The pontine Kölliker-Fuse nucleus gates facial, hypoglossal, and vagal upper airway related motor activity.

The pontine Kölliker-Fuse nucleus (KFn) is a core nucleus of respiratory network that mediates the inspiratory-expiratory phase transition and gates eupneic motor discharges in the vagal and hypoglossal nerves. In the present study, we investigated whether the same KFn circuit may also gate motor activities that control the resistance of the nasal airway, which is of particular importance in rodents. To do so, we simultaneously recorded phrenic, facial, vagal and hypoglossal cranial nerve activity in an in situ perfused brainstem preparation before and after bilateral injection of the GABA-receptor agonist isoguvacine (50-70 nl, 10 mM) into the KFn (n = 11). Our results show that bilateral inhibition of the KFn triggers apneusis (prolonged inspiration) and abolished pre-inspiratory discharge of facial, vagal and hypoglossal nerves as well as post-inspiratory discharge in the vagus. We conclude that the KFn plays a critical role for the eupneic regulation of naso-pharyngeal airway patency and the potential functions of the KFn in regulating airway patency and orofacial behavior is discussed.

Heterogeneous ozone effects on the DNA methylome of bronchial cells observed in a crossover study.

We used a randomized crossover experiment to estimate the effects of ozone (vs. clean air) exposure on genome-wide DNA methylation of target bronchial epithelial cells, using 17 volunteers, each randomly exposed on two separated occasions to clean air or 0.3-ppm ozone for two hours. Twenty-four hours after exposure, participants underwent bronchoscopy to collect epithelial cells whose DNA methylation was measured using the Illumina 450 K platform. We performed global and regional tests examining the ozone versus clean air effect on the DNA methylome and calculated Fisher-exact p-values for a series of univariate tests. We found little evidence of an overall effect of ozone on the DNA methylome but some suggestive changes in PLSCR1, HCAR1, and LINC00336 DNA methylation after ozone exposure relative to clean air. We observed some participant-to-participant heterogeneity in ozone responses.

Effects of pharmacological lesion of the nucleus retroambiguus region on the pharyngeal phase of swallowing.

Pharyngeal swallowing is controlled by synaptic interactions within a swallowing central pattern generator (sw-CPG) that is composed of a dorsal and a ventral swallowing group (VSG). Here, we used electrical stimulation (10 s) of the superior laryngeal nerve (SLN; 20 Hz; pulse width: 100 µs) to explore the role of the VSG in an arterially-perfused brainstem preparation of rats. To investigate the effects of pharmacological lesion (local microinjection of an GABA(A)-R agonist) of the nucleus retroambiguus (NRA), a designated component of the VSG, we recorded phrenic (PNA) and vagal nerve (VNA) activities. Control SLN stimulation with stepwise increasing stimulus intensities (from 20 µA to 160 µA) elicited robust suppression of PNA and evoked sequential swallowing activity in the VNA. Lesioning of the NRA had no effect on the pattern of pharyngeal swallowing, but significantly increased the sensory gating of SLN inputs. We conclude that the NRA is not part of the VSG, but appears to have important roles for the central gating of swallowing.

Thoracic sympathetic chain stimulation modulates and entrains the respiratory pattern.

Stimulation of thoracic sympathetic chain (TSC) afferents has been shown to slow the respiratory rhythm in dogs, monkeys and humans. However, sparse information exists about the physiological role of TSC afferents in modulating respiration or the central pathways of these afferents. Here, we sought to investigate whether the perfused preparation of juvenile rats is a suitable experimental model to study the role of TSC-afferents in the modulation of respiration. We show that tonic (30s) TSC stimulation initially triggered either prolonged post-inspiratory vagal nerve discharge, or when the stimulus onset occurred in the second half of expiration, TSC stimulation also modulated late-expiratory abdominal nerve activity. Independent of the timing of the TSC-stimulation the net effect was lengthening of the expiratory interval and subtle shortening of inspiration. TSC evoked respiratory modulation showed progressive habituation during the stimulus period. Importantly, high thoracic spinal cord transections abolished the TSC-evoked respiratory modulation, indicating that TSC afferents are likely to be relayed within the thoracic spinal cord. Next, we repeatedly applied 400 ms trains of stimuli at an inter-burst interval near that of the intrinsic respiratory rate and show that rhythmic TSC stimulation has a strong potential to entrain the central respiratory rhythm. Importantly, under the imposed rhythm, TSC stimuli became aligned with the late expiratory phase. The entrainment pattern supports the hypothesis that the TSC pathway may convey extra-pulmonary visceral mechano-sensory feedback that might be sensitive to visceral mass movements during locomotion. The latter was previously discussed to significantly contribute to the locomotor-respiratory coupling in various mammalian species.

