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Background: The interaction between cerebral vessel disease (CVD) pathology and Alzheimer’s disease (AD) pathology in the development of dementia is controversial. We examined the association of cerebral vascular neuropathology and cerebrovascular risk factors with the mild stage of Alzheimer's dementia and cognitive function. Methods: This cross-sectional study included men and women aged 60 years or over who had yearly clinical assessments and had agreed to brain autopsy at the time of death, and who contributed to data stored at the National Alzheimer's Coordinating Center (NACC) in the USA. Cognitively normal and impaired subjects with presumptive aetiology of AD, including mild cognitive impairment (ADMCI) and dementia (Alzheimer’s dementia), and with complete neuropathological data, were included in our analyses. We used neuropsychological data proximate to death to create summary measures of global cognition and cognitive domains. Systematic neuropathological assessments documenting the severity of cerebral vascular pathology were included. Logistic and linear regression analyses corrected for age at death, sex and Lewy body pathology were used to examine associations of vessel disease with the severity of Alzheimer's disease dementia, and cognitive function, respectively. Results: No significant relationship was observed between late-life risk factors and Alzheimer’s dementia. The severity of arteriosclerosis and presence of global infarcts/lacunes were related to mild Alzheimer’s dementia (B=0.423, p Conclusion: Our study found the significant relation of global, old, acute/subacute and regional cerebral vascular pathologies, but not white matter rarefaction, to the onset and severity of Alzheimer’s dementia. We also showed that late-life risk factors were found to have no relation with Alzheimer’s dementia, and the increased risk of dementia with APOE ε4 is not mediated by CVD. The best interpretation of these findings is that CVD has a potential additive effect with AD pathologies in the development and progression of what is clinically diagnosed as Alzheimer's dementia.

Members of the AraC family of transcriptional regulators (AFTRs) control the expression of many genes important to cellular processes, including virulence. In Shigella species, the type III secretion system (T3SS), a key determinant for host cell invasion, is regulated by the three-tiered VirF/VirB/MxiE transcriptional cascade. Both VirF and MxiE belong to the AFTRs and are characterized as positive transcriptional regulators. Here, we identify a novel regulatory activity for MxiE and its coregulator IpgC, which manifests as a negative feedback loop in the VirF/VirB/MxiE transcriptional cascade. Our findings show that MxiE and IpgC downregulate the virB promoter and, hence, VirB protein production, thus decreasing VirB-dependent promoter activity at ospD1, one of the nearly 50 VirB-dependent genes. At the virB promoter, regions required for negative MxiE- and IpgC-dependent regulation were mapped and found to be coincident with regions required for positive VirF-dependent regulation. In tandem, negative MxiE- and IpgC-dependent regulation of the virB promoter only occurred in the presence of VirF, suggesting that MxiE and IpgC can function to counter VirF activation of the virB promoter. Lastly, MxiE and IpgC do not downregulate another VirF-activated promoter, icsA, demonstrating that this negative feedback loop targets the virB promoter. Our study provides insight into a mechanism that may reprogram Shigella virulence gene expression following type III secretion and provides the impetus to examine if MxiE and IpgC homologs in other important bacterial pathogens, such as Burkholderia pseudomallei and Salmonella enterica serovars Typhimurium and Typhi, coordinate similar negative feedback loops. IMPORTANCE The large AraC family of transcriptional regulators (AFTRs) control virulence gene expression in many bacterial pathogens. In Shigella species, the AraC/XylS protein MxiE and its coregulator IpgC positively regulate the expression of type III secretion system genes within the three-tiered VirF/VirB/MxiE transcriptional cascade. Our findings suggest a negative feedback loop in the VirF/VirB/MxiE cascade, in which MxiE and IpgC counter VirF-dependent activation of the virB promoter, thus making this the first characterization of negative MxiE- and IpgC-dependent regulation. Our study provides insight into a mechanism that likely reprograms Shigella virulence gene expression following type III secretion, which has implications for other important bacterial pathogens with functional homologs of MxiE and IpgC.

