Financial incentives for infection prevention and antimicrobial stewardship to reduce antibiotic use: Japan's nationwide observational study.

BACKGROUND: The Japanese government introduced financial incentives to reduce nationwide antibiotic use in hospital settings. AIM: This study aimed to determine whether the nationwide financial incentives for creating infection prevention and control (IPC) teams introduced in 2012 and antimicrobial stewardship (ASP) teams introduced in 2018 were associated with changes in antibiotic use and health resource utilization at a national level. METHODS: We conducted time-series analyses and a difference-in-differences study consisting of 3,057,517 inpatients with infectious diseases from 472 medical facilities during fiscal years 2011-2018 using a nationally representative inpatient database in Japan. The primary outcome was the days of therapy (DOT) of antibiotic use per 100 patient-days (PDs). The secondary outcomes consisted of types of antibiotic used, health resource utilization, and mortality. RESULTS: A total of 5,201,304 financial incentives were observed during 2012-2018, which resulted in a total of 12.1 billion JPY (≈110 million USD). Time-series analyses found decreasing trends in total antibiotic use (79.3-72.5 DOTs/100 PDs (8.6% reduction)) and carbapenem use (9.0-7.0 DOTs/100 PDs (7.8% reduction)) from 2011 to 2018 without adversely affecting other healthcare outcomes (e.g., mortality). In the difference-in-differences analyses, we did not observe meaningful changes in total antibiotic use between the incentivized and unincentivized hospitals for ASP teams, except for the northern part of Japan. No dose-response relationships were observed between the amount of financial incentives and reductions in antibiotic use during 2011-2019. CONCLUSIONS: Further research and efforts are needed to accelerate antimicrobial stewardship in hospital settings in Japan.

Molecular and catalytic properties of an arginine kinase from the nematode Ascaris suum.

We amplified the cDNA coding for arginine kinase (AK) from the parasitic nematode Ascaris suum, cloned it in pMAL plasmid and expressed the enzyme as a fusion protein with the maltose-binding protein. The whole cDNA was 1260 bp, encoding 400 amino acids, and the recombinant protein had a molecular mass of 45,341 Da. Ascaris suum recombinant AK showed significant activity and strong affinity ( K(m)(Arg) = 0.126 mM) for the substrate L-arginine. It also exhibited high catalytic efficiency ( k(ca)/K(m)(Arg) = 352) comparable with AKs from other organisms. Sequence analysis revealed high amino acid sequence identity between A. suum AK and other nematode AKs, all of which cluster in a phylogenetic tree. However, comparison of gene structures showed that A. suum AK gene intron/exon organization is quite distinct from that of other nematode AKs. Phosphagen kinases (PKs) from certain parasites have been shown to be potential novel drug targets or tools for detection of infection. The characterization of A. suum AK will be useful in the development of strategies for control not only of A. suum but also of related species infecting humans.

Antianaphylactic effects of dipivalyl epinephrine and related compounds in rat conjunctiva.

Topically applied dipivalyl epinephrine (DPE) and related compounds have been found to inhibit passive anaphylactic reaction in rat conjunctiva. The order of activity is as follows: isoproterenol greater than DPE greater than epinephrine greater than norepinephrine. The antianaphylactic effect of DPE was antagonized by propranolol but was not affected by phentolamine. The effects of epinephrine, norepinephrine, and isoproterenol were also antagonized by propranolol but potentiated by pentolamine. From these findings, it was suggested that DPE not only exerts its antianaphylactic action through activation of beta-adrenergic receptor but also itself has a little different action from epinephrine.

Changes in serum diamine oxidase activity during chemotherapy in patients with hematological malignancies.

Serum diamine oxidase (DAO) activity is very low, but is considered to reflect quantitative changes in small intestinal mass. Therefore, we measured DAO activity during chemotherapy in patients with hematological malignancies in order to evaluate mucosal injury. DAO activity decreased from 1-3 weeks after chemotherapy but returned to initial levels after 4 weeks. As the dosage of anti-cancer drugs increased, DAO activity decreased more, but its activity was not related to other parameters. These findings suggest that serum DAO could be used as an indicator of mucosal injury during chemotherapy.

Effect of taurocholate on CCK release and pancreatic secretion produced by two CCK-releasing peptides in conscious rats.

The role of luminal bile salts (taurocholate) in regulation of rat pancreatic secretion was examined by studies on the effects of luminal stimulants on the pancreas during infusion of various concentrations of taurocholate into the duodenum of conscious rats. Rats with external bile and pancreatic fistulae were used. For 24 h before the experiment, pancreatic juice was excluded from the intestine but bile was continuously returned to the duodenum. From the beginning of the experiment, 8-200 mM of taurocholate was infused at a rate of 1 ml/h instead of returning the bile. Pancreatic juice was collected for a 2-h period and then 2 micrograms of pancreatic secretory trypsin inhibitor-61 (PSTI-61) (= monitor peptide) or partially purified putative CCK-releasing peptide from rat intestine (intestinal CCK-RP) was injected into the duodenum (1 ml/min). Continuous infusion of taurocholate maintained a constant rate of pancreatic secretion, except at a concentration of 8 mM, which resulted in a slight increase in pancreatic secretion. Both PSTI-61 and intestinal CCK-RP significantly increased pancreatic secretions during infusion of 20 or 40 mM taurocholate, but had no significant effect during infusion of 80 or 200 mM taurocholate. Therefore, higher concentrations of taurocholate in the intestine prevented the stimulatory effects of luminal stimulants, probably by preventing the latter from reaching CCK cells.

