Successful preoperative chemotherapy with S-1 plus low-dose cisplatin for advanced gastric cancer with synchronous liver metastases: report of 2 cases

We report 2 cases of advanced gastric cancer with synchronous liver metastases who were successfully downstaged using S-1 plus low-dose cisplatin chemotherapy followed by surgical resection. S-1 was administered orally (80 mg/m(2)/day) twice daily for 14 consecutive days, and cisplatin (15 mg/m(2)) was infused over 1 h on days 1 and 8. Successful downstaging of the hepatic metastases was confirmed by imaging analyses; however, neither patient showed a complete response of the primary lesion in the stomach. Toxicities, according to the WHO criteria, were mild. The patients underwent surgical resection within 4 weeks after the last chemotherapy. Postoperatively, they were discharged without complications and received adjuvant chemotherapy. Both patients remained alive and well at 17 and 12 months after surgery, respectively, without recurrence. These cases provide further evidence that S-1 plus low-dose cisplatin chemotherapy enables downstaging of advanced gastric cancer and a subsequent potentially curative resection without serious complications.     

Carotid endarterectomy in chronic renal failure patients: report of two cases

Chronic renal failure is one of the risk factors for carotid atherosclerosis. We report two cases of stenosis of the carotid bifurcation treated by carotid endarterectomy. A 66-year-old man with a 17-year history of hemodialysis experienced repeated episodes of right hemiparesis. Cerebral angiography showed severe stenosis of the cervical carotid bifurcation bilaterally. Left and right carotid endarterectomy operations were performed one month apart. The postoperative course was uneventful, and the patient returned home without neurological symptoms. The second case was in a 49-year-old woman with a 15-year history of hemodialysis had vertigo of one month duration. Cerebral angiography revealed occlusion of the left subclavian artery, and the distal left axillary artery was filled by retrograde flow from the left vertebral artery. Stenosis of the right carotid bifurcation was also noted. Right carotid endarterectomy was performed without any complications. Although a high incidence of intraoperative complications and of recurrent stroke after carotid endarterectomy (CEA) has been reported in chronic renal failure patients, the poor prognosis of the natural history of severe carotid stenosis in chronic renal failure should be taken into consideration. The cases reported indicate that carotid endarterectomy is safe and justified for carotid stenosis in chronic renal failure patients.     

A decrease in mother-to-child transmission of human T lymphotropic virus type I (HTLV-I) in Okinawa, Japan

To investigate the chronologic change of mother-to-child transmission of human T lymphotropic virus type I (HTLV-I) in Okinawa, Japan, the presence of antibody to HTLV-I was tested in 4,187 healthy residents between, 4,528 nursery school children, and 3,837 pregnant women between 1968 and 2000. The chronologic change of the feeding method and the length of the breast-feeding period among 1,117 healthy mothers from 1937 to 1995 were also obtained by interview. Age-adjusted prevalence of HTLV-I among healthy residents decreased from 9.1% in 1968-1970 to 7.8% in 1981-1984 and to 6.3% in 1996-1998. The crude prevalence of antibody to HTLV-I among healthy residents less than 20 years old decreased significantly from 4.6% in 1968-1970 to 0.1% in 1996-1998 (P < 0.0001). The prevalence of antibody to HTLV-I among nursery school children decreased significantly over the study period, from a high of 1.8% in 1984 to a low of 0.2% in 1998 (P = 0.03). The prevalence among pregnant women decreased significantly from 5.6% in 1989-1992 to 3.7% in 1997-2000 (P = 0.0275). Prior to 1967, all healthy mothers breast-fed their children. After 1968, the use of bottled and mixed milk (breast milk and bottled milk) increased, with bottled milk becoming predominant after 1990 (89%). The percentage of healthy mothers breast-feeding for more than one year significantly decreased from 68.3% in 1937-1947 to 0.4% in 1990-1995 (P < 0.0001). Infection with HTLV-I in Okinawa has decreased mainly due to a reduction in the number of mothers breast-feeding and a shortening of the breast-feeding period. However, because the mother-to-child transmission rate among non-breast-feeders decreased from 12.8% in 1986-1991 to 3.2% in 1995-1999, there may be other factors involved in the decrease in mother-to-child transmission.     