Endoscopic and clinical responses to anti-tubercular therapy can differentiate intestinal tuberculosis from Crohn's disease.

BACKGROUND: Differentiation between intestinal tuberculosis and Crohn's disease is difficult and may require therapeutic trial with anti-tubercular therapy in tuberculosis-endemic regions. AIM: To evaluate the role of therapeutic trial with anti-tubercular therapy in patients with diagnostic confusion between intestinal tuberculosis and Crohn's disease. METHODS: We performed retrospective-comparative (n = 288: 131 patients who received anti-tubercular therapy before being diagnosed as Crohn's disease and 157 intestinal tuberculosis patients) and prospective-validation study (n = 55 patients with diagnostic confusion of intestinal tuberculosis/Crohn's disease). Outcomes assessed were global symptomatic response and endoscopic mucosal healing. RESULTS: In the derivation cohort, among those eventually diagnosed as Crohn's disease, global symptomatic response with anti-tubercular therapy was seen in 38% at 3 months and in 37% who completed 6 months of anti-tubercular therapy. Ninety-four per cent of intestinal tuberculosis patients showed global symptomatic response by 3 months. Endoscopic mucosal healing was seen in only 5% of patients with Crohn's disease compared with 100% of intestinal tuberculosis patients. In the validation cohort, all the patients with intestinal tuberculosis had symptomatic response and endoscopic mucosal healing after 6 months of anti-tubercular therapy. Among the patients with an eventual diagnosis of Crohn's disease, symptomatic response was seen in 64% at 2 months and in 31% who completed 6 months of anti-tubercular therapy, none had mucosal healing. CONCLUSIONS: Disproportionately lower mucosal healing rate despite an overall symptom response with 6 months of anti-tubercular therapy in patients with Crohn's disease suggests a need for repeat colonoscopy for diagnosing Crohn's disease. Patients with intestinal tuberculosis showing significant symptomatic response after 2-3 months of anti-tubercular therapy, suggest that symptom persistence after a therapeutic trial of 3 months of anti-tubercular therapy may indicate the diagnosis of Crohn's disease.

Blockade of dorsolateral pontine 5HT1A receptors destabilizes the respiratory rhythm in C57BL6/J wild-type mice.

The neurotransmitter serotonin (5HT) acting via 5HT1a receptors (5HT1aR) is a potent determinant of respiratory rhythm variability. Here, we address the 5HT1aR-dependent control of respiratory rhythm variability in C57BL6/J mice. Using the in situ perfused preparation, we compared the effects of systemic versus focal blockade of 5HT1aRs. Blocking 5HT1aRs in the Kölliker-Fuse nucleus (KFn) increased the occurrence of spontaneous apneas and accounted for the systemic effects of 5HT1aR antagonists. Further, 5HT1aRs of the KFn stabilized the respiratory rhythm's response to arterial chemoreflex perturbations; reducing the recovering time, e.g., the latency to return to the baseline pattern. Together, these results suggest that the KFn regulates both intrinsic and sensory determinants of respiratory rhythm variability.

Assessment of safety and efficacy of an indigenous self-expandable fully covered esophageal metal stent for palliation of esophageal cancer.

BACKGROUND: Patients with unresectable esophageal cancer require palliation for dysphagia. Placement of a self-expandable metal stent (SEMS) is the procedure of choice for palliation of dysphagia. OBJECTIVE: To evaluate the safety and efficacy of an indigenous fully-covered SEMS in patients with esophageal cancer. METHODS: Eligible patients with unresectable esophageal cancer requiring palliation for dysphagia were included in the study. An indigenous fully covered SEMS of appropriate length was placed under endoscopic and fluoroscopic guidance. Outcome measures assessed were adverse events and improvement in dysphagia. RESULTS: Twenty one patients (mean age 57.71±13.14 years; 17 males) were included. After stenting, dysphagia score decreased from 3.2+0.4 to 0.35+0.74 at 4 weeks. Adverse events included retrosternal pain, respiratory distress and aspiration pneumonia in 12, 2 and 1 patients respectively. Five patients required repeat stenting due to stent migration in 4 (following radiotherapy in 3) and tumour ingrowth in 1. There was primary stent malfunction in one patient. The median survival of patients was 140 (76-199) days, which was higher in those who received radiotherapy. CONCLUSION: The stent was reasonably safe and effective to relieve dysphagia due to unresectable esophageal cancer.

