Effects of negative dietary cation-anion difference and calcidiol supplementation in transition diets fed to sows on piglet survival, piglet weight, and sow metabolism.

Diets that provide a negative dietary anion cation difference (DCAD) and supplement with a vitamin D metabolite 25-OH-D3 (calcidiol) may increase calcium availability at parturition, and enhance piglet survival and performance. This factorial study assessed the effects of DCAD, calcidiol (50 µg/kg), and parity (parity 1 or >1) and their interactions. Large White and Landrace sows (n = 328), parity 1 to 8 were randomly allocated in blocks to treatment diets from day 103 of gestation until day 3 postfarrow: 1) negative DCAD without calcidiol (negative DCAD + no CA), n = 84, 2) negative DCAD with calcidiol (negative DCAD + CA) n = 84, 3) positive DCAD without calcidiol (negative DCAD + no CA), n = 81, and 4) positive DCAD with calcidiol (positive DCAD + CA), n = 79. Negative DCAD diets were acidified with an anionic feed (2 kg/t) and magnesium sulfate (2 kg/t). All treatment diets contained cholecalciferol at 1,000 IU/kg. Dry sow diets contained 14.8% crude protein (CP), 5.4% crude fiber (CF), 0.8% Ca, and 83 mEq/kg DCAD. Treatment diets 1 and 2 contained 17.5% CP, 7.3% CF, 0.8% Ca, and -2 mEq/kg DCAD. Treatment diets 3 and 4 contained 17.4% CP, 7.4% CF, 0.8% Ca, and 68 mEq/kg DCAD. Before farrowing, all negative DCAD sows had lower urine pH than all sows fed a positive DCAD (5.66 ± 0.05 and 6.29 ± 0.05, respectively; P < 0.01); urinary pH was acidified for both DCAD treatments indicating metabolic acidification. The percentage of sows with stillborn piglets was not affected by DCAD, calcidiol, or parity alone but sows fed the negative DCAD + CA diet had a 28% reduction in odds of stillbirth compared to the negative DCAD + no CA diet and even lesser odds to the positive DCAD + CA diet. At day 1 after farrowing, blood gas, and mineral and metabolite concentrations were consistent with feeding a negative DCAD diet and that negative DCAD diets influence energy metabolism, as indicated by increased glucose, cholesterol, and osteocalcin concentrations and reduced nonesterified free fatty acids and 3-hydroxybutyrate concentrations. In the subsequent litter, total piglets born and born alive (14.7 ± 0.3 and 13.8 ± 0.3 piglets, respectively; P = 0.029) was greater for positive DCAD diets compared to negative DCAD diets; and there was an interaction between DCAD, calcidiol, and parity (P = 0.002). Feeding a negative DCAD diet influenced stillbirth, subsequent litter size, and metabolic responses at farrowing. More studies are needed to define optimal diets prefarrowing for sows.

The transition period between late gestation and lactation is critical to farrowing and successful lactation; sows with higher blood calcium have less risk of dystocia. We evaluated transition diets that provided a negative dietary cation­anion difference (DCAD) and supplemented with calcidiol (CA), both of which influence calcium metabolism. Purebred Landrace or Large White sows (n = 328) were enrolled in the experiment and selected sows that were either primiparous (n = 99) or multiparous (n = 229; average parity = 2.59 ± 1.51; parity range = 1 to 8) were fed a dry sow ration until day 103 of gestation and were then fed transition diets until day 3 postfarrowing in a factorial study. The diets were formulated to include 1) negative DCAD + no CA, 2) negative DCAD + CA, 3) positive DCAD + no CA, or 4) positive DCAD + CA. All diets induced a metabolic acidosis as indicated by urinary pH. Sows fed the negative DCAD with added calcidiol had a >28% reduction in odds of stillbirth over negative DCAD + no CA and positive DCAD + CA diets. Following weaning and re-mating, there were 0.9 more piglets born in the subsequent litter for both positive DCAD diets compared to negative DCAD diets. Blood gas, and mineral and metabolite concentrations provided evidence that negative DCAD diets positively influenced energy metabolism.

Linc-MYH configures INO80 to regulate muscle stem cell numbers and skeletal muscle hypertrophy.

Chromatin remodeling complexes have functions in transcriptional regulation and chromosome maintenance, but it is mostly unknown how the function of these normally ubiquitous complexes is specified in the cellular context. Here, we describe that the evolutionary conserved long non-coding RNA linc-MYH regulates the composition of the INO80 chromatin remodeler complex in muscle stem cells and prevents interaction with WDR5 and the transcription factor YY1. Linc-MYH acts as a selective molecular switch in trans that governs the pro-proliferative function of the ubiquitous INO80 complex but does not affect its role in maintaining genomic stability. The molecular switch is essential for restricting generation of quiescent MuSCs and proliferation of myoblasts in homeostasis and regeneration. Since linc-MYH is expressed in proliferating myoblasts but not in quiescent MuSCs, we reason that the extent of myoblast proliferation has decisive effects on the size of the quiescent MuSC pool.