Conformational alterations in unidirectional ion transport of a light-driven chloride pump revealed using X-ray free electron lasers

Light-driven chloride-pumping rhodopsins actively transport anions, including various halide ions, across cell membranes. Recent studies using time-resolved serial femtosecond crystallography (TR-SFX) have uncovered the structural changes and ion transfer mechanisms in light-driven cation-pumping rhodopsins. However, the mechanism by which the conformational changes pump an anion to achieve unidirectional ion transport, from the extracellular side to the cytoplasmic side, in anion-pumping rhodopsins remains enigmatic. We have collected TR-SFX data of Nonlabens marinus rhodopsin-3 (NM-R3), derived from a marine flavobacterium, at 10-µs and 1-ms time points after photoexcitation. Our structural analysis reveals the conformational alterations during ion transfer and after ion release. Movements of the retinal chromophore initially displace a conserved tryptophan to the cytoplasmic side of NM-R3, accompanied by a slight shift of the halide ion bound to the retinal. After ion release, the inward movements of helix C and helix G and the lateral displacements of the retinal block access to the extracellular side of NM-R3. Anomalous signal data have also been obtained from NM-R3 crystals containing iodide ions. The anomalous density maps provide insight into the halide binding site for ion transfer in NM-R3.

Microbial ion-pumping rhodopsins are integral membrane proteins that actively transport ions across membranes upon light stimulation (1). Bacteriorhodopsin (bR) and halorhodopsin (HR) are well-known microbial ion-pumping rhodopsins found in halophilic archaea (2, 3). bR is a light-driven outward proton pump and HR is a light-driven inward anion pump, specific for chloride ion. Microbial ion-pumping rhodopsins possess common structural features consisting of seven α-helices with an all-trans retinal covalently bound to a lysine residue as the chromophore, despite the transport of different ions (4). The retinal undergoes photoisomerization from the all-trans to 13-cis configuration, which initiates the photocycle accompanied by several intermediates to export ions (4, 5). Its light-controllable function is suitable for optogenetics applications for manipulating cells, such as neurons, by changing the ion concentration inside or outside the membrane (6, 7). In fact, microbial rhodopsins, including channelrhodopsins and HRs, are employed as optogenetic tools (8–10).Nonlabens marinus rhodopsin-3 (NM-R3) is a light-driven chloride pump recently discovered in a marine flavobacterium (11). It is a distinct chloride pump from HRs and shows low amino acid sequence homology with HRs (11). To date, HR-type chloride pumps have been found in haloarchaea, marine bacteria, and cyanobacteria, including Halobacterium salinarum, Natronomonas pharaonis, and Mastigocladopsins repens, with sequence identities of 20%, 21%, and 20% to NM-R3, respectively (3, 12–15). Interestingly, NM-R3 has higher sequence identity (36%) to Krokinobacter rhodopsin 2 (KR2), a sodium pump found in Krokinobacter eikastus (16). NM-R3 possesses a unique NTQ motif (Asn98, Thr102, Gln109) in the third helix (helix C), which corresponds to key residues (DTD motif, Asp85, Thr89, Asp96) for proton transport in bR (11, 17, 18) (SI Appendix, Table S1). Asp85 acts as the primary proton acceptor of bR from the protonated Schiff-base (PSB), with assistance from Thr89 and Asp96, which is the proton donor (5, 17, 18). HRs from haloarchaea have a highly conserved TSA (Thr, Ser, Ala) motif, while the Ala residue is replaced by Asp in HR from cyanobacteria (19). In the X-ray crystal structure of NM-R3 (SI Appendix, Fig. S1A), a chloride ion located between the PSB and Asn98 (SI Appendix, Fig. S1B) is stabilized by the positive charge of the PSB (20). The position of this chloride ion is similar to those in the H. salinarum HR and N. pharaonis HR (NpHR) structures except for Thr and Ser, which correspond to Asn98 and Thr102 in NM-R3, respectively (20–22). Several amino acid residues around the retinal, including Arg95, Trp99, Trp201, and Asp231, are highly conserved among ion-pumping rhodopsins. Previous spectroscopic studies suggested that NM-R3 displays a similar sequence of intermediates, with K-, L-, N-, and O-like species, as in other HRs (23) (Fig. 1A). Recently, intermediate structures of NM-R3 obtained by low-temperature trapping X-ray crystallography and serial femtosecond crystallography (SFX) have been reported (24, 25). However, the detailed ion-pump mechanism still remains unclear, due to the lack of dynamic structures of anion transport at atomic resolution.Open in a separate windowFig. 1.TR-visible absorption spectroscopy for microcrystals. (A) Photocycle model of NM-R3 in the 1 M NaCl buffer solution (23). (B) TR difference spectra ΔA upon the 532-nm excitation. The difference was calculated by subtracting the spectrum of NM-R3. (C) Global fitting analysis with two exponentials. The A₁ and A₂ amplitude spectra correspond to the differences of [ΔA_O – ΔA_{10 µs}] and [ΔA_{200 ms} − ΔA_O], respectively. Here, ΔA_O represents the difference spectrum of the O intermediate minus NM-R3. (D) The isomeric forms of the retinal chromophore in bacterial-type rhodopsins.Time-resolved serial femtosecond crystallography (TR-SFX) is a powerful tool for visualizing reactions and motions in proteins at the atomic level (26–28). In SFX, myriads of microcrystals are continuously injected by a sample injector into an irradiation point of X-ray free electron lasers (XFELs) at room temperature, thus providing diffraction patterns before the onset of radiation damage by the intense X-ray pulse. Combined with a visible-light pump laser for reaction initiation, TR-SFX has been applied to light-driven ion pumps to observe the structural dynamics during the ion transfer. While TR-SFX has revealed femto-to-millisecond structural dynamics in light-driven cation pumps, including bR and KR2 (29–31), TR-SFX studies of anion pumps have been limited to early-stage structures adopted at picoseconds after light illumination (32). In addition, although NM-R3 pumps a chloride ion (Cl⁻) as a physiological substrate, it can also transport bromide (Br⁻), iodide (I⁻), and other anions from the extracellular side to the cytoplasmic side (23). I⁻ or Br⁻ serves as a marker for tracking the positions of ions, due to the greater number of electrons, whereas Cl⁻ is less distinguishable in X-ray crystallography. Therefore, TR-SFX experiments using I⁻ or Br⁻ are expected to directly visualize the process of ion transport.Here, we report the conformational alterations in NM-R3 during Br⁻ or I⁻ pumping, obtained by both TR-SFX and time-resolved spectroscopy of crystals. The resulting sequence of movements in NM-R3 demonstrates how the chloride pump transports anions with a large ionic radius and prevents the backflow of anions from the cytoplasmic side.     

