Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.      

Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons

Metabotropic glutamate receptors are important mediators of excitatory amino acid neurotransmission in the striatum. Two-color immunofluorescence histochemistry and immunohistochemistry in combination with retrograde tract-tracing techniques were used to examine the distribution of metabotropic glutamate receptor subtypes 1a and 5 (mGluR1a and mGluR5) among identified subpopulations of striatal projection neurons and interneurons. The majority of striatopallidal and striatonigral neurons were double-labeled for both mGluR1a or mGluR5. Approximately 60% to 70% of either striatonigral or striatopallidal neurons expressed mGluR1a- or mGluR5-like immunoreactivity. The percentage of double-labeled striatopallidal or striatonigral projection neurons did not differ among striatal quadrants. Striatal interneurons expressing parvalbumin or somatostatin or choline acetyltransferase exhibited varying degrees of expression of mGluR1a or mGluR5. Virtually all (94%) parvalbumin-immunoreactive striatal neurons expressed mGluR1a-like immunoreactivity with a majority (79%) of these neurons expressing mGluR5-like immunoreactivity. A high percentage (89%) of striatal choline acetyltransferase-immunoreactive neurons were double-labeled for mGluR1a-like immunoreactivity. Approximately 65% of striatal choline acetyltransferase-immunoreactive neurons expressed mGluR5-like immunoreactivity. A majority (65%) of somatostatin-immunoreactive striatal interneurons expressed mGluR1a-like immunoreactivity with a slightly lower percentage (55%) expressing mGluR5-like immunoreactivity. These findings indicate considerable heterogeneity among striatal projection and interneurons with respect to mGluR1a and mGluR5 expression. There may be subpopulations of striatonigral and striatopallidal projection neurons. These results are consistent as well with prior data indicating subpopulations of the different classes of striatal interneurons.     

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.     

A qualitative study of work-life choices in academic internal medicine

The high attrition rate of female physicians pursuing an academic medicine research career has not been examined in the context of career development theory. We explored how internal medicine residents and faculty experience their work within the context of their broader life domain in order to identify strategies for facilitating career advancement. Semi-structured interviews were conducted with a purposeful sample of 18 residents and 34 faculty members representing male and female physicians at different career stages. Using thematic analysis, three themes emerged: (1) the love of being a physician (“Raison d’être”), (2) family obligations (“2nd Shift”), and (3) balancing work demands with non-work life (“Negotiating Academic Medicine”). Female researchers and educators reported more strategies for multiple role planning and management than female practitioners. Interventions aimed at enhancing academic internists’ planning and self-efficacy for multiple role management should be investigated as a potential means for increasing participation and facilitate advancement.     

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.     

In vivo measurement of the human epidermal thickness in different localizations by multiphoton laser tomography

Background: The in vivo measurement of epidermal thickness is still challenging. While ultrasound, optical coherence tomography and confocal laser microscopy are used with moderate success, this issue has not been addressed by multiphoton laser tomography. Objectives: In the present study, an in vivo measurement of four different morphometric epidermal parameters is performed. Methods: Thirty healthy volunteers aged 21–82 years were included in the study after informed consent and approval of the local ethics committee. At the dorsal forearm and the dorsum of the hand, the thicknesses of the total epidermis, viable epidermis and stratum corneum and the depth of the papillary dermis were calculated from depth‐resolved intensity curves after correlation with multiphoton images. Results: We have shown consistently that in all age groups, the four morphometric parameters are significantly higher at the hand compared with the forearm, while there were no differences between age groups. This is consistent with most previous findings. Conclusion: The method presented here provides a novel in vivo investigation tool for the measurement of epidermal morphometric parameters that may be useful for the observation of epidermal changes over time in skin disorders, therapy side effects or in cosmetic science.