Autonomic response to auditory stimulation

Autonomic and behavioral response to fear stimulation (sudden noise 80 dB) was studied in 12 sleeping infants at ages 8–50 weeks. The aim of the present study was to identify a possible passive defense response in infants. The response, which is widespread in birds and mammals, is characterized by apnea and bradycardia with circulatory changes as seen during the forced diving response. Upon stimulation, two respiratory responses were elicited: apnea preceded by irregular respiration or simple irregular respiration. Apnea was elicited in 58% of stimulations at ages 8–16 weeks compared to 14% at 28–50 weeks. The mean duration of apnea decreased from 7.8 s(± 1.8 s) at 8–13 weeks to 4.7s (± 1.1s) at 17–20 weeks. The preceding irregular respiration increased from 5.3 s (± 4.4 s) to 10.6 s (± 5.4 s) at the same ages. The heart rate response was biphasic and were interpreted as the orienting response. The mean deceleration in relation to apnea was 16% at 8–16 weeks and was reduced to 8% at 28–50 weeks. Infants of smoking mothers were more prone to respond with apnea than infants of nonsmoking mothers (73% versus 38%). REM sleep and long postprandial sleep time increased the probability of apnea response (62% versus 38% and 66% versus 35%). The responses seen may be interpreted as expressions of the passive defense response.     

A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy

We performed a phase I trial of recombinant human interleukin-11 (rhIL- 11) in women with breast cancer. Cohorts of three to five women were accrued to five dosage levels of rhIL-11 (10, 25, 50, 75, and 100 micrograms/kg/d). rhIL-11 alone was administered by a daily subcutaneous injection for 14 days during a 28-day prechemotherapy "cycle 0." Patients (pts) subsequently received up to four 28-day cycles of cyclophosphamide (1,500 mg/m2) and doxorubicin (60 mg/m2) chemotherapy followed by rhIL-11 at their assigned dose (days 3 through 14). Sixteen pts (13 stage IV, 3 stage IIIB) were accrued to this study. Median age was 53 years and median Eastern Cooperative Oncology Group Performance Status was 0. A grade 3 neurologic event was seen in 1 pt at 100 micrograms/kg. Because of the degree of grade 2 constitutional symptoms (myalgias/arthralgias and fatigue) at 75 micrograms/kg, dose escalation was stopped and 75 micrograms/kg was the maximally tolerated dose. No other grade 3 or 4 adverse events related to rhIL-11 were seen. The administration of rhIL-11 was not associated with fever. Reversible grade 2 fatigue and myalgias/arthralgias were seen in all pts at 75 micrograms/kg. Weight gain of 3% to 5% associated with edema was seen at doses > 10 micrograms/kg but a capillary leak syndrome was not seen. rhIL-11 alone was associated with a mean 76%, 93%, 108%, and 185% increase in platelet counts at doses of 10, 25, 50, and 75 micrograms/kg, respectively. No significant changes in leukocytes were seen. A mean 19% decrease in hematocrit was observed. Acute-phase proteins increased with treatment at all doses. Compared with patients at the 10 micrograms/kg dose, patients receiving doses > or = 25 micrograms/kg experienced less thrombocytopenia in the first two cycles of chemotherapy. We conclude that rhIL-11 has thrombopoietic activity at all doses studied, is well tolerated at doses of 10, 25, and 50 micrograms/kg, and at doses > or = 25 micrograms/kg has the potential to reduce chemotherapy-induced thrombocytopenia in this model.     

Light-chain-induced renal tubular acidosis: effect of sodium bicarbonate on sodium-proton exchange

We measured sodium-proton (Na⁺/H⁺) exchange in lymphocytes andplatelets of a 46-year-old woman with the adult Fanconi syndromebefore, during, and after treatment with NaHCO₃. Kappa lightchains in her urine and unique but rarely observed crystallinestructures confirmed the presence of light-chain nephropathy.Her glomerular filtration rate was only moderately impairedat 72 ml/min. NaHCO₃ at 1, 3, and 5 mmol/kg/day for 5 days increasedher serum HCO₃ and pH from 17 to 21 mmol/l and 7.28 to 7.39respectively. Plasma renin and aldosterone values were decreasedby NaHCO₃. Na⁺/H⁺ exchange (H_i/min) was measured with the fluorescentmarker BCECF after acidification of lymphocytes and plateletswith sodium propionate at five (10–50mM) doses. Na⁺/H⁺exchange was accelerated in this patient compared to normalcontrols. NaHCO₃ treatment significantly decreased Na⁺/H⁺ exchangein lymphocytes, but not in platelets. These findings suggestthat Na⁺/H⁺ exchange can be influenced by NaHCO₃ ingestion atdoses that only modestly affect systemic pH. Since Na⁺/H⁺ exchangeis involved in stimulus response coupling, cell growth regulation,cell differentiation, and perhaps the progression of nephrosclerosis,these observations may have clinical relevance.     

Long-term Surgical Outcomes for Vertical Deviations in Thyroid Eye Disease

Introduction: Vertical deviations in thyroid eye disease (TED) can present a surgical challenge due to the difficulty and unpredictability of surgery and the high risk of postoperative drift towards overcorrection. This study reports the postoperative outcomes of patients who underwent adjustable vertical strabismus surgery with Vicryl sutures for thyroid eye disease. Methods: We reviewed the records of patients seen for vertical TED strabismus surgery from January 2005 through December 2009. Clinical details were recorded preoperatively, post-adjustment, and at 3 weeks, 3 months, and 1 year postoperatively. Results: The study included 42 patients. Mean age was 62.4 years and 70% were female. All patients were diplopic preoperatively. The mean near vertical deviation was 21.1 prism diopters (PD) preoperatively, 4.0 PD at 3 weeks postoperatively, 5.0 PD at 3 months, and 4.4 PD at 1 year (all mean results representing undercorrection). 71.4% were free of diplopia postoperatively. Seven patients required further surgery, 2 patients needed further botulinum toxin A. Eight patients experienced an overcorrection; five at 3 weeks, seven at 3 months, and eight at 1 year. There was a significant difference in the mean near angle at tie-off post-adjustment in the patients that overcorrected compared to those that did not reverse (3.1 PD vs 7.1 PD; P=0.005). Discussion: Adjustable surgery for vertical strabismus in thyroid eye disease may result in late overcorrection and the need for further intervention. We propose that aiming for an immediate post-adjustment angle of 8 PD undercorrection for near would allow for postoperative drift and reduce the chances of a late overcorrection. This would require careful preoperative counseling of the patient in order to explain that immediate undercorrection and persistent diplopia were necessary in order to generate a better long-term result.     

Characterization of novel Mycobacterium tuberculosis pncA gene mutations in clinical isolates from the Ukraine

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis cases in the Ukraine are increasing. Pyrazinamide (PZA) is critically important for first- and second-line tuberculosis (TB) treatment regimes. However, PZA drug susceptibility testing is time consuming and technically challenging. The present study utilized Next-generation sequencing (NGS) to identify mutations in the pncA gene from clinical isolates and to assess the prevalence of pncA gene mutations in MDR/XDR-TB patients. Clinical isolates were inactivated in molecular transport media and shipped from Kharkiv, Ukraine, to San Antonio, TX. Whole-genome and targeted pncA gene sequencing was carried out using Illumina MiSeq instrumentation. Mutations were noted in 67 of 91 (74%) clinical isolates comprising substitutions, insertions, and deletions in the pncA coding and upstream promoter region. Of 45 mutation types, there were 11 novel, i.e., to date unknown, pncA mutations identified of which 3 were confirmed PZA resistant. Seven isolates contained mixed base mutations, whereas 4 harbored doubled mutations. Data reported here further support use of NGS for pncA gene characterization and may contribute in significant fashion to PZA therapy, especially in MDR- and XDR-TB patients.     

Combining Viral Vectored and Protein-in-adjuvant Vaccines Against the Blood-stage Malaria Antigen AMA1: Report on a Phase 1a Clinical Trial

The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines—chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising “mixed-modality” regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible.     

Esophageal manometry and 24-hour pH monitoring to evaluate laparoscopic Lind fundoplication in gastroesophageal reflux disease.