Controversy persists regarding metformin’s role in cancer therapy. Our recent work suggested metformin acts by impacting the tumor microenvironment (TME), normalizing the epigenetic profile of cancer-associated mesenchymal stem cells (CA-MSC). As CA-MSC can negatively impact tumor immune infiltrates, we evaluated metformin’s impact on the human TME, focusing on the interplay of stroma and immune infiltrates. Tumor samples from (i) 38 patients treated with metformin and chemotherapy and (ii) 44 non-metformin matched controls were included in a tissue microarray (TMA). The TMA was used to compare the presence of CA-MSC, desmoplasia and immune infiltrates in the TME. In vitro and in vivo models examined metformin’s role in alteration of the CA-MSC phenotype. The average percentage of CA-MSC was significantly lower in metformin-treated than in chemotherapy alone-treated tumors (p = 0.006). There were fewer regulatory T-cells in metformin-treated tumors (p = 0.043). Consistent with CA-MSC’s role in excluding T-cells from tumor islets, the T-cells were primarily present within the tumor stroma. Evaluation of metformin’s impact in vitro suggested that metformin cannot reverse a CA-MSC phenotype; however, the in vivo model where metformin was introduced prior to the establishment of the CA-MSC phenotype supported that metformin can partially prevent the reprogramming of normal MSC into CA-MSC. Metformin treatment led to a decrease in both the presence of protumorigenic CA-MSC and in immune exclusion of T cells, leading to a more immune-permissive environment. This suggests clinical utility in prevention and in treatment for early-stage disease and putatively in immune therapy.

Members of the AraC Family of Transcriptional Regulators (AFTRs) control the expression of many genes important to cellular processes, including virulence. In Shigella species, the type III secretion system (T3SS), a key determinant for host cell invasion, is regulated by the three-tiered VirF/VirB/MxiE transcription cascade. Both VirF and MxiE belong to the AFTRs and are characterized as positive transcriptional regulators. Here, we identify a novel regulatory activity for MxiE and its co-regulator IpgC, which manifests as a negative feedback loop in the VirF/VirB/MxiE transcription cascade. Our findings show that MxiE and IpgC down-regulate the virB promoter and hence VirB protein production, thus, decreasing VirB-dependent promoter activity at ospD1, one of the nearly 50 VirB-dependent genes. At the virB promoter, regions required for negative MxiE- and IpgC-dependent regulation were mapped and found to be coincident with regions required for positive VirF-dependent regulation. In tandem, negative MxiE- and IpgC-dependent regulation of the virB promoter only occurred in the presence of VirF suggesting that MxiE and IpgC can function to counter VirF activation of the virB promoter. Lastly, MxiE and IpgC do not down-regulate another VirF-activated promoter, icsA, demonstrating that this negative feedback loop targets the virB promoter. Our study provides insight into a mechanism that may reprogram Shigella virulence gene expression following type III secretion and provides the impetus to examine if MxiE and IpgC homologs in other important bacterial pathogens such as Burkholderia pseudomallei and Salmonella enterica serovars Typhimurium and Typhi coordinate similar negative feedback loops.IMPORTANCEThe large AraC Family of Transcriptional Regulators (AFTRs) control virulence gene expression in many bacterial pathogens. In Shigella species, the AraC/XylS protein MxiE and its co-regulator IpgC positively regulate the expression of type III secretion system genes within the three-tiered VirF/VirB/MxiE transcription cascade. Our findings suggest a negative feedback loop in the VirF/VirB/MxiE cascade in which MxiE and IpgC counter VirF-dependent activation of the virB promoter, thus, making this the first characterization of negative MxiE- and IpgC-dependent regulation. Our study provides insight into a mechanism that likely reprograms Shigella virulence gene expression following type III secretion, which has implications for other important bacterial pathogens with functional homologs of MxiE and IpgC.

Nevada ranks among the lowest in the United States regarding the number of Total Active Physicians per capita. The Association of American Medical Colleges (AAMC) calculated an overall 77% in-state...

