Intermittent parathyroid hormone enhances the healing of medication-related osteonecrosis of the jaw lesions in rice rats.

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event in patients treated with antiresorptives. Management of MRONJ is challenging, and no non-antibiotic, established medical treatment exists. Intermittent parathyroid hormone (iPTH) has been used off-label to treat MRONJ with favorable results. However, its medical efficacy has rarely been substantiated in clinical or preclinical experiments. Using a validated rice rat, infection-based model of MRONJ, we evaluated the effects of iPTH on established MRONJ. We hypothesize that iPTH contributes to MRONJ resolution by enhancing alveolar bone turnover and healing oral soft tissues. Eighty-four rice rats began a standard rodent chow diet at age 4 weeks to induce localized periodontitis. Rats were simultaneously randomized to receive saline (vehicle, VEH) or zoledronic acid (ZOL, 80 µg/kg IV) every 4 weeks. Oral exams were conducted bi-weekly to assign a gross quadrant grade (GQG, 0-4) to evaluate any lesion at the lingual aspect of the interdental space between maxillary molar (M2) and M3. 14 of 20 VEH-treated rice rats (70%) developed maxillary localized periodontitis with GQG 2-3 after 30 ± 10 weeks of saline. Additionally, 40 of 64 ZOL-treated rice rats with periodontitis developed MRONJ-like lesions after 30 ± 10 weeks of ZOL treatment. Rice rats with localized periodontitis or MRONJ-like lesions were treated with saline or iPTH (40 µg/kg) subcutaneously (SC) 3 times/week For 6 weeks until euthanasia. We found that iPTH -treated ZOL rats had a lower prevalence of MRONJ (p < 0.001), with lower severity extent of oral lesions (p = 0.003) and percentage of empty osteocyte lacunae (p < 0.001). ZOL rats treated with iPTH displayed a higher osteoblast surface (p < 0.001), more osteoblasts (p < 0.001), higher osteoclast surface (p < 0.001) and more osteoclasts (p = 0.002) at alveolar bone surfaces than ZOL/VEH rats. Greater gingival epithelial thickness and epithelial cell proliferation rate was found in the oral mucosa and gingiva of ZOL/PTH rats than in ZOL/VEH rats (p < 0.001). Our data suggest that iPTH is an efficacious non-operative medicinal therapy that accelerates oral healing and enhances the resolution of MRONJ lesions in ZOL-treated rice rats.

Organotypic brain slice cultures to model neurodegenerative proteinopathies.

Organotypic slice cultures of brain or spinal cord have been a longstanding tool in neuroscience research but their utility for understanding Alzheimer's disease (AD) and other neurodegenerative proteinopathies has only recently begun to be evaluated. Organotypic brain slice cultures (BSCs) represent a physiologically relevant three-dimensional model of the brain. BSCs support all the central nervous system (CNS) cell types and can be produced from brain areas involved in neurodegenerative disease. BSCs can be used to better understand the induction and significance of proteinopathies underlying the development and progression of AD and other neurodegenerative disorders, and in the future may serve as bridging technologies between cell culture and in vivo experiments for the development and evaluation of novel therapeutic targets and strategies. We review the initial development and general use of BSCs in neuroscience research and highlight the advantages of these cultures as an ex vivo model. Subsequently we focus on i) BSC-based modeling of AD and other neurodegenerative proteinopathies ii) use of BSCs to understand mechanisms underlying these diseases and iii) how BSCs can serve as tools to screen for suitable therapeutics prior to in vivo investigations. Finally, we will examine i) open questions regarding the use of such cultures and ii) how emerging technologies such as recombinant adeno-associated viruses (rAAV) may be combined with these models to advance translational research relevant to neurodegenerative disorders.

Cryptic ins(4;11)(q21;q23q23) detected by fluorescence in situ hybridization: a variant of t(4;11)(q21;q23) in an infant with a precursor B-cell acute lymphoblastic leukemia report of a second case.

We report the chromosomal findings in a 4-year-old female with precursor B-cell acute lymphoblastic leukemia (ALL). The diagnostic karyotype showed an isochromosome 7q, i(7)(q10), as well as questionable rearrangements on 9p and 11q. Fluorescence in situ hybridization (FISH) studies on both interphase and metaphase cells using the MLL "break-apart" and the centromeric chromosome 4 probes were instrumental in the characterization of an MLL gene rearrangement, which was cryptic by conventional cytogenetic analysis. Specifically, the FISH pattern was consistent with an insertion of the 5' region of the MLL gene into chromosome 4 at band q21, most likely a variant t(4;11)(q21;q23). This is the second case of FISH detection of an ins(4;11) in ALL. Our case exemplifies the importance of FISH in the further characterization of precursor B-cell ALL cases without any apparent prognostically significant chromosomal abnormalities.