Laninamivir octanoate for post-exposure prophylaxis of influenza in household contacts: a randomized double blind placebo controlled trial

Laninamivir octanoate, a long-acting neuraminidase inhibitor, is an effective treatment for influenza. However, its effectiveness for the prevention of influenza has not yet been demonstrated. We conducted a double-blind, multicenter, randomized, placebo-controlled trial to determine whether laninamivir octanoate was superior to a placebo for post-exposure prophylaxis of influenza in household contacts. Eligible participants, who were household members who did not have influenza and were in contact with an influenza-infected index patient, were randomly assigned (1:1:1) to one of three groups: 20 mg of laninamivir octanoate once daily for 2 days (LO-2), 20 mg of laninamivir octanoate once daily for 3 days (LO-3), or a placebo. The primary endpoint was the proportion of participants who developed clinical influenza during a 10-day period. A total of 1711 participants were enrolled, and 1451 participants were included in the primary analysis. The proportion of participants with clinical influenza was 3.9 % (19/487) in the LO-2 group, 3.7 % (18/486) in the LO-3 group, and 16.9 % (81/478) in the placebo group (P < 0.001 for each of the laninamivir octanoate group). The relative risk reductions, compared with the placebo group, were 77.0 % [95 % confidence interval (CI) 62.7–85.8] and 78.1 % (95 % CI 64.1–86.7 %) for the LO-2 and LO-3 groups, respectively. The incidences of adverse events in the laninamivir octanoate groups were similar to that in the placebo group. The inhalation of 20 mg of laninamivir octanoate once daily for 2 or 3 days was well tolerated and effectively prevented the development of influenza in household contacts.     

Metastatic hypopharyngeal and esophageal cancer to a percutaneous endoscopic gastrostomy site

The patient was a 63-year-old man who underwent percutaneous endoscopic gastrostomy (PEG) for nutritional management while undergoing radiochemotherapy for hypopharyngeal and esophageal cancer. At about 6 months after PEG, redness and swelling were seen around the gastrostomy site, and pathological testing confirmed the same poorly differentiated squamous cell carcinoma as the hypopharyngeal and esophageal cancer. The tumor caused symptoms associated with buried bumper syndrome to increase significantly.     

Are cerebrovascular factors involved in Alzheimer's disease?

Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD.