Activation of inflammasomes results in cleavage of caspase-1, which subsequently induces downstream initiation of several potent pro-inflammatory cascades. Therefore, it has been proposed that targeting inflammasome activity may be a novel and effective therapeutic strategy for these pain-related diseases. The purpose of this narrative review article is to provide the reader with an overview of the activation and regulation of inflammasomes and to investigate the potential therapeutic role of inflammasome inhibition in the treatment of diseases characterized by pain, including the following: complex regional pain syndrome, gout, rheumatoid arthritis, inflammatory pain, neuropathic pain, chronic prostatitis, chronic pelvic pain syndrome, and fibromyalgia. We conclude that the role of the inflammasome in pain-associated diseases is likely to be inflammasome subtype and disease specific. The currently available evidence suggests that disease-specific targeting of the assembly and activity of the inflammasome complex may be a novel therapeutic opportunity for the treatment of refractory pain in many settings.

Stall cleanliness and stall temperature of two different freestall bases.

The objective of this study was to describe the differences in freestall cleanliness and stall temperature between a barn with Dual Chamber Cow Waterbeds (DCCW; Advanced Comfort Technology, Reedsburg, WI) and a barn with rubber-filled mattresses at the University of Kentucky Coldstream Dairy Research Farm from January 18, 2012, to May 3, 2013. Stall cleanliness was measured twice weekly (n=134) by the same 2 observers using a 0.91 m×0.91 m wire grid containing 128 equally sized rectangles (10.16 cm×5.08 cm). This grid was centered at the rear portion of the stall; a rectangle that was visibly wet or had any amount of feces present was defined as a dirty rectangle. Weekly stall temperature (n=66) was measured by the same observer during a.m. milkings in the same predetermined stalls. Feces and wet sawdust were removed from the stalls before stall temperatures were acquired. Temperatures were obtained using a handheld thermometer at 30.48 cm above the stall base as determined via dual laser measurements. Stall temperature was measured on the front, middle, and back of the stall first with clean sawdust and then with the sawdust removed from the stall and wiped clean with a towel. Daily temperature-humidity index (THI) was calculated using Kentucky climate data calculated through the University of Kentucky College of Agriculture via a data logger, located 5.63 km from the Coldstream Dairy Farm. Stall cleanliness was not different between the DCCW barn (26.09±0.89 rectangles) and the rubber-filled mattress barn (23.70±0.89 rectangles). Mean THI throughout the study was 64.39±0.82. Stall temperature was different among THI categories. Temperature-humidity index categories 1 (coldest), 2, 3, and 4 (warmest) had THI ranges of 22.94 to 50.77, 50.77 to 64.88, 64.88 to 78.75, and 78.75 to 101.59, respectively. Stall temperatures (°C; least squares means±SE) were 2.26±0.30, 8.86±0.30, 15.52±0.30, and 20.95±0.30 for THI categories 1 to 4, respectively. Stalls with rubber-filled mattresses had a lower temperature (°C) than DCCW with least squares means±SE of 10.52±0.21°C and 13.29±0.21°C, respectively. The DCCW were probably significantly warmer because water holds heat well. The DCCW may have more of a heat-insulating effect compared with rubber-filled mattresses.

Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment.

BACKGROUND: The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210). OBJECTIVES: To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis. METHODS: Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up. RESULTS: Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B-cell counts. Natural killer cell counts declined with tofacitinib. CONCLUSIONS: Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

Influence of breed, milk production, season, and ambient temperature on dairy cow reticulorumen temperature.

Automatic monitoring of core body temperature in dairy cattle could be useful for identification of illness, heat stress, general physiological stress, and estrus. The SmartBolus (TenXSys Inc., Eagle, ID) system used a reticulorumen bolus to automatically record and transmit dairy cow temperatures. The objective of this research was to characterize the influence of milk yield (MY), time of day, breed, ambient temperature (AT), and season on reticulorumen temperatures (RT) in lactating dairy cows. Continuous RT and AT were collected by SmartBolus transponders every 15 min (96 records per d) from 93 cows (65 Holstein, 18 crossbred, and 10 Jersey) for 615 d. Mean (±SD) daily RT, AT, and MY were 40.14±0.32°C, 12.20±10.61°C, and 33.85±8.67 kg, respectively. The maximum and minimum RT were recorded at 2330 and 1000 h, respectively. Ambient temperature increased RT. Summer RT was significantly greater than spring, fall, or winter RT. The effect of MY on RT varied by breed, season, and AT. Crossbred RT was significantly lower than Holstein RT after adjusting for MY. Crossbred RT responded less to increasing AT than did Holstein RT, potentially indicating improved heat tolerance among these crossbred dairy cows. Reticulorumen temperature increased more dramatically for cows with greater milk yield as AT increased, demonstrating that high-producing cows are more susceptible to heat stress than low-producing cows. These results could be useful in interpretation of automatic temperature system data, heat stress management, and genetic selection of heat-tolerant cows.

Opiate-induced changes in brain adenosine levels and narcotic drug responses.

We have very little information about the metabolomic changes that mediate neurobehavioral responses, including addiction. It was possible that opioid-induced metabolomic changes in brain could mediate some of the pharmacodynamic effects of opioids. To investigate this, opiate-induced brain metabolomic responses were profiled using a semi-targeted method in C57BL/6 and 129Sv1 mice, which exhibit extreme differences in their tendency to become opiate dependent. Escalating morphine doses (10-40 mg/kg) administered over a 4-day period selectively induced a twofold decrease (p<0.00005) in adenosine abundance in the brainstem of C57BL/6 mice, which exhibited symptoms of narcotic drug dependence; but did not decrease adenosine abundance in 129Sv1 mice, which do not exhibit symptoms of dependence. Based on this finding, the effect of adenosine on dependence was investigated in genetically engineered mice with alterations in adenosine tone in the brain and in pharmacologic experiments. Morphine withdrawal behaviors were significantly diminished (p<0.0004) in genetically engineered mice with reduced adenosine tone in the brainstem, and by treatment with an adenosine receptor(1) (A(1)) agonist (2-chloro-N6-cyclopentyladenosine, 0.5mg/kg) or an A(2a) receptor (A(2a)) antagonist (SCH 58261, 1mg/kg). These results indicate that adenosine homeostasis plays a crucial role in narcotic drug responses. Opiate-induced changes in brain adenosine levels may explain many important neurobehavioral features associated with opiate addiction and withdrawal.

In vitro allergen challenge of peripheral blood induces differential gene expression in mononuclear cells of asthmatic patients: inhibition of cytosolic phospholipase A2alpha overcomes the asthma-associated response.

BACKGROUND: Existing treatments for asthma are not effective in all patients and disease exacerbations are common, highlighting the need for increased understanding of disease mechanisms and novel treatment strategies. The leukotriene pathway including the enzyme responsible for arachidonic acid release from cellular phospholipids, cPLA(2)alpha, is a major contributor to asthmatic responses and an attractive target in asthma therapies. OBJECTIVE: The study reported here investigates (a) the differential effects of in vitro exposure of peripheral blood mononuclear cells (PBMCs) to allergen between asthma and healthy subjects, and (b) the contribution of cPLA(2)alpha to these differences in gene expression. METHODS: In vitro responses of asthma (N=26) and healthy (N=11) subject PBMC samples to allergen stimulation in the presence and absence of cPLA(2)alpha inhibition or 5-lipoxygenase inhibition were compared at the gene expression level using oligonucleotide arrays and at the protein level using ELISA. RESULTS: Subject samples within both asthma and healthy groups showed allergen-dependent cytokine production and allergen-dependent gene expression changes, although transcriptional profiling identified 153 genes that were modulated significantly differently by allergen between asthma and healthy subjects. Among these were genes previously associated with asthma, but the majority (about 80%) have not previously been associated with asthma. CONCLUSIONS: Transcriptional profiling elucidated novel gene expression differences between the asthmatic and healthy subject samples. Although 5-lipoxygenase inhibition did not significantly affect allergen-modulated gene expression, the inhibition of cPLA(2)alpha activity affected many of the allergen-dependent, asthma-associated gene expression changes.

Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: a microdialysis study.

Animal studies have documented a critical role for cytokines in cell signaling events underlying inflammation and pain associated with tissue injury. While clinical reports indicate an important role of cytokines in inflammatory pain, methodological limitations have made systematic human studies difficult. This study examined the utility of a human in vivo bioassay combining microdialysis with multiplex immunoassay techniques for measuring cytokine arrays in tissue. The first experiment measured cytokines in interstitial fluid collected from non-inflamed and experimentally inflamed skin (UVB). The effects of noxious heat on cytokine release were also assessed. The second experiment examined whether anti-hyperalgesic effects of the COX-inhibitor ibuprofen were associated with decreased tissue levels of the pro-inflammatory cytokines IL-1 beta and IL-6. In the first experiment, inflammation significantly increased IL-1 beta, IL-6, IL-8, IL-10, G-CSF, and MIP-1 beta. Noxious heat but not experimental inflammation significantly increased IL-7 and IL-13. In the second experiment, an oral dose of 400 and 800 mg ibuprofen produced similar anti-hyperalgesic effects suggesting a ceiling effect. Tissue levels of IL-1 beta and IL-6 were not affected after the 400mg dose but decreased significantly (44+/-32% and 38+/-13%) after the 800 mg dose. These results support the utility of explored method for tracking cytokines in human tissue and suggest that anti-hyperalgesic and anti-inflammatory effects of ibuprofen are at least partially dissociated. The data further suggest that high clinical doses of ibuprofen exert anti-inflammatory effects by down-regulating tissue cytokine levels. Explored human bioassay is a promising tool for studying the pathology and pharmacology of inflammatory and chronic pain conditions.

"On Track"--an educational resource to support dental SHO training.

This paper describes the development, implementation and evaluation of an educational resource, "On Track", designed to support dental SHOs throughout their time in post, thereby helping them gain optimum benefit from this important stage in their early postgraduate training. The need for such a resource was highlighted by a previous study undertaken by the paper's key authors with SHOs and their trainers in a UK dental school. Among several areas of change identified by both trainers and trainees were the needs to develop the SHO experience into more than an apprenticeship by improving the trainer/trainee relationship, and to encourage trainee-centred learning and self-appraisal. The key aims of "On Track" were therefore to define the outcomes of SHO training, to facilitate the relationship between SHO and educational supervisor (trainer), and to encourage the SHO in reflective learning and self-appraisal."On Track" was subject to developmental testing with both trainers and trainees to ensure that it could achieve these aims and the resultant resource is described, along with its implementation and evaluation. "On Track" met with mixed success and the reasons behind this and conclusions drawn for the introduction of any future similar resources are outlined.

The specification of learning outcomes in dentistry.

Increasing emphasis is being placed in dentistry, as in other areas, on outcome-based education and on the specification of learning outcomes. This paper describes the adaptation for dentistry of the medical three circle model as described by Harden to specify learning outcomes. The model offers an effective and user-friendly format based on the three dimensions of the work of a dentist. What the dentist is able to do ('doing the right thing'), how the dentist approaches their practice ('doing the thing right'), and the dentist as a professional ('the right person doing it'). The model also facilitates curriculum and examination planning, reconciles tensions between vocational and academic education and is readily understood and accepted by students and teachers.

Applying learning outcomes to dental education.

Increasing emphasis is being placed in dentistry, as in other areas, on outcome-based education and on the specification of learning outcomes. An earlier paper by the same authors described the adaptation for dentistry of Harden's medical three-circle model to specify learning outcomes. This paper shows how learning outcomes can be applied in dental education, in particular in the areas of student selection, curriculum planning, teaching, learning and assessment.

Increased expression of Ca2+/calmodulin-dependent protein kinase II alpha during chronic morphine exposure.