This paper investigates the growth behavior, morphology of intermetallic compound (IMC) layer and hardness of low melting temperature Sn–35Bi–1Ag (wt%) solders on different surface-finished Cu substrates i.e., immersion Ag (ImAg)-plated Cu and Ag/Ni-plated Cu substrates. From SEM observation, a scallop-shaped Cu6Sn5 IMC layer was found to adhere at initial reaction stage on Sn–Bi–Ag solders/ImAg-plated Cu substrate system. However, a very thin Cu3Sn IMC layer was clearly also observed between the Cu6Sn5 IMC layer and substrate after a lengthy reaction. On the other hand, in Sn–Bi–Ag solder and Ag/Ni-plated Cu substrate system, a scallop-shaped Ni3Sn4 IMC layer was observed at the interface without any Cu3Sn IMC layer formation. These IMC layers thicknesses were increased with increasing the reaction time and temperature. However, the growth behavior of Ni3Sn4 IMC layer was slower than that of Cu6Sn5 and Cu3Sn IMC layers. In solder ball regions, bright contrast Bi and needle-shaped Ag3Sn phases were clearly observed in the dark contrast β-Sn matrix in both type of solder systems. Furthermore, bright contrast Bi phase size was increased with the reaction time. However, in the Sn–35Bi–1Ag solder and Ag/Ni-plated Cu substrate system, the Bi phase appeared with fine microstructure as compared with the Sn–35Bi–1Ag solder/ImAg-plated Cu substrate system because the Ag layer dissolved into the molten solder and changed the diffusivity and chemical affinity. The hardness values of Sn–Bi–Ag solder joints on ImAg-plated Cu and Ag/Ni-plated Cu substrates after 5 min reaction at 230 °C were about 23.0 and 24.1 HV, respectively—and about 18.9 and 20.4 HV after 30 min reaction at 230 °C, respectively.

BACKGROUND: Epidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC). METHODS: Thirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase–positive (ALDH(+)) CD133(+) CSCs and (b) a relapse-free survival at 18 months of more than 50%. RESULTS: Metformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0–21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6–70.5). Median overall survival was 57.9 months (95% CI 28.0–not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH(+)CD133(+) CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC–driven chemoresistance in vitro. CONCLUSION: Translational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01579812.

Nano-sized, non-reacting, non-coarsening CeO2 particles with a density close to that of solder alloy were incorporated into Sn–3.0 wt%Ag–0.5 wt%Cu solder paste. The interfacial microstructure and hardness of Ag surface-finished Cu substrates were investigated, as a function of reaction time, at various temperatures. After the initial reaction, an island-shaped Cu6Sn5 intermetallic compound (IMC) layer was clearly observed at the interfaces of the Sn–Ag–Cu based solders/immersion Ag plated Cu substrates. However, after a prolonged reaction, a very thin, firmly adhering Cu3Sn IMC layer was observed between the Cu6Sn5 IMC layer and the substrates. Rod-like Ag3Sn IMC particles were also clearly observed at the interfaces. At the interfaces of the Sn–Ag–Cu based solder-Ag/Ni metallized Cu substrates, a (Cu, Ni)–Sn IMC layer was found. Rod-like Ag3Sn and needle-shaped Cu6Sn5 IMC particles were also observed on the top surface of the (Cu, Ni)–Sn IMC layer. As the temperature and reaction time increased, so did the thickness of the IMC layers. In the solder ball region of both systems, a fine microstructure of Ag3Sn, Cu6Sn5 IMC particles appeared in the β-Sn matrix. However, the growth behavior of the IMC layers of composite solder doped with CeO2 nanoparticles was inhibited, due to an accumulation of surface-active CeO2 nanoparticles at the grain boundary or in the IMC layers. In addition, the composite solder joint doped with CeO2 nanoparticles had a higher hardness value than the plain Sn–Ag–Cu solder joints, due to a well-controlled fine microstructure and uniformly distributed CeO2 nanoparticles. After 5 min of reaction on immersion Ag-plated Cu substrates at 250 °C, the micro-hardness values of the plain Sn–Ag–Cu solder joint and the composite solder joints containing 1 wt% of CeO2 nanoparticles were approximately 16.6 and 18.6 Hv, respectively. However after 30 min of reaction, the hardness values were approximately 14.4 and 16.6 Hv, while the micro-hardness values of the plain Sn–Ag–Cu solder joints and the composite solder joints on Ag/Ni metallized Cu substrates after 5 min of reaction at 250 °C were approximately 15.9 and 17.4 Hv, respectively. After 30 min of reaction, values of approximately 14.4 and 15.5 Hv were recorded.

