Strains of human immunodeficiency virus type 1 differ in their abilities to infect and replicate in primary human macrophages. Chimeric clones were constructed from a provirus unable to infect macrophages (NLHX) and envelope sequences (V3 loop) of viruses derived without cultivation from brain (YU2 and wl-lcl) or spleen (w2-1b4) tissues. The substituted V3 loop sequences in each case were sufficient to confer upon NLHX the ability to infect macrophages. Furthermore, an envelope domain immediately N terminal to the V3 loop also was found to modulate the level of replication in macrophages. These results demonstrate that an envelope determinant derived directly from patients with AIDS confers HIV-1 tropism for macrophages.

SUMMARY The esophagogastric junction contractile integral (EGJ-CI), designed similar to distal contractile integral (DCI), has been proposed as a metric to evaluate EGJ barrier function. We determined normative values and evaluated EGJ-CI in predicting esophageal acid exposure time (AET) and symptomatic outcome in this observational cohort study. High-resolution manometry (HRM) studies were reviewed in 188 patients (55.2 ± 0.9 years, 64% female) undergoing ambulatory pH monitoring off therapy. Dominant symptoms and global symptom severity (GSS) were determined on questionnaires initially and upon follow-up. EGJ-CI was measured using the DCI tool placed across the EGJ and compared to normal controls (n = 21, 27.6 ± 0.6 years, 52% female). EGJ-CI was calculated both for a single respiratory cycle (SRC, in mmHg.cm.s) and corrected for respiratory cycle (CRC, mmHg.cm). Univariate and multivariate analyses determined the predictive potential of EGJ-CI in terms of AET and post-therapy GSS at follow-up, controlling for medical versus surgical therapy. Mean EGJ-CI values were significantly lower when AET was abnormal; EGJ-CI/SRC and EGJ-CI/CRC were 86% concordant (r = 0.84). Using receiver operating characteristic analysis, values below 121.8 mmHg.cm.s (EGJ-CI/SRC) and 39.3 mmHg.cm (EGJ-CI/CRC) predicted abnormal AET best (sensitivity 0.61 and 0.65, specificity 0.61 and 0.57, respectively). On univariate and multivariate analysis, the EGJ-CI discriminated normal from abnormal AET better than conventional LES parameters (P ≤ 0.02). After 2.7 ± 0.1 years follow-up, EGJ-CI below identified thresholds predicted better symptom response to antireflux surgery compared to medical therapy (P = 0.009). EGJ-CI is a novel HRM metric that has potential to complement or replace currently used basal LES and EGJ parameters.

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Although Wnt signaling activation is frequently observed in human breast cancer, mutations in the genes encoding intracellular components of the Wnt signaling pathway are rare. We found that expression of Wnt signaling co-receptor LRP6 is up-regulated in a subset of human breast cancer tissues and cell lines. To examine whether overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of β-catenin from membrane to cytoplasmic/nuclear fractions. Expression of several Wnt-target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared to wild-type littermate controls. Several matrix metalloproteinases are up-regulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell surface receptor level can contribute to breast cancer tumorigenesis.

Background Ineffective esophageal motility (IEM) is associated with reflux disease, but its natural history is unclear. We evaluated patients undergoing repeat esophageal high resolution manometry (HRM) for symptomatic presentations after antireflux surgery (ARS) to understand the progression of IEM. Methods Patients with repeat HRM after ARS were included. Ineffective esophageal motility was diagnosed if ≥5 sequences had distal contractile integral (DCI) <450 mmHg cm s. Augmentation of DCI following multiple rapid swallows (MRS) was assessed. The esophagogastric junction (EGJ) was interrogated using the EGJ contractile integral (EGJ-CI). Esophageal motor function was compared between patients with and without IEM. Key Results Sixty-eight patients (53.9 ± 1.8 years, 66.2% female) had pre- and post-ARS HRM studies 2.1 ± 0.19 years apart. Esophagogastric junction-CI augmented by a mean of 26.3% following ARS. Four IEM phenotypes were identified: 14.7% had persistent IEM, 8.8% resolved IEM after ARS, 19.1% developed new IEM, and 57.4% had no IEM at any point. Patients with IEM had a lower DCI pre- and post-ARS, lower pre-ARS EGJ CI, and lower pre-ARS-integrated relaxation pressure (p ≤ 0.02 for all comparisons); presenting symptoms and other EGJ metrics were similar (p ≥ 0.08 for all comparisons). The IEM phenotypes could be predicted by MRS DCI response patterns (p = 0.008 across groups); patients with persistent IEM had the least DCI augmentation (p = 0.007 compared to no IEM), while those who resolved IEM had DCI augmentation comparable to no IEM (p = 0.08). Conclusions & Inferences Distinct phenotypes of IEM exist among symptomatic reflux patients following ARS. Provocative testing with MRS may help identify these phenotypes pre-ARS.