GnRH neurogenesis depends on embryonic pheromone receptor expression.

Gonadotropin-releasing hormone (GnRH) neurons control mammalian reproduction and migrate from their birthplace in the nasal placode to the hypothalamus during development. Despite much work on the origin and migration of GnRH neurons, the processes that control GnRH lineage formation are not fully understood. Here, we demonstrate that Nhlh genes control vomeronasal receptor expression in the developing murine olfactory placode associated with the generation of the first GnRH neurons at embryonic days (E)10-12. Inactivation of ß2-microglobulin (ß2-m), which selectively affects surface expression of V2Rs, dramatically decreased the number of GnRH neurons in the Nhlh2 mutant background, preventing rescue of fertility in female Nhlh2 mutant mice by male pheromones. In addition, we show that GnRH neurons generated after E12 fail to establish synaptic connections to the vomeronasal amygdala, suggesting the existence of functionally specialized subpopulations of GnRH neurons, which process pheromonal information.

Pro-opiomelanocortin Neurons and the Transcriptional Regulation of Motivated Exercise.

Hypothalamic pro-opiomelanocortin (POMC) neurons are key sensory neurons for energy balance. The basic helix-loop-helix transcription factor NHLH2 is expressed in POMC neurons, and Nhlh2 knockout mice show adult-onset obesity with low exercise behavior. Evidence is presented to explore the hypothesis that NHLH2 transcriptional activity within POMC neurons is crucial for maintaining motivated spontaneous activity and enforced exercise.

Clinical Relevance of IgE to Profilin and/or Polcalcin in Pollen-Sensitized Patients.

BACKGROUND: Component-resolved diagnostics is gaining importance in allergy diagnostics. Allergen extracts contain components with different rates of prevalence and clinical relevance, which can be subdivided at molecular level into major and minor allergens. Clinical complaints are usually triggered by major allergens, while the role of sensitization to the panallergens profilin and polcalcin still remains unclear. METHODS: Eighty-six patients from southern Bavaria with sensitization to the panallergens profilin (Bet v 2/Phl p 12) and/or polcalcin (Bet v 4/Phl p 7) were examined in regard to their sensitization to the 4 main botanic denominations Betulaceae, Oleaceae, Poaceae and Asteraceae by skin prick test and measurement of specific immunoglobulin E antibodies to natural allergen extracts as well as major allergen components rPhl p 1/5, rBet v 1, rOle e 1 and nArt v 1. Sensitization was rated as clinically relevant or irrelevant depending on anamnesis or intranasal allergen challenge. RESULTS: Regarding the 4 botanic denominations, there was no significant difference in the incidence of sensitization to the panallergens profilin, polcalcin or both. The sensitization pattern does not alter when subdividing the cohort into clinically relevant and silent sensitization. We did not find clinically symptomatic sensitization to panallergens without cosensitization to a major allergen. CONCLUSIONS: Our results suggest that sole sensitization to panallergens seems to have no clinical relevance in allergic rhinoconjunctivitis. Clinical complaints seem to be triggered manly by major allergens. Thus, component-resolved allergy diagnostics is crucial in the diagnosis and treatment of polysensitized patients.

Animal Models and "Omics" Technologies for Identification of Novel Biomarkers and Drug Targets to Prevent Heart Failure.

It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an "omics" toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future.

Periodontal Health in Women With Early-Stage Postmenopausal Breast Cancer Newly on Aromatase Inhibitors: A Pilot Study.

BACKGROUND: Aromatase inhibitor (AI) use results in low estrogen levels, which in turn affect bone mineral density (BMD). Periodontitis, alveolar bone loss, and tooth loss are associated with low BMD. The goal of this study is to assess the prevalence of periodontitis and perceived oral health and evaluate salivary biomarkers in postmenopausal women who are survivors of early-stage (I to IIIA) breast cancer (BCa) and receive adjuvant AI therapy. METHODS: Participants included 58 postmenopausal women: 29 with BCa on AIs and 29 controls without BCa diagnoses. Baseline periodontal status was assessed with: 1) periodontal probing depth (PD); 2) bleeding on probing (BOP); and 3) attachment loss (AL). Demographic and dental utilization information was gathered by questionnaire. Linear regression modeling was used to analyze the outcomes. RESULTS: No differences were found in mean PD or number of teeth. The AI group had significantly more sites with BOP (27.8 versus 16.7; P = 0.02), higher worst-site AL (5.2 versus 4.0 mm; P <0.01), and more sites with dental calculus (18.2 versus 6.4; P <0.001) than controls. Linear regression adjusted for income, tobacco use, dental insurance, and previous radiation and chemotherapy exposure demonstrated that AI use increased AL by >2 mm (95% confidence interval, 0.46 to 3.92). Median salivary osteocalcin and tumor necrosis factor-α levels were significantly higher in the AI group than the control group. CONCLUSION: This first investigation of the periodontal status of women initiating adjuvant AI therapy identifies this population as having an increased risk for periodontitis.

Effects of acoustic stimuli used for vestibular evoked myogenic potential studies on the cochlear function.

OBJECTIVE: To study if acoustic stimuli used for vestibular evoked myogenic potential (VEMP) studies can damage the cochlea. STUDY DESIGN: Prospective diagnostic study. SETTING: Academic tertiary referral center. METHODS: In 30 young healthy adults aged between 20 and 35 years without any audiovestibular disorders, cVEMP studies were performed in a standard setting (tone burst, 500 Hz, 133 dB SPL, stimuli rate 200). Before and after acoustic stimulation for the cVEMP examination, the cochlear function was measured using pure tone audiometry and distortion product otoacoustic emissions (DPOAE). Additionally, the subjects were asked about ear symptoms. RESULTS: In all subjects, cVEMP could be recorded. Eight (27%) of them reported subjective hearing symptoms direct after the VEMP examination. All were again free of complaints on the next day. Hearing thresholds did not deteriorate in pure tone audiometry. DPOAE levels decreased on the exposed side in the high-frequency range (4,000-6,000 Hz). The subjects with subjective ear symptoms had a stronger level decrease. In a follow-up measurement 24 hours later, the DPOAE levels showed recovery. CONCLUSION: Acoustic stimuli used to elicit VEMP were found to have an adverse effect on the cochlear function. A clinically relevant hearing loss was not found in our study in healthy adults. Subjective auditory symptoms were reversible within 24 hours. Nevertheless, the stimulus levels and the number of repetitions should be kept as low as possible.

Loss of NSCL-2 in gonadotropin releasing hormone neurons leads to reduction of pro-opiomelanocortin neurons in specific hypothalamic nuclei and causes visceral obesity.

Regulation of sexual reproduction and energy homeostasis are closely interconnected, but only few efforts were made to explore the impact of gonadotropic neurons on metabolic processes. We have used Nscl-2 mutant mice suffering from adult onset of obesity and hypogonadotropic hypogonadism to study effects of gonadotropin releasing hormone (GnRH) neurons on neuronal circuits controlling energy balance. Inactivation of Nscl-2 in GnRH neurons but not in pro-opiomelanocortin (POMC) neurons reduced POMC neurons and increased visceral fat mass, suggesting a critical role of GnRH cells in the regulation of POMC neurons. In contrast, absence of POMC processing in the majority of Nscl-2-deficient POMC neurons had no effect on energy homeostasis. Finally, we investigated the cellular basis of the reduction of GnRH neurons in NSCL-2 mutants using a lineage tracing approach. We found that loss of Nscl-2 results in aberrant migration of GnRH neurons in Nscl-2 mutant mice causing a lineage switch of ectopically located GnRH neurons.

Systemic Teriparatide Administration Promotes Osseous Regeneration of an Intrabony Defect: A Case Report.

INTRODUCTION: Teriparatide comprises the first 34 amino acids of parathyroid hormone and is a systemic anabolic agent that is Food and Drug Administration approved for the treatment of osteoporosis but not for periodontitis. To our knowledge, this is the first clinical case report to document the treatment of a patient with severe periodontitis using an open-flap debridement procedure in conjunction with teriparatide. CASE PRESENTATION: A 45-year-old female patient was diagnosed with severe chronic periodontitis, including the presence of an intrabony defect on tooth #6. She received open-flap debridement surgery in conjunction with daily systemic administration of 20 µg teriparatide, oral vitamin D, and calcium supplements for 6 weeks. Radiographic, clinical, gingival crevicular fluid (pyridinoline cross-linked carboxy-terminal propeptide of type I procollagen, procollagen type 1 N-propeptide, and osteocalcin), and serum parameters (parathyroid hormone, bone alkaline phosphatase, calcium, and 25-hydroxyvitamin D) were assessed. Treatment outcomes were evaluated over 4 years, with successful radiographic and clinical results throughout the follow-up period. CONCLUSION: Teriparatide administration in conjunction with traditional open-flap debridement surgery offers potential for the treatment of severe intrabony defects resulting from chronic periodontitis.