Sn–Ag–Cu composite solder has been prepared by adding Ni nanoparticles. Interfacial reactions, the morphology of the intermetallic compounds (IMC) that were formed, the hardness between the solder joints and the plain Cu/immersion Ag-plated Cu pads depending on the number of the reflow cycles and the aging time have all been investigated. A scallop-shaped Cu6Sn5 IMC layer that adhered to the substrate surface was formed at the interfaces of the plain Sn–Ag–Cu solder joints during the early reflow cycles. A very thin Cu3Sn IMC layer was found between the Cu6Sn5 IMC layer and the substrates after a lengthy reflow cycle and solid-state aging process. However, after adding Ni nanoparticles, a scallop-shaped (Cu, Ni)–Sn IMC layer was clearly observed at both of the substrate surfaces, without any Cu3Sn IMC layer formation. Needle-shaped Ag3Sn and sphere-shaped Cu6Sn5 IMC particles were clearly observed in the β-Sn matrix in the solder-ball region of the plain Sn–Ag–Cu solder joints. Additional fine (Cu, Ni)-Sn IMC particles were found to be homogeneously distributed in the β-Sn matrix of the solder joints containing the Ni nanoparticles. The Sn–Ag–Cu–0.5Ni composite solder joints consistently displayed higher hardness values than the plain Sn–Ag–Cu solder joints for any specific number of reflow cycles–on both substrates–due to their well-controlled, fine network-type microstructures and the homogeneous distribution of fine (Cu, Ni)–Sn IMC particles, which acted as second-phase strengthening mechanisms. The hardness values of Sn–Ag–Cu and Sn–Ag–Cu–0.5Ni on the Cu substrates after one reflow cycle were about 15.1 and 16.6 Hv, respectively–and about 12.2 and 14.4 Hv after sixteen reflow cycles, respectively. However, the hardness values of the plain Sn–Ag–Cu solder joint and solder joint containing 0.5 wt% Ni nanoparticles after one reflow cycle on the immersion Ag plated Cu substrates were about 17.7 and 18.7 Hv, respectively, and about 13.2 and 15.3 Hv after sixteen reflow cycles, respectively.

In order to identify the effect on the properties and behavior of tin–zinc–bismuth (Sn-8 wt% Zn-3 wt% Bi or Sn-13.6 at.% Zn-1.6 at.% Bi) based solders produced by adding nickel (Ni) nano-particles, the interfacial microstructure between plain and composite solders with newly developed immersion silver (Ag) plated copper (Cu) substrates has been investigated as a function of reaction time, at various temperatures. For plain Sn–8Zn–3Bi solder joints, a scallop-shaped Cu–Zn–Ag intermetallic compound layer was found to adhere to the surface of the immersion Ag-plated Cu substrate. However, after addition of Ni nano-particles into the Sn–8Zn–3Bi solder, Cu–Zn–Ag (at the bottom) and (Cu, Ni)–Zn (at the top) intermetallic compound layers were observed at the interfaces. In addition, these intermetallic compound layer thicknesses increased substantially with increases in the temperature and reaction time. In the solder ball region, needle-shaped α-Zn rich phase and spherically-shaped Bi-particles appeared to be homogeneously distributed throughout a beta-tin (β-Sn) matrix. However, after the addition of Ni nano-particles, needle-shaped α-Zn rich phase appeared that exhibited a fine microstructure, due to the heterogeneous nucleation of the Ni nano-particles. The calculated activation energy for the Cu–Zn–Ag intermetallic compound layer for the plain Sn–8Zn–3Bi solder/immersion Ag-plated Cu system was 29.95 kJ/mol—while the activation energy for the total [Cu–Zn–Ag + (Cu, Ni)–Zn] intermetallic compound layers formed in the Sn–8Zn–3Bi–0.5Ni (Sn-13.6 at.% Zn-1.6 at.% Bi ~1 at.% Ni) composite solder/immersion Ag-plated Cu system was 27.95 kJ/mol. Addition of Ni nano-particles reduces the activation energy which enhanced the reaction rate as we know that lower the activation energy indicates faster the reaction rate.

Improvements in narrow band imaging (NBI) may provide an improved view of colonic mucosa for detection of polyps and adenomas. In this issue, Leung et al. report findings to suggest that this next-generation NBI technology is superior to conventional high-definition white light endoscopy in polyp detection. These findings are based on brighter illumination, which has been a problem with older generations of NBI, which did not increase polyp detection but were useful for polyp characterization. Although these findings are very promising for this new role of second-generation NBI in polyp detection, the study must be viewed with consideration of the history of the older NBI system, the analysis of which through multiple positive and negative studies ultimately led to the conclusion that it was not beneficial for detection.

Optical coherence tomography (OCT) is a high-resolution imaging modality that uses principles of light interferometry. It has achieved clinical application in several other specialties such as ophthalmology and cardiology where its high resolution and deeper penetration into the surface permits much more detailed examination of the mucosa. In the field of gastroenterology, the technology has evolved through several iterations beginning with a focal magnifying imaging technique and evolving into currently a widefield imaging modality that can scan a relatively large area of mucosa with high resolution. OCT has been used to detect dysplasia in Barrett’s esophagus, differentiate between inflammatory bowel disease subtypes, and define pancreaticobiliary strictures, among other applications. This chapter provides an overview of the principles of OCT and its applications in gastrointestinal imaging with emphasis on recently commercially available OCT technologies.

Myosin is the molecular motor in muscle-binding actin and executing a power stroke by rotating its lever arm through an angle of approximately 70 degrees to translate actin against resistive force. A green fluorescent protein (GFP)-tagged human cardiac myosin regulatory light chain (HCRLC) was constructed to study in situ lever arm orientation one molecule at a time by polarized fluorescence emitted from the GFP probe. The recombinant protein physically and functionally replaced the native RLC on myosin lever arms in the thick filaments of permeabilized skeletal muscle fibers. Detecting single molecules in fibers where myosin concentration reaches 300 microM is accomplished using total internal reflection fluorescence microscopy. With total internal reflection fluorescence, evanescent field excitation, supercritical angle fluorescence detection, and CCD detector pixel size limits detection volume to just a few attoliters. Data analysis manages both the perturbing effect of the TIR interface on probe emission and the effect of high numerical aperture collection of light. The natural myosin concentration gradient in a muscle fiber allows observation of fluorescence polarization from C-term GFP-tagged HCRLC exchanged myosin from regions in the thick filament containing low and high myosin concentrations. In rigor, cross-bridges at low concentration at the end of the thick filament maintain GFP dipole moments at two distinct polar angles relative to the fiber symmetry axis. The lower angle, where the dipole is nearly parallel to fiber axis, is more highly populated than the alternative, larger angle. Cross-bridges at higher concentration in the center of the thick filament are oriented in a homogeneous band at approximately 45 degrees to the fiber axis. The data suggests molecular crowding impacts myosin conformation, implying mutual interactions between cross-bridges alter how the muscle generates force. The GFP-tagged RLC is a novel probe to assess single-lever-arm orientation characteristics in situ.

PurposeThis study seeks to examine the advantages of mildly alkaline immersion silver as a final finish for solderability in order to combat the shortcomings of acidity in some popular immersion silver solutions.Design/methodology/approachThe paper describes in detail the necessary steps in the mildly alkaline immersion silver process.FindingsThe process can overcome the problems of conventional acidic immersion silvers, especially in thermal shock and stress testing. Also it does not affect soldering or aluminium wire bonding.Originality/valueThis is arguably a pioneering study in that it posits the benefits of mildly alkaline immersion silver as a final finish for solderability.

Background and Aims Probe-based confocal laser endomicroscopy (pCLE) and volumetric laser endomicroscopy (VLE) (also known as frequency domain optical coherence tomography) are advanced endoscopic imaging modalities that may be useful in the diagnosis of dysplasia associated with Barrett's esophagus (BE). We performed pCLE examination in ex-vivo EMR specimens and compared the diagnostic performance of using the current VLE scoring index (previously established as OCT-SI) and a novel VLE diagnostic algorithm (VLE-DA) for the detection of dysplasia. Methods A total of 27 patients with BE enrolled in a surveillance program at a tertiary-care center underwent 50 clinically indicated EMRs that were imaged with VLE and pCLE and classified into neoplastic (N = 34; high-grade dysplasia, intramucosal adenocarcinoma) and nonneoplastic (N = 16; low-grade dysplasia, nondysplastic BE), based on histology. Image datasets (VLE, N = 50; pCLE, N = 50) were rated by 3 gastroenterologists trained in the established diagnostic criteria for each imaging modality as well as a new diagnostic algorithm for VLE derived from a training set that demonstrated association of specific VLE features with neoplasia. Sensitivity, specificity, and diagnostic accuracy were assessed for each imaging modality and diagnostic criteria. Results The sensitivity, specificity, and diagnostic accuracy of pCLE for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The optimal diagnostic performance of OCT-SI showed a sensitivity of 70% (95% CI, 52-84), specificity of 60% (95% CI, 36-79), and diagnostic accuracy of 67%; (95% CI, 58-78). The use of the novel VLE-DA showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI ( P Conclusion The use of a new VLE-DA showed enhanced diagnostic performance for detecting BE dysplasia ex vivo compared with the current OCT-SI. Further validation of this algorithm in vivo is warranted.

Background Dyssynergic defecation is a complex bowel problem that leads to chronic constipation and abdominal pain. Management is often challenging owing to the incoordination of multiple pelvic floor muscles involved in normal defecation. Case We report a case of dyssynergic defecatory dysfunction in a patient with cerebral palsy treated with sacral neuromodulation. At presentation, Sitz marker study and magnetic resonance defecography showed evidence of chronic functional constipation. Anorectal manometry, rectal anal inhibitory reflex, and rectal sensation study showed intact reflex and decreased first sensation of lower canal at 50 mL. After stage 2 of InterStim implant placement, bowel habits improved to once- to twice-daily soft solid bowel movements from no regular solid bowel movements. Fecal incontinence improved from daily liquid and small solid loss to no stool leakage. Conclusions In patients with systemic medical problems contributing to defecatory dysfunction and bowel incontinence, such as cerebral palsy, sacral neuromodulation was found to provide significant relief of bowel symptoms in addition to associated abdominal pain. As a result of intervention, the patient reported significant improvement in quality of life and less limitations due to dyssynergic defecation.

Nano-sized, non-reacting, non-coarsening CeO 2 particles with a density close to that of solder alloy were incorporated into Sn-3.0wt%Ag-0.5wt%Cu solder paste. The interfacial microstructure and shear strength of Au/Ni metallized Cu substrates were investigated, as a function of aging time, at various temperatures. After solid state aging at low temperature, an island-shaped Cu 6 Sn 5 intermetallic compound (IMC) layer was found to be adhered at the interfaces of the Cu/Sn-Ag-Cu solder systems. However, after a prolonged aging, a very thin, firmly adhering Cu 3 Sn IMC layer was observed between the Cu 6 Sn 5 IMC layer and the Cu substrate. On the other hand, a scallop-shaped (Cu, Ni)-Sn IMC layer was found at the interfaces of the Sn-Ag-Cu based solder-Au/Ni metallized Cu substrates. As the solid-state aging time and temperature increase, the thicknesses of the IMC layers also remarkably increased. In the solder ball region of both systems, a fine microstructure of Ag 3 Sn and Cu 6 Sn 5 IMC particles appeared in the β-Sn matrix. However, the growth behavior of the IMC layers of composite solders doped with CeO 2 nanoparticles was inhibited, due to an accumulation of surface-active CeO 2 nanoparticles at the grain boundary or in the IMC layers. In addition, the composite solder joints doped with CeO 2 nanoparticles had higher shear strengths than that of the plain Sn-Ag-Cu solder joints, due to a well-controlled fine IMC particles and uniformly distributed CeO 2 nanoparticles.

Background Metformin has been shown to inhibit cell proliferation and induce cell death in many cancer cell lines. However, some cell lines exhibit resistance to the cytotoxic effects of metformin in tissue culture medium with high glucose levels (25 mM). Recent studies suggest when glucose is lowered; metformin becomes increasingly cytotoxic to cancer cells. However, the precise mechanism for metformin’s cancer cytotoxicity remains unidentified.

Resident in Internal Medicine (D.K.C.) and Fellow in Gastroenterology (D.A.S.), Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN; Adviser to resident and fellow and Consultant in Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN (S.C.H.). A 60-year-old man was transferred to our hospital with a 5-year history of worsening daily watery, nonbloody, nongreasy diarrhea. One year previously, recurrent vomiting had developed. Over the month preceding the current admission, he experienced 4 episodes of intractable, largevolume diarrhea with abdominal pain, upper and lower extremity muscle cramping, and orthostatic light-headedness. His diarrhea did not improve with fasting, and each of these episodes required hospitalization for intravenous fluid and electrolyte replacement. On the fourth episode, he was transferred to our institution for further diagnostic evaluation. The patient reported no symptomatic correlation to dietary habits and no associated fever, gastrointestinal bleeding, flushing, arthralgia, or rash. He had not experienced fecal incontinence. His medical history was notable for gastroesophageal reflux disease diagnosed 4 years previously and treated with 40 mg of esomeprazole daily. He had no surgical history. His only other medication was lisinopril for hypertension, and he reported no recent medication changes or antibiotic therapy. His family history did not include any gastrointestinal illness or malignant neoplasms, and he did not use tobacco or alcohol. His last screening colonoscopy was within the past 5 years and yielded normal findings. The patient had been stabilized with intravenous fluids before arrival at our institution, and physical examination at presentation revealed a well-nourished man with a body mass index of 26.3 kg/m, normal orthostatic vital signs, and normal physical examination findings, including no evidence of rash, abdominal tenderness, fecal impaction, or other abnormality. The results of laboratory studies including red and white blood cell count, complete metabolic profile, calcium level, liver function tests, total protein, albumin, thyrotropin, and tissue transglutaminase antibody values, erythrocyte sedimentation rate, and C-reactive protein