The chronic administration of morphine and related opioid drugs results in tolerance and dependence which limits the clinical utility of these agents. Neuronal plasticity is probably responsible in large part for tolerance and dependence. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a crucial role in the neuroplastic events underlying memory formation and other phenomena. However, the role of this kinase in morphine tolerance remains unclear. To clarify this issue we explored mRNA and protein expression of CaMKIIalpha in spinal cord tissue from control and morphine treated mice using real-time polymerase chain reaction, Western blot analysis and confocal microscopy. Our chronic exposure paradigm involved the subcutaneous implantation of morphine pellets for 6 days prior to tissue analysis. The results indicate that the levels of CaMKIIalpha mRNA and protein were robustly increased in spinal cord tissue from morphine-treated mice. Confocal microscopy demonstrated that the increase in CaMKIIalpha expression was primarily localized to superficial laminae of the dorsal horn. In addition, the abundance of phosphorylated CaMKIIalpha was increased in spinal cord tissue from morphine-treated mice. We conclude that enhanced CaMKIIalpha expression and activity in spinal cord tissue may contribute to the development of morphine tolerance in mice. The involvement of this enzyme in opioid tolerance suggests other parallels may exist between the neuroplastic events related to memory formation and those related to opioid tolerance or pain.

Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine.

The heme oxygenase (HO) enzyme system has been shown to participate in nociceptive signaling in a number of different models of pain. In these experiments we investigated the role of the HO type 2 (HO-2) isozyme in tolerance to the analgesic effects of morphine, and the hyperalgesia and allodynia which are measurable upon cessation of administration. Wild type C57Bl/6 wild type mice or HO-2 null mutants in that background strain were treated with morphine for 5 days. The morphine administration protocol consisted of either twice daily repeated s.c. boluses of 15 mg/kg or s.c. implantation of a morphine pellet. At the end of the treatment period wild type mice treated by either protocol exhibited tolerance, but the HO-2 null mutants did not. The HO-2 null mutants also exhibited less mechanical allodynia following cessation of morphine administration, though only modest differences in thermal hyperalgesia were noted. There was no correlation between the degree of tolerance obtained in the bolus and pellet protocols and the degree of hyperalgesia and allodynia observed after cessation of morphine administration in the wild type mice. Our final experiments analyzed increases in expression of mRNA for nitric oxide synthase type 1, N-methyl-D-aspartate (NMDA) receptor NMDAR1 subunit and prodynorphin in spinal cord tissue. In pellet-treated mice two- to three-fold increases were observed in the abundance of these species, but very little change was observed in the null-mutant mice. Taken together our results indicate that HO-2 participates in the acquisition of opioid tolerance, the expression of mechanical allodynia after cessation of opioid administration and in gene regulation occurring in the setting of treatment with morphine. Furthermore, these studies suggest that the mechanisms underlying analgesic tolerance and opioid-induced hypersensitivity are at least somewhat distinct.

Socioeconomic status and orofacial clefts in Scotland, 1989 to 1998.

OBJECTIVE: The purpose of this study was to investigate the association between socioeconomic status and orofacial clefts (OFC) in Scotland. DESIGN: Study of prevalence at birth over a 10-year period using an area-based measure of material deprivation. SETTING: Population-based study throughout Scotland. PARTICIPANTS: Eight hundred thirty-four live births with OFC born between January 1, 1989, and December 31, 1998, ascertained from the nationwide register of the Cleft Service in Scotland, compared with the total 603,825 live births in Scotland in this period. RESULTS: There was a strong positive relationship whereby the prevalence of OFC at birth increased with increasing deprivation. This trend was statistically significant for cleft lip and/or palate (CL[P]: p =.016) but not for cleft palate (CP; p =.078). For each type of cleft, the relative risk among those resident in the most deprived areas, compared with those resident in the least deprived areas, was 2.33. CONCLUSIONS: The association between OFC and socioeconomic status is consistent with a report for an earlier period in a smaller part of Scotland. Unlike the earlier study, this pattern appears to be stronger for CL(P) than for CP. These observations do not appear to be an artifact of recording. It is possible that they reflect the association between deprivation and risk factors for OFC, most likely tobacco smoking during pregnancy. Because the relationship between OFC and socioeconomic status appears to have been virtually unstudied in other populations, it would be valuable to investigate this relationship elsewhere and determine whether known risk factors account for the relationship.