Management of temporomandibular joint ankylosis type III: lateral arthroplasty as a treatment of choice.

Many surgical techniques for the management of temporomandibular joint (TMJ) ankylosis have been described in the literature. The purpose of this study was to report our experience using a lateral arthroplasty technique in the management of type III ankylosis. The records of 15 patients treated for TMJ ankylosis at our institution between 2007 and 2011 were reviewed. Pre- and postoperative information collected included age, gender, aetiology, ankylosis type/classification, existing facial asymmetry, maximum pre- and postoperative mouth opening, complications, and recurrence of ankylosis. The mean maximum inter-incisal opening in the preoperative period was 12.9 mm and in the postoperative period was 36.2mm. No major complication was observed in any patient. No recurrence was noted in any patient. Our working hypothesis was that for patients with ankylosis type III, the medially displaced condyle and disc can fulfil their role in mandibular function and growth after extirpation of the ankylozed mass. Although they are located in an awkward medial position, they should function exactly as they would after a properly treated, displaced condylar fracture.

Vagal-dependent nonlinear variability in the respiratory pattern of anesthetized, spontaneously breathing rats.

Physiological rhythms, including respiration, exhibit endogenous variability associated with health, and deviations from this are associated with disease. Specific changes in the linear and nonlinear sources of breathing variability have not been investigated. In this study, we used information theory-based techniques, combined with surrogate data testing, to quantify and characterize the vagal-dependent nonlinear pattern variability in urethane-anesthetized, spontaneously breathing adult rats. Surrogate data sets preserved the amplitude distribution and linear correlations of the original data set, but nonlinear correlation structure in the data was removed. Differences in mutual information and sample entropy between original and surrogate data sets indicated the presence of deterministic nonlinear or stochastic non-Gaussian variability. With vagi intact (n = 11), the respiratory cycle exhibited significant nonlinear behavior in templates of points separated by time delays ranging from one sample to one cycle length. After vagotomy (n = 6), even though nonlinear variability was reduced significantly, nonlinear properties were still evident at various time delays. Nonlinear deterministic variability did not change further after subsequent bilateral microinjection of MK-801, an N-methyl-D-aspartate receptor antagonist, in the Kölliker-Fuse nuclei. Reversing the sequence (n = 5), blocking N-methyl-D-aspartate receptors bilaterally in the dorsolateral pons significantly decreased nonlinear variability in the respiratory pattern, even with the vagi intact, and subsequent vagotomy did not change nonlinear variability. Thus both vagal and dorsolateral pontine influences contribute to nonlinear respiratory pattern variability. Furthermore, breathing dynamics of the intact system are mutually dependent on vagal and pontine sources of nonlinear complexity. Understanding the structure and modulation of variability provides insight into disease effects on respiratory patterning.

An evaluation of the referral transport system of Patna, Bihar.

OBJECTIVES: The key objective of the study was to evaluate the coverage and functioning of the referral transport system under NRHM in block PHCs of district Patna in Bihar. METHODS: A cross-sectional descriptive study was conducted during October-November, 2008 in 16 block PHCs in Patna. In-depth interviews were conducted at 811 households where there was an occasion to transfer a patient to a hospital in the previous two months time. Medical officer in-charge and civil surgeon of the district were also interviewed. Besides, focus group discussions were conducted with the community members and leaders regarding the functioning of referral transport. RESULTS: Availability of the referral transport services was irregular mainly due to deputation of the vehicles for flood relief activities or other purposes. 93 (11.5%) of respondents used the PHC transport facilities, of which 52.7% got it instantaneously. 'Dial an ambulance 102' services were mainly used by urban clients. The system was following an arbitrary cost structure. 84.2% of the clients belonging to below poverty line had to pay for the service and are afraid of availing the services. CONCLUSION: Inadequate number of ambulances in PHCs, unequipped ambulances, lack of life saving equipments, 24 hours duty by single driver, arbitrary cost frame work and urban preference for services were some of the factors leading to unpopularity of the scheme.

An open-label study of darbepoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis.

OBJECTIVE: To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W). SUBJECTS: This open-label study enrolled subjects > or =18 years of age who had glomerular filtration rate > or =15 and < or =60 mL min(-1)/1.73 m(2), had Hb 11.0-13.0 g dL(-1), and were receiving Q2W darbepoetin alfa. DESIGN: Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or =11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure. RESULTS: The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or =11.0 g dL(-1) during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL(-1). Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb > or =11.0 g dL(-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 mug (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects. CONCLUSION: Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.

An experimental design for induction of non-specific aortoarteritis.

BACKGROUND: An attempt was made to induce aortoarteritis in mice by using various antigens. METHODS AND RESULTS: The Swiss mice were immunized with eight different antigens and were grouped A to G. Group H served as control. The mice were then bled at 1st, 2nd, 4th, 6th and 8th month interval post-immunization for estimating antibody titer. Then the mice were sacrificed and the heart, aorta and kidney were taken out and processed for hematoxylin-eosin staining. There was gradual increase in the antibody titer from 1st month till 4th month within all the experimental groups (A-G), when compared with control group H. The titer started falling sharply from 6th month post-immunization. However, the control group H did not show much variation. When each individual group was compared separately with control group H, the significant statistical value was obtained. Histopathological examination revealed mild inflammation (+) in kidney by 2nd month, moderate inflammation (++) by 6th month, extensive inflammation (+++) by 8th month and alteration in the normal parenchyma of kidney by 8th month. CONCLUSIONS: The histopathological changes brought out through antigens were more pronounced by 8th month following injection of tunica media, tunica adventitia, tunica intima and aorta collagen as compared to that of standard collagen and mouse aorta injections.

Use of ACE inhibitors is associated with prolonged survival of arteriovenous grafts.

Vascular access complications are common in hemodialysis patients. To investigate whether the use of angiotensin-converting enzyme (ACE) inhibitors influences the rate of polytetrafluoroethylene (PTFE) graft complications, we compared the rate of intervention-free graft survival among patients treated versus not treated with ACE inhibitors. We retrospectively analyzed the survival of grafts placed at our institution between January 1, 1995, and October 31, 1999. Among 121 grafts, 25 grafts were placed in 19 patients treated with ACE inhibitors and 96 grafts were placed in 68 patients not treated with ACE inhibitors. Follow-up ranged from 1 month to 5 years. Ten of 25 grafts failed in the ACE-inhibitor group and 62 of 95 grafts failed in the non-ACE-inhibitor group. Actuarial intervention-free access survival rates (Kaplan-Meier) were significantly greater in the ACE-inhibitor than non-ACE-inhibitor group (71% versus 53% at 6 months, 58% versus 35% at 12 months, and 44% versus 22% at 24 months; P = 0.04). Using a Cox model adjusting for age, race, sex, and diabetes, the relative risk (RR) for access failure in the ACE-inhibitor group was 53% less than in the non-ACE-inhibitor group (RR, 0.47; p < 0.03). In a more complex Cox model with additional adjustment for comorbid conditions, the RR was even lower (RR, 0.32; P = 0.003) for the ACE-inhibitor compared with non-ACE-inhibitor group (reference = 1.00). The lower RR was observed for patients with and without congestive heart failure. These results suggest that ACE inhibitors offer clinical promise in the prevention of PTFE graft failure. A prospective randomized trial is warranted to confirm the benefit of ACE inhibitors.

Analysis of variable flow Doppler hemodialysis access flow measurements and comparison with ultrasound dilution.

The variable flow (VF) Doppler method determines access blood flow from the pump speed-induced change in Doppler signal between the arterial and venous needles. This study evaluated 35 patients in two analyses to assess VF Doppler measurement reproducibility (54 paired measurements) and compared VF Doppler and ultrasound dilution flow measurements (24 paired measurements). VF Doppler measurement variations were 4% for access flow less than 800 mL/min (n = 17), 6% for access flow of 801 to 1,600 mL/min (n = 22), and 11% for access flow greater than 1,600 mL/min (n = 15). The mean measurement coefficient of variation was 7% for VF Doppler compared with 5% for ultrasound dilution. Correlation coefficients (r) between VF Doppler and ultrasound dilution access flow measurements were 0.79 (n = 24; P < 0.0001), 0.84 for access flow less than 2,000 mL/min (n = 20; P < 0.0001), and 0.91 for access flow less than 1,600 mL/min (n = 18, P < 0.0001). VF Doppler measurements using indicated versus measured pump flow rates correlated highly (r = 0.99; P < 0.0001). VF Doppler therefore yields reproducible access volume flow measurements that correlate with ultrasound dilution measurements. The VF Doppler method is dependent on the pump-induced change in access Doppler signal and therefore is inherently most accurate and reproducible at lower access blood flow rates. This method appears capable of determining access flow rates in the clinically useful range.

Type of vascular access and mortality in U.S. hemodialysis patients.