Septal injection of botulinum neurotoxin A for idiopathic rhinitis: a pilot study.

PURPOSE: Botulinum neurotoxin A (BTA) is a promising therapeutic option in the treatment of idiopathic rhinitis (IR), a disease characterized by nasal obstruction and hydrous rhinorrhea. The conventional localization for the injection of BTA in IR is the nasal turbinates. In our own clinical experience, submucoperichondrial injection of BTA in the nasal septum is an alternative that is easy to perform for the therapist and also well tolerated by the patient. MATERIAL AND METHODS: Five patients received an injection of in total 80 mouse units Dysport (Ipsen Pharma, Ettlingen, Germany) in the nasal septum. The unpleasantness of the nasal injection of BTA was measured on a visual analogue scale. Over the course of 14 days, nasal symptoms (rhinorrhea, nasal obstruction, urge to sneeze, nasal pruritus), the number of facial tissues used daily, and possible complications were evaluated. RESULTS: The unpleasantness of the injection of BTA into the nasal septum after local anesthesia was rated low (visual analogue scale, 0.76 on average). A good subjective symptom control was achieved in 3 patients concerning rhinorrhea and in all patients concerning nasal obstruction. The number of facial tissues used daily as a parameter for rhinorrhea was on average 21.0 before the injection of BTA, decreased in 4 patients over the course of time, and was on average 5.8 after 14 days. No patient reported any adverse effects after the injection of BTA. CONCLUSIONS: This pilot study demonstrates that septal injection of BTA in patients with IR can achieve good symptom control and patient comfort and should be compared in further studies to the conventional turbinal injection technique.

The yin and yang of polycomb repression in regenerating muscle.

Tumor necrosis factor-α (TNF-α) has complex effects on muscle regeneration. In this issue of Cell Stem Cell, Palacios et al. (2010) report that TNF-α-activated p38α kinase controls differentiation of muscle stem cells by promoting polycomb repressive complex 2 (PRC2) silencing of the Pax7 promoter.

Teriparatide and osseous regeneration in the oral cavity.

BACKGROUND: Intermittent administration of teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone, has anabolic effects on bone. Although teriparatide has been evaluated for the treatment of osteoporosis and for the healing of fractures, clinical trials evaluating it for the treatment of osseous conditions of the oral cavity in humans are lacking. METHODS: A total of 40 patients with severe, chronic periodontitis underwent periodontal surgery and received daily injections of teriparatide (20 µg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for 6 weeks. The patients were followed for 1 year. The primary outcome was a radiographic linear measurement of alveolar bone level. Secondary outcomes included clinical variables, bone turnover markers in serum and oral fluid, systemic bone mineral density, and quality of life. RESULTS: Radiographic linear resolution of osseous defects was significantly greater after teriparatide therapy than after placebo beginning at 6 months, with a mean linear gain in bone at 1 year of 29% as compared with 3% (P<0.001). Clinical improvement was greater in patients taking teriparatide than in those taking placebo, with a reduction in periodontal probing depth of 33% versus 20% (2.42 mm vs. 1.32 mm) and a gain in clinical attachment level of 22% versus 7% (1.58 mm vs. 0.42 mm) in target lesions at 1 year (P = 0.02 for both comparisons). No serious adverse events were reported; however, the number of patients in the study was small. No significant differences were noted with respect to the other variables that were assessed. CONCLUSIONS: Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity. Teriparatide may offer therapeutic potential for localized bone defects in the jaw. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00277706 .).

NSCL-1 and NSCL-2 synergistically determine the fate of GnRH-1 neurons and control necdin gene expression.

To study the role of the bHLH genes NSCL-1 and NSCL-2 in the development of GnRH-1 neurons, we have generated compound mutant mice. Mutant animals die at birth and show a virtually complete absence of GnRH-1 neurons in the posterior parts of the brain at E18.5 and an aberrant morphology of the remaining GnRH-1 neurons in the anterior parts of the brain indicating that NSCL-1 and NSCL-2 might concomitantly control differentiation/migration of GnRH-1 neurons in a cell autonomous manner. To gain further insights into this process, we screened for NSCL target genes using DNA array hybridization and detected necdin, which is deleted in the human Prader-Willi syndrome phenotypically resembling the NSCL-2 mutation. Using chromatin immunoprecipitation and site-directed mutagenesis of the necdin promoter, we demonstrate that NSCLs together with additional cofactors directly control transcription of the necdin gene. NSCL-dependent control of necdin expression might be instrumental for proper neuronal cell differentiation and enable GnRH-1 neurons to migrate.