Laparoscopic and thoracoscopic techniques have provided a new dimension in the correction of functional disorders of the esophagus. Therapeutic success, however, depends on the confirmation of esophageal disease as a cause of the symptoms, on understanding the basic cause of dysfunction and on identifying the surgical patient. This study is a retrospective study of patients submitted to surgery using the Lind procedure for gastroesophageal reflux disease (GERD). The purpose of this study is to establish the value of the routine use of esophageal manometry and 24-hour pH monitoring in order to select patients and perform pre and postoperative functional evaluation. Forty-one patients (68.3%) had a hypotonic lower esophageal sphincter. The average pressure was 9.2 mm Hg preoperatively and 15.2 mm Hg postoperatively, with an increase of 6.0 mm Hg. This increase was 8.8 mm Hg in hypotonics and 4.3 mm Hg in the normotonics. There was a certain degree of hypomotility of the esophageal body in 14 patients (23.3%) and, of this group, 4 (28.5%) improved postoperatively. Pathological acid reflux was found in 51 cases (85.0%) by pH monitoring. The mean of the preoperative DeMeester score was 31.4, later dropping to 3.2. Esophageal manometry and 24-hour pH monitoring are effective methods for revealing the level of functional modification established by anti-reflux surgery and for helping to objectively perform the selection.     

Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors

It was shown before that the soluble form of VEGFR-1 (sVEGFR-1) is present in serum of pregnant women. The aim of the present study was to investigate the presence of this endogenous vascular endothelial growth factor-A (VEGF-A) antagonist in human serum in more detail. sVEGFR-1 was detected in human serum and plasma from normal healthy male and female donors by ELISA. sVEGFR-1 levels ranged from non-detectable up to 440 pg/ml, with no significant difference between male and female donors. In addition, vein endothelial cells (ECs) from an intact vascular bed, the umbilical cord, were shown to secrete sVEGFR-1. Furthermore, human peripheral blood monocytes, a non-EC type expressing VEGFR-1, were shown to contribute to the sVEGFR-1 detectable in human serum and plasma for the first time. EC- and monocyte-derived sVEGFR-1 proved capable of inhibiting the VEGF-induced proliferation and migration of ECs in vitro. Finally, secretion of sVEGFR-1 was increased by the angiogenic factor basic fibroblast growth factor (bFGF) in human ECs and was also enhanced in lipopolysaccharide-activated human monocytes. In human umbilical vein endothelial cells, both the membrane-bound and the sVEGFR-1 seem to be equally regulated on the mRNA as well as the protein level. The presence of an sVEGFR-1 in human serum and plasma of normal male and female donors strongly suggests that it plays an important role as a naturally occurring VEGF antagonist in the regulation and availability of VEGF-mediated biological activities in vivo. This revised version was published online in June 2006 with corrections to the Cover Date.     

Na+/H+ exchange in human lymphocytes and platelets in chronic and subacute metabolic acidosis.

The effect of acid-base disturbances on sodium/proton (Na+/H+) exchange has been examined in animal models; however, few data are available from human studies. To test the effect of metabolic acidosis on Na+/H+ exchange in man, as well as to examine the relationship between Na+/H+ exchange and cytosolic calcium ([Ca2+]i), we measured both variables in patients with decreased renal function with mild metabolic acidosis (pH 7.34 +/- 0.06), in normal control subjects (pH 7.41 +/- 0.02), and in subjects before (pH 7.40 +/- 0.01), and after (pH 7.26 +/- 0.04) ammonium chloride (NH4Cl) 15 g for 5 d. Lymphocytes and platelets were loaded with the cytosolic pH (pHi) indicator 2'-7'-bis(carboxyethyl)-5,6-carboxyfluorescein and acidified to pH approximately 6.6 with propionic acid. To quantitate Na+/H+ exchange, dpHi/dt was determined at 1 min. [Ca2+]i was measured with fura-2. Na+/H+ exchange was significantly increased only in lymphocytes of patients with renal insufficiency. Neither intracellular pH (pHi) nor [Ca2+]i was different from controls. NH4Cl resulted in a significant increase in Na+/H+ exchange in lymphocytes, but not in platelets of normal subjects. Values of pHi and [Ca2+]i in either cell type remained unaffected. Since metabolic acidosis influenced Na+/H+ only in lymphocytes, but not in platelets, it is possible that protein synthesis may be involved in increasing Na+/H+ exchange.