BACKGROUND: Vascular access (VA) complications account for 16 to 25% of hospital admissions. This study tested the hypothesis that the type of VA in use is correlated with overall mortality and cause-specific mortality. METHODS: Data were analyzed from the U.S. Renal Data System Dialysis Morbidity and Mortality Study Wave 1, a random sample of 5507 patients, prevalent on hemodialysis as of December 31, 1993. The relative mortality risk during a two-year observation was analyzed by Cox-regression methods with adjustments for demographic and comorbid conditions. Using similar methods, cause-specific analyses also were performed for death caused by infection and cardiac causes. RESULTS: In diabetic mellitus (DM) patients with end-stage renal disease, the associated relative mortality risk was higher for those with arteriovenous graft (AVG; RR = 1.41, P < 0.003) and central venous catheter (CVC; RR = 1.54, P < 0.002) as compared with arteriovenous fistula (AVF). In non-DM patients, those with CVC had a higher associated mortality (RR = 1.70, P < 0.001), as did to a lesser degree those with AVG (RR = 1.08, P = 0.35) when compared with AVF. Cause-specific analyses found higher infection-related deaths for CVC (RR = 2.30, P < 0.06) and AVG (RR = 2.47, P < 0.02) compared with AVF in DM; in non-DM, risk was higher also for CVC (RR = 1.83, P < 0.04) and AVG (RR = 1.27, P < 0.33). In contrast to our hypothesis that AV shunting increases cardiac risk, deaths caused by cardiac causes were higher in CVC than AVF for both DM (RR = 1.47, P < 0.05) and non-DM (RR = 1.34, P < 0.05) patients. CONCLUSION: This case-mix adjusted analysis suggests that CVC and AVG are correlated with increased mortality risk when compared with AVF, both overall and by major causes of death.

Posttransplant bone disease: a case illustrating dramatic improvements in bone density with vitamin D replacement therapy.

Although bisphosponates are proposed as first-line treatment for posttransplant bone disease they are not optimal in all situations. A kidney transplant recipient developed hypercalcemia from mobilization of extraskeletal calcium. He had low serum parathyroid hormone and vitamin D; high calcium excretion; and normal calcium intake. Bone biopsy revealed severe osteomalacia. Bisphosphonates, used in the early treatment of acute hypercalcemia, were not indicated to treat osteomalacia. However, over several months serum calcium declined sufficiently to allow treatment of the bone disease with oral calcitriol. Dual-energy radiographic absorptiometry over the next 2 years documented dramatic improvements in bone density (percent of young-normal controls) : from 63 to 85%, at the lumbar spine; from 38 to 67%, at the femoral neck. This response to treatment could not have been achieved with an antiresorptive strategy. Optimal management of posttransplant bone disease requires a diagnostic approach, which considers all plausible contributing factors.

Enzyme-linked immunosorbent assay and immunoblot study in Takayasu's arteritis patients.

Takayasu's arteritis or non-specific aortoarteritis is an inflammatory and stenotic disease of the aorta of questionable aetiology. Immunopathogenic mechanism, the precise nature of which is uncertain, is often suspected to be one of the basic causes of this disease. The present study was designed to estimate the antiaorta antibody titre in Takayasu's arteritis patients and to further locate the antigen in the vessel wall. Thirty clinically and angiographically proven cases of Takayasu's arteritis patients with appropriate controls were studied. Antiaorta antibody titres were estimated using Enzyme-Linked Immunosorbent Assay method. The controls included patients of vascular diseases other than Takayasu's arteritis, autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosis and normal healthy individuals. Absorbance value at 492 nm at a dilution of 1:500 of the patients' sera was expressed as the antiaorta, antibody titre. There was significant difference (p < 0.005) between the mean value of the antibody titre in patients (0.471 +/- 0.073) and patients of other vascular diseases (0.209 +/- .056); autoimmune diseases (0.143 +/- .024); and, controls (0.108 +/- 0.012). Collagenase treatment of the aorta resulted in the fall of the antibody titre of aortitis patients (0.162 +/- 0.036) suggesting that the collagen might be one of the components responsible for autoantigenecity of aorta resulting in aortitis. The aortic extract was further subjected to 10 percent sodium dodecyle sulphate-polyacrylamide gel electrophoresis and immunoblot was done with Takayasu's arteritis patients' sera as well as controls' sera. The sera in 80 percent of Takayasu's arteritis patients immunoprecipitated a protein of molecular weight 45,000 (45 kilodalton) whereas only 15 percent patients of autoimmune disease group showed precipitation band though of lower molecular weight. Normal human sera gave no immunoprecipitation band. The precise nature of the antigen still needs to be identified.