Preliminary investigation of a modified Huddart/Bodenham scoring system for assessment of maxillary arch constriction in unilateral cleft lip and palate subjects.

The objective of this study was to describe a numerical scoring system for the measurement of maxillary arch constriction in patients born with unilateral cleft lip and palate (UCLP). A modification of the Huddart/Bodenham scoring system was compared and contrasted with the current methods of measuring treatment outcome, the GOSLON and 5-year indices. The GOSLON and 5-year indices are represented by 10 sets of study models grouped into five categories representing the range of possible outcomes in terms of dental arch relationship, with two sets of models in each of the five categories, whilst the modified Huddart/Bodenham method uses the frequency and severity of crossbite of the dental occlusion to evaluate maxillary arch constriction. The latter system was found to be more objective and reliable, and to correlate well with current recommended standards. It was also more versatile and more sensitive to interarch discrepancies. However, further work is required to refine it to reflect the potential for orthodontic treatment to mask interarch discrepancy following surgery.

Prostaglandin E2 inhibits the potassium current in sensory neurons from hyperalgesic Kv1.1 knockout mice.

Prostaglandin E(2) (PGE(2)) enhances the sensitivity of sensory neurons to various forms of noxious stimulation. This occurs, in part, by the suppression of a delayed rectifier-like potassium current in these neurons. However, the molecular identity of this current remains unclear. Recent studies demonstrated that a mutant mouse lacking a delayed rectifier potassium channel gene, Kv1.1, displayed lowered thresholds to thermal stimulation in behavioral assays of pain perception, i.e. the Kcna1-null mice were hyperalgesic. Here we examined whether PGE(2) can alter the sensitivity of Kcna1-null mice to noxious stimulation and examine the capability of PGE(2) to inhibit the potassium current in these knockout mice. Behavioral assays were used to assess the effect of PGE(2) on either thermal hyperalgesia or mechanical sensitivities. In addition, the whole-cell patch-clamp technique was used to study the effects of PGE(2) on the total potassium current recorded from isolated mouse sensory neurons. Even with a reduced threshold to thermal stimulation, PGE(2) could still sensitize the response of Kcna1-null mice to thermal and mechanical stimulation by amounts that were similar to that in wild type mice. The activation properties of the potassium current were similar for both the wild type and the Kcna1-null mice, whereas the inactivation properties were different in cells exhibiting large amounts of steady-state inactivation (>50%) measured at +20 mV. PGE(2) suppressed the total potassium current in both groups of mice by 40-50% without altering the voltage dependence of activation. In addition, PGE(2) produced similar amounts of suppression in both groups of mice when currents were examined with the steady-state inactivation protocol. Based on these results, it is unlikely that Kv1.1 is the molecular identity of the potassium channel(s) modulated by PGE(2) to sensitize nociceptive sensory neurons. Also, the enhanced thermal sensitivity as observed in the Kcna1-null mice might be due to more central neurons of the pain sensing pathway.

A novel approach to promoting change in SHO training in a dental teaching hospital.

An action research study using a series of staged focus groups with senior house officers (SHOs) and educational supervisors (ES) was used to identify the perceptions of the strengths and challenges in the SHO training programme and to indicate areas for improvement. The basic findings were not entirely surprising, with SHOs wanting more detailed feedback from educational supervisors and educational supervisors challenged (by time constraints and competing clinical and research responsibilities) in meeting the expectations of the SHOs. However the novel approach of using staged focus groups enhanced the educational supervisors' perception of the SHOs' view of their training and the SHOs' perception'of the challenges faced by educational supervisors. Thus a culture of dialogue was created which supported change and innovation. This process was able to directly inform and influence the development of a new induction programme for SHOs and provide valuable insight into the use of the portfolio of learning and the provision of study opportunities. These findings may only be of local interest, however the method employed can be transferred to other contexts to support a grass roots approach to change. Indeed, since this study has been completed, the method has been replicated in a medical setting.