Celon radiofrequency thermo-ablative palatoplasty for snoring - a pilot study.

A prospective non-randomized study was designed to investigate the effects of Celon radio-frequency thermo-ablation (RFTA) of the soft palate in patients with snoring/mild obstructive sleep apnoea. Ten patients, fulfilling various inclusion/exclusion criteria, underwent single operator sub-mucosal RFTA palatoplasty as an office procedure. Two separate procedures six weeks apart involved each patient receiving six distinct sub-mucosal lesions on each visit. Questionnaires including visual analogue scales (VAS) were used to evaluate post-operative pain and subjective snoring (scored by patient/partner). Polysomnography (PSG) was performed pre-operation and three months following the second procedure. Using non-parametric statistical analysis, a significant reduction in VAS snoring was noted from initial levels to those scored at six and 16 weeks in nine of 10 patients (p = 0.013 and p = 0.007 respectively). (Five of these nine showed a greater than 50 per cent reduction in score). Objectively, six of 10 patients had a reduction in the apnoea-hypopnea Index between the two PSGs, (four of these six showed a greater than 50 per cent reduction) however, this was not statistically significant. Subjective assessment of the PSG snoring signal by the senior author showed eight of 10 patients had either a reduced or much reduced signal at four months. VAS pain confirmed both procedures are well tolerated with minimal analgesia requirements. Minor complaints of transient mild palatal swelling, dry throat, catarrh and referred otalgia were noted and one patient developed mucosal ulceration following both procedures that healed within three weeks. Swallowing and speech were unaffected. These results confirm similar findings using the Somnus Unit, although the Celon device provides additional advantages including inherent safety in a bipolar electrode tip, auto-stop energy application and reduced procedure time.

Bone morphogenetic protein 9: a potent modulator of cartilage development in vitro.

Few publications describe the activity of bone morphogenetic protein-9 (BMP-9), but the consensus of these largely in vivo studies is that while BMP-9 can induce ectopic bone formation at relatively large concentrations, it is primarily active in non-skeletal locations--including the liver, nervous system and marrow. To study the effects of BMP-9 on chondrogenesis in a well-defined environment, calf articular chondrocytes were seeded onto biodegradable PGA scaffolds. The resulting cell-polymer constructs were cultured in either control medium or medium supplemented with 1, 10, 50 or 100 ng/ml of BMP-9. After 4 weeks of in vitro culture, all concentrations of BMP-9 increased the total mass of the constructs, and the amounts of collagen, glycosaminoglycans (GAG) and cells per construct. On a mass percentage basis, BMP-9 tended to increase GAG, to decrease the relative amount of collagen and had little effect on the relative amount of cells. BMP-9 elicited qualitatively similar responses as BMP-2, -12 and -13. However, in contrast to BMP-12 and -13, BMP-9 (at concentrations > or = 10 ng/ml) induced hypertrophic chondrocyte formation and was the only BMP tested to induce mineralization. Taken together, these data suggest that BMP-9 is a potent modulator of cartilage development in vitro.

Somnoplasty for simple snoring--a pilot study.

A prospective pilot study was conducted to investigate the efficacy of radiofrequency thermal ablation (RFTA) of the soft palate to treat simple snoring. Ten consecutive, consenting patients were recruited following history, examination, Epworth scoring, sleep nasendoscopy and full polysomnography. All the patients received two treatments of three lesional RFTA of the soft palate under local anaesthesia, using the Somnus S2 generator. Each treatment was separated by 6 weeks. Patients completed a questionnaire which used visual analogue scales to score pain during the procedure as well as the postoperative period. Snoring was also scored on visual analogue scales by both the patient and the partner. Objective assessment was based on full polysomnography 3 months after the second treatment. Sixty per cent of patients subjectively reported improvement in snoring. Objectively, only 30% showed improvement in duration of snoring (38-48% better) with no change in intensity. There was high patient acceptability of the procedure.

A twin study of attachment in preschool children.

The degree to which individual differences in child-parent attachment were mediated by genetic, shared environmental, and nonshared environmental influences was investigated. One hundred and ten preschool-aged twin pairs (N = 220) were assessed in the Strange Situation and coded using conventional four-way classifications and a continuous measure of attachment security. The degree of sibling similarity in attachment was substantial, with an overall concordance rate of 67% at the secure/insecure level. The degree of concordance was equally high in monozygotic and dizygotic twin pairs, 70% and 64%, respectively, suggesting little genetic influence but a moderate degree of discordance. Twin similarity on the continuous measure of attachment security was r(57) = .48 and r(53) = .38 for monozygotic and dizygotic twin pairs, respectively, also consistent with a modest role for genetic influence but a significant effect for shared and nonshared environment. The implications for genetic influences on the environment and for understanding nonshared and shared environmental influences are discussed.

Isolated hypoglossal nerve palsy due to internal carotid artery dissection.

A case of an isolated hypoglossal nerve palsy is reported. The differential diagnosis is discussed, in the context of the requirement for careful scrutiny of the entire course of the hypoglossal nerve on imaging, to detect underlying pathology remote from the tongue, and to avoid unnecessary invasive diagnostic procedures prompted by the appearance of a 'pseudomass' of the weak tongue both clinically and radiologically.

Longitudinal change in parenting associated with developmental delay and catch-up.

The current study examined the predictors of parent-child relationship quality and developmental change in a sample of children adopted into the U.K. following severe early privation, and in a comparison sample of nondeprived, within-country adoptees. One hundred and fifty-eight children adopted from Romania and 52 U.K. adoptees were assessed at age 6 years; longitudinal data (age 4 and 6 years) were available on the 110 Romanian adoptees placed into U.K. homes before 24 months of age and all U.K. adoptees. Ratings of parent-child positivity and negativity during a semistructured interaction task were obtained from coders who were blind to the child's background. Results indicated that adoptive parent-child relationship quality was related to duration of deprivation and that cognitive/developmental delay mediated this association. The magnitude of this effect was modest and diminished over time. Longitudinal analyses revealed that positive change in parent-child relationship quality was most marked among children who exhibited cognitive catch-up between assessments. The direction of effects appeared to be primarily child to parent. The findings underscore the need for further research on the long-term impact of early experiences on psychosocial development.

Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-alpha.

This study examined the hypothesis that burn trauma promotes cardiac myocyte secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and produces cardiac contractile dysfunction via the p38 mitogen-activated protein kinase (MAPK) pathway. Sprague-Dawley rats were divided into four groups: 1) sham burn rats given anesthesia alone, 2) sham burn rats given the p38 MAPK inhibitor SB203580 (6 mg/kg po, 15 min; 6- and 22-h postburn), 3) rats given third-degree burns over 40% total body surface area and treated with vehicle (1 ml of saline) plus lactated Ringer solution for resuscitation (4 ml x kg(-1). percent burn(-1)), and 4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at several times postburn to examine p38 MAPK activity (by Western blot analysis or in vitro kinase assay); myocardial function and myocyte secretion of TNF-alpha were examined at 24-h postburn. These studies showed significant activation of p38 MAPK at 1-, 2-, and 4-h postburn compared with time-matched shams. Burn trauma impaired cardiac mechanical performance and promoted myocyte secretion of TNF-alpha. SB203580 inhibited p38 MAPK activity, reduced myocyte secretion of TNF-alpha, and prevented burn-mediated cardiac deficits. These data suggest p38 MAPK activation is one aspect of the signaling cascade that culminates in postburn secretion of TNF-alpha and contributes to postburn cardiac dysfunction.

Evaluation of the Herbst Mandibular Advancement Splint in the management of patients with sleep-related breathing disorders.

Sleep-related breathing disorders such as snoring and obstructive sleep apnoea syndrome are the cause of significant social disruption and hypersomnolence. Several intraoral appliances for the treatment of these disorders have been described, especially where nasal continuous positive airway pressure is poorly tolerated. Mandibular Advancement Splints, such as the Herbst splint used in this study can also be offered to patients with mild to moderate sleep apnoea and simple snorers. The success and compliance rate noted in the literature are quite diverse. Few side-effects have been reported. We therefore undertook this study to assess: (1) the compliance; (2) the effectiveness; and (3) the side-effects in the long- and short-term. All patients for whom a Herbst splint had been prescribed in the last 18 months were sent a postal questionnaire regarding the above mentioned issues. In all, 179 questionnaires were posted and on analysis of the 132 returned it was noted that 82% of splints were worn and 88% of patients found the device to be effective. The long-term side-effects were minimal. In addition objective assessment on 10 patients with and without a jaw-retaining device was also obtained. We conclude that the Herbst Mandibular Advancement Splint is a justifiable option in selected subjects with sleep-related breathing disorders.

Cardioprotective effect of chronic hyperglycemia: effect on hypoxia-induced apoptosis and necrosis.

It is generally accepted that mild forms of diabetes render the heart resistant to an ischemic insult. Because myocytes incubated chronically in medium containing high concentrations of glucose (25 mM) develop into a diabetes-like phenotype, we tested the hypothesis that high-glucose treatment diminishes hypoxia-induced injury. In support of this hypothesis, we found that cardiomyocytes incubated for 3 days with medium containing 25 mM glucose showed less hypoxia-induced apoptosis and necrosis than cells exposed to medium containing 5 mM glucose (control). Indeed, whereas 27% of control cells became necrotic after 1 h of chemical hypoxia with 10 mM deoxyglucose and 5 mM amobarbital (Amytal), only 11% of the glucose-treated cells became necrotic. Similarly, glucose treatment reduced the extent of apoptosis from 32% to 12%. This beneficial effect of glucose treatment was associated with a 40% reduction in the Ca(2+) content of the hypoxic cell. Glucose treatment also mediated an upregulation of the cardioprotective factor Bcl-2 but did not affect the cellular content of the proapoptotic factors Bax and Bad. Nonetheless, the phosphorylation state of Bad was shifted in favor of its inactive, phosphorylated form after high-glucose treatment. These data suggest that glucose treatment renders the cardiomyocyte resistant to hypoxia-induced apoptosis and necrosis by preventing the accumulation of Ca(2+) during hypoxia, promoting the upregulation of Bcl-2, and enhancing the inactivation of Bad.

Quality of life issues in recurrent respiratory papillomatosis.

Twenty-six adult patients attending the Royal National Throat, Nose, and Ear Hospital with Recurrent Respiratory Papillomatosis completed two postal questionnaires. One was the generic Short Form-36 (SF-36) quality of life instrument. Severely affected patients had lower scores in all dimensions of this instrument, with large differences from normal controls in dimensions of pain, physical limitation, and energy/vitality. The second questionnaire was newly devised, and designed to ask about a wide variety of larynx-specific symptoms. Answers by patients were compared with those of normal controls, and symptoms selected as significantly more likely to be reported by patients were studied further. Correlation was seen with clinical parameters, and questions likely to be responsive to clinical change in disease burden were identified.

The contributions of behavioural genetic studies to attachment theory.

This review considers the ways in which the methods and theories of behavioural genetics and attachment theory are mutually informative. Four issues are discussed. First, the benefits of the adoptive and twin research designs for testing attachment theory proposals are examined. Second, the ways in which attachment research may elucidate the behavioural genetic concepts of 'shared' and 'non-shared' environment are assessed. Third, the methods use to clarify the role of child effects on child-parent attachment quality are addressed. Finally, the limitations and data analytic considerations of synthesizing behavioural genetic and attachment research are outlined.

Changes in airway and hyoid position in response to mandibular protrusion in subjects with obstructive sleep apnoea (OSA).

This prospective clinical study examined the alterations in airway and hyoid position in response to mandibular advancement in subjects with mild and moderate obstructive sleep apnoea (OSA). Pairs of supine lateral skull radiographs were obtained for 13 female and 45 male, dentate Caucasians. In the first film, the teeth were in maximal intercuspation, while in the second the mandible was postured forwards into a position of maximum comfortable protrusion. Radiographs were traced and digitized, and the alterations in the pharyngeal airway and position of the hyoid were examined. Males and females were analysed separately. In males only, correlations were sought between the changes in hyoid and airway parameters, and the initial and differential radiographic measurements. In males, mean mandibular protrusion at the tip of the lower incisor was 5.3 mm, increasing its distance from the posterior pharyngeal wall by 6.9 mm (or 9 per cent). Movement of the hyoid showed extreme inter-subject variability, both in the amount and direction. In relation to the protruded lower jaw, the hyoid became closer to the gonion by 6.9 mm and to the mandibular plane by 4.3 mm. With respect to the upper face, a 1.3-mm upward and 1.1-mm forward repositioning was seen. The percentage alterations in airway dimensions matched or bettered the mandibular advancement. The minimum distances behind the soft palate and tongue improved by 1.0 and 0.8 mm, respectively. Despite their smaller faces, females frequently showed greater responses to mandibular protrusion than males. No cephalometric features could be identified which might indicate a favourable response of the airway to mandibular protrusion. Larger increments of hyoid movement were associated with an improved airway response, but the strength of the correlations was generally low.