Background Multiple rapid swallows (MRS) during esophageal high resolution manometry (HRM) assess esophageal neuromuscular integrity by evaluating post deglutitive inhibition and rebound contraction, but most reports performed only a single MRS sequence. We assessed patterns of MRS reproducibility during clinical HRM in comparison to a normal cohort. Methods Consecutive clinical HRM studies were included if two separate MRS sequences (4–6 rapid swallows ≤4 sec apart) were successfully performed. Chicago Classification diagnoses were identified; contraction wave abnormalities were additionally recorded. MRS induced inhibition (contraction ≤3 cm during inhibition phase) and rebound contraction was assessed, and findings compared to 18 controls (28.0 ±0.7 year, 50.0% female). Reproducibility consisted of similar inhibition and contraction responses with both sequences; discordance was segregated into inhibition and contraction phases. Results MRS was successfully performed in 89.3% patients and all controls; 225 subjects (56.2 ±0.9 year, 62.7% female) met study inclusion criteria. MRS was reproducible in 76.9% patients and 94.4% controls (inhibition phase: 88.0% vs. 94.4%, contraction phase 86.7% vs. 100% respectively, p=ns). A gradient of reproducibility was noted, highest in well-developed motor disorders (achalasia spectrum, hypermotility disorders and aperistalsis, 91.7–100%, p=ns compared to controls); and lower in lesser motor disorders (contraction wave abnormalities, esophageal body hypomotility) or normal studies (62.2–70.8%, p<0.0001 compared to well-developed motor disorders). Inhibition phase was most discordant in contraction wave abnormalities, while contraction phase was most discordant when studies were designated normal. Conclusions MRS is highly reproducible, especially in well-developed motor disorders, and complements the standard wet swallow manometry protocol.

Background Two smooth muscle contraction segments (S2, S3) on esophageal high-resolution manometry (HRM) demonstrate varying contraction vigor in symptomatic patients. Significance of isolated exaggerated smooth muscle contraction remains unclear. Methods High-resolution manometry studies were reviewed in 272 consecutive patients (56.4 ± 0.8 years, 62% F) and compared to 21 healthy controls (27.6 ± 0.6 years, 52% F), using HRM tools (distal contractile integral, DCI; distal latency, DL; integrated relaxation pressure, IRP), Chicago Classification (CC) and multiple rapid swallows (MRS). Segments were designated merged when the trough between S2 and S3 was ≥150 mmHg, and exaggerated S3 when peak S3 amplitude was ≥150 mmHg without merging with S2. Presenting symptoms and global symptom severity (on 100 mm visual analog scale) were recorded. Prevalence of merged and exaggerated segments was determined, and characteristics compared to symptomatic patients with normal HRM, and to healthy controls. Key Results Merged segments were identified in 5.6%, and exaggerated S3 in another 12.5%, but only 17–50% had a CC diagnosis; one healthy control had merged segments. DCI with wet swallows was similar in cohorts with merged and exaggerated segments (p = 0.7), significantly higher than symptomatic patients with normal HRM and healthy controls (p ≤ 0.003 for each comparison). Incomplete inhibition and prominent DCI augmentation on MRS (p ≤ 0.01), and presenting symptoms (chest pain and dysphagia, p = 0.04) characterized exaggerated segments, but not demographics or symptom burden. Conclusions & Inferences Merged esophageal smooth muscle segments and exaggerated S3 may represent hypermotility phenomena from abnormal inhibition and/or excitation, and are not uniformly identified by the CC algorithm.

Background: Brain amyloid-beta (Aβ) plaques, a hallmark of the pathophysiology of Alzheimer’s disease, have been associated with frailty. Whether the plasma Aβ markers show similar relationship with frailty is unknown. OBJECTIVES: To investigate the prospective associations between plasma Aβ42/40 ratio and overtime frailty in community-dwelling older adults. METHODS: From the 5-year Multidomain Alzheimer Preventive Trial (MAPT), we included 477 adults ≥70 years with available data on plasma Aβ42/40 ratio (lower is worse). Fried frailty phenotype (robust, pre-frail and frail) was assessed at the same time-point of plasma Aβ measures and after until the end of follow-up. The outcomes of interest were the change in the frailty phenotype over time (examined by mixed-effect ordinal logistic regressions) and incident frailty (examined by Cox proportional hazard models). RESULTS: Plasma Aβ42/40 did not show significant associations with incident frailty; however, after adjusting for Apolipoprotein E (APOE) ε4 genotype, people in the lower quartile of plasma Aβ42/40 (≤0.103) had higher risk of incident frailty (HR=2.63; 95% CI, 1.00 to 6.89), compared to those in the upper quartile (>0.123). Exploratory analysis found a significant association between the lower quartile of plasma Aβ42/40 and incident frailty among APOE ε4 non-carriers (HR=3.48; 95% CI, 1.19 to 10.16), but not among carriers. No associations between plasma Aβ42/40 and evolution of frailty were observed. CONCLUSION: No significant associations between plasma Aβ42/40 and frailty were found when APOE ε4 status was not accounted into the model. Nevertheless, APOE ε4 non-carriers with high Aβ burden might be more susceptible to develop frailty.