Improvements in narrow band imaging (NBI) may provide an improved view of colonic mucosa for detection of polyps and adenomas. In this issue, Leung et al. report findings to suggest that this next-generation NBI technology is superior to conventional high-definition white light endoscopy in polyp detection. These findings are based on brighter illumination, which has been a problem with older generations of NBI, which did not increase polyp detection but were useful for polyp characterization. Although these findings are very promising for this new role of second-generation NBI in polyp detection, the study must be viewed with consideration of the history of the older NBI system, the analysis of which through multiple positive and negative studies ultimately led to the conclusion that it was not beneficial for detection.

Different cancer cells exhibit altered sensitivity to metformin treatment. Recent studies suggest these findings may be due in part to the common cell culture practice of utilizing high glucose, and when glucose is lowered, metformin becomes increasingly cytotoxic to cancer cells. In low glucose conditions ranging from 0 to 5 mM, metformin was cytotoxic to breast cancer cell lines MCF7, MDAMB231 and SKBR3, and ovarian cancer cell lines OVCAR3, and PA-1. MDAMB231 and SKBR3 were previously shown to be resistant to metformin in normal high glucose medium. When glucose was increased to 10 mM or above, all of these cell lines become less responsive to metformin treatment. Metformin treatment significantly reduced ATP levels in cells incubated in media with low glucose (2.5 mM), high fructose (25 mM) or galactose (25 mM). Reductions in ATP levels were not observed with high glucose (25 mM). This was compensated by enhanced glycolysis through activation of AMPK when oxidative phosphorylation was inhibited by metformin. However, enhanced glycolysis was either diminished or abolished by replacing 25 mM glucose with 2.5 mM glucose, 25 mM fructose or 25 mM galactose. These findings suggest that lowering glucose potentiates metformin induced cell death by reducing metformin stimulated glycolysis. Additionally, under low glucose conditions metformin significantly decreased phosphorylation of AKT and various targets of mTOR, while phospho-AMPK was not significantly altered. Thus inhibition of mTOR signaling appears to be independent of AMPK activation. Further in vivo studies using the 4T1 breast cancer mouse model confirmed that metformin inhibition of tumor growth was enhanced when serum glucose levels were reduced via low carbohydrate ketogenic diets. The data support a model in which metformin treatment of cancer cells in low glucose medium leads to cell death by decreasing ATP production and inhibition of survival signaling pathways. The enhanced cytotoxicity of metformin against cancer cells was observed both in vitro and in vivo.

Different surface finished lead-free electroplated Cu substrates were prepared using an electrolytic process jointly developed for special applications. The surface morphology and plated layer thicknesses were investigated using atomic force microscope (AFM) and seanning electron microscope (SEM). From SEM micrographs, it was confirmed that the plated layers i.e., Au/Ni and Ag/Ni were well deposited on Cu substrates uniformly. In addition, the plated layer thicknesses were increased with an increasing processing temperature. The average Au/Ni p lated layers thicknesses atplated temperatures of30°C, 40°C and 5 0°C were about 0.67μm, 0.71μm and 0.77 μm, respectively. On the other hand, the average Ag/Ni plated layers thicknesses at plated temperatures of 10°C, 20°C and 30°C were about 6.5μm, 7.7μm and 8.4μm, respectively. From AFM observations, it was confirmed that the plated layer appeared to have a very smooth surface without any defects such as cra cks, delamination etc., confirming the successful application of the specially developed electrolytic process.