A three-centre prospective pilot study to elucidate the effect of uvulopalatopharyngoplasty on patients with mild obstructive sleep apnoea due to velopharyngeal obstruction.

In this paper we describe the outcome of a prospective study designed to investigate the role of uvulopalatopharyngoplasty in the management of mild obstructive sleep apnoea. A group of 21 patients fulfilling strict inclusion and exclusion criteria underwent uvulopalatopharyngoplasty performed by a single surgeon using a modified technique. Specifically designed daily pain questionnaires were completed by the patients for 2 weeks after surgery and the morbidity associated with the procedure was assessed at 2, 6 and 12 weeks after operation. Thirteen of the 21 patients underwent a postoperative sleep study at 3 months after operation. The outcome measures used were the apnoea/hypopnoea index, the minimum O2 saturation, the sleep arousal index, the sleep architecture the Epworth Sleepiness Scale score, the subjective improvement in both the patient's and their partner's sleep and the morbidity associated with uvulopalatopharyngoplasty. We conclude that the patients with mild obstructive sleep apnoea most likely to obtain significant benefit from uvulopalatopharyngoplasty are those with a body mass index of between 27 and 30 with no cephalometric disproportion, those with frequent arousals not associated with periodic limb movements, those whose sleep related breathing disorder is not positional and most importantly those with symptomatic day time sleepiness.

Laser Assisted Uvulopalatoplasty: an objective evaluation of the technique and results.

The operation of Laser Assisted Uvulopalatoplasty (LAUP) as described by Kamami is now becoming more commonly used in the treatment of snoring and obstructive sleep apnoea. The authors have treated 95 snoring patients, varying the lengths of the soft palate incisions and percentage of uvula excised. All operations were carried out under general anaesthesia using a CO2 laser. Pilot studies showed incisions that are 25% of the distance between the free edge of the soft palate to the hard palate junction and excision of 50% of the uvula give good results with minimal complications. A further study using these parameters was conducted and postoperative evaluation including polysomnography confirmed this procedure to be effective in reducing snoring levels both subjectively and objectively.

Effect of taurine depletion on angiotensin II-mediated modulation of myocardial function.

Taurine depletion was induced by either incubation of isolated myocytes with 5 mM beta-alanine or feeding rats with water containing 3% beta-alanine. Hearts of taurine depleted rats exhibited an impairment in myocardial relaxation, associated with a decrease in Na(+)-Ca2+ exchanger activity. Exposure of the heart to angiotensin II, an activator of the Na(+)-Ca2+ exchanger, eliminated the relaxation defect. In agreement with the contractile results, taurine depletion prolonged the calcium transient, an effect which was partially eliminated by exposure to angiotensin II. Although peak systolic [Ca2+]i was modestly depressed in the taurine depleted myocyte, peak ventricular pressure was normal. This may be related to an elevation in pHi induced by taurine depletion. Angiotensin II had little effect on contractility of the taurine depleted heart, presumably because of two opposing effects, a reduction in pHi and an increase in [Ca2+]i. Thus, taurine depletion alters contractile function and ion transport and both of these effects are modulated by exposure of the heart to angiotensin II.

Shape and size changes induced by taurine depletion in neonatal cardiomyocytes.

Taurine is a very important organic osmolyte in most adult cells. Because of this property it has been proposed that large changes in the intracellular content of taurine can osmotically stress the cell, causing changes in its size and shape. This hypothesis was examined by measuring cell dimensions of taurine deficient cardiomyocytes using confocal microscopy. Incubation of isolated neonatal rat myocytes with medium containing 5 mM beta-alanine led to a 55% decrease in intracellular taurine content. Associated with the loss of taurine was a reduction in cell size. Two factors contributed to the change in cell size. First, there was a shift in cell shape, favoring the smaller of the two cellular configurations commonly found in the myocyte cell culture. Second, the size of the polyhedral configuration was reduced after beta-alanine treatment. These same two events also contributed to size reduction in cardiomyocytes incubated with medium containing 30 mM mannitol. Nonetheless, some qualitative differences exist between cells osmotically stressed by increasing the osmolality of the incubation medium and decreasing intracellular osmolality. The results support a role for taurine in the regulation of osmotic balance in the neonatal cardiomyocyte.