Immunocytochemical localization of substance P in the rat spinal cord with special reference to fibers within the ventral column of the rostral lumbar segments.

The distribution of substance P (SP) in the rat spinal cord was investigated by peroxidase-anti-peroxidase (PAP) immunocytochemistry. A dense network of SP-immunoreactive fibers and terminals was detected in the ventral column of the rostral lumbar cord with a different density and extent from the other segmental levels. These fibers and terminals were accumulated within and around the centromedial nucleus (CM) of the L1 and L2 segments, with some bundles of immunoreactive fibers between the CM and other areas; i.e. laminae V and X and the contralateral CM. They formed a dense network, such as in arborization of immunoreactive fibers and terminals on the transverse plane and in a comb-shaped structure on the horizontal plane. The origin of the SP in this network was examined. It was determined that neither a total transection of spinal cord at a low thoracic level or mid-lumbar level, nor at an ipsilateral or bilateral section of the 3-5 dorsal roots, containing L1 and L2 roots, induced any visible changes in the SP staining pattern. An intrathecal injection of colchicine revealed the presence of SP-immunoreactive neurons in the dorsal horn and intermediate gray matter at the spinal cord including the rostral lumbar cord. The present findings suggested that the majority of SP immunoreactivities in the above network are derived from local circuit interneurons of the spinal cord.

Sexual differences in the distribution of substance P immunoreactive fibers in the ventral horn of the rat lumbar spinal cord.

The distribution of substance P (SP) in the rat spinal cord was investigated by peroxidase-anti-peroxidase immunocytochemistry combined with retrograde horseradish peroxidase (HRP) labeling via the cremaster muscle. In the male rats, a dense network of SP immunoreactive (SP-IR) fibers and terminals was detected in the ventral column of the L1 and L2 segments (Vent L1-2) with a different density and extent from the other segmental levels. These fibers and terminals were accumulated within and around the nucleus centromedialis lumbaris (CM) of the L1 and L2 segments. However, in the female rats, SP-IR fibers and terminals were sparse in the Vent L1-2 without particular segmental differences. HRP-positive motoneurons were located in the CM and surrounded by SP-IR fibers and terminals. These results indicate that the Vent L1-2 of the rat spinal cord shows sexual dimorphism with respect to the regional distribution of SP-IR fibers and terminals, and that motoneurons that innervate the cremaster muscle are innervated by dense SP-IR fibers and terminals.

Vasoactive intestinal peptide- and peptide histidine isoleucine amide-like immunoreactivity colocalize with vasopressin-like immunoreactivity in the canine hypothalamo-neurohypophysial neuronal system.

The distribution of vasoactive intestinal peptide (VIP) and peptide histidine isoleucine amide (PHI) was investigated in the canine hypothalamus by immunocytochemistry. VIP- and PHI-like immunoreactive neurons were detected in the magnocellular supraoptic and paraventricular nucleus. These magnocellular VIP- and PHI-producing neurons coexist with vasopressin-like immunoreactivity and send axons to the median eminence and neurohypophysis. These findings may serve as an anatomical basis for studying the function of VIP and PHI on pituitary hormone secretion.

Distribution of human leumorphin-like immunoreactivity in the monkey spinal cord revealed by immunocytochemistry.

The regional distribution of human leumorphin (HL)-like immunoreactivity (HL-LI) in monkey (Macaca fuscata) spinal cord and dorsal root ganglia was investigated by peroxidase-anti-peroxidase immunocytochemistry using specific antiserum. HL-LI-positive fibers and terminals were distributed densely in laminae (Rexed) I and II, and sparsely in laminae III-VII and X, but no immunoreactive elements were observed in the ventral horn, the white matter or the dorsal root ganglia. Many immunoreactive neuronal perikarya were found in laminae I and II. Intrathecal injection of colchicine also revealed the presence of immunoreactive neuronal perikarya in laminae III-VII and X. These results suggest the presence of HL-LI, which represents HL and/or its C-terminal fragment, in the neuronal elements of the monkey spinal cord.

Efficacy of oral adsorbent for treatment of peristomal fistula associated with Crohn's disease.

Perianal fistulae are frequently seen complications in Crohn's disease. Although surgical procedures such as Seton's method have been devised, many patients still suffer from fistulae that are resistant to conventional therapy. We administered oral adsorbent to a patient with disease Crohn's who had a complicated peristomal fistula that did not improve with conventional therapy. Six grams of oral adsorbent (AST-120) were added daily to a regimen of elemental diet therapy and prednisolone. The fistula gradually decreased in size after the administration of the oral adsorbent, and had healed completely after 40 days' treatment. There were no side effects from the oral adsorbent. This case report suggests that oral adsorbent is an effective treatment for peristomal fistula associated with Crohn's disease.

Clinical importance of n-3 fatty acid-rich diet and nutritional education for the maintenance of remission in Crohn's disease.

Elemental diet (ED) therapy has been established as primary therapy for Crohn's disease, and home enteral nutrition (HEN) has been reported to control relapse at a dose of more than 30kcal/kg of ideal body weight. However, a decrease in ED compliance with long-term use is becoming problem. We developed an n-3 fatty acid-rich diet and carried out nutritional education specifically for Crohn's disease patients using HEN to facilitate compliance and to improve their nutritional status. After the introduction of this n-3 rich diet, disease activity was not altered, and nutritional status, especially serum n-3 fatty acid levels, improved. The remission periods in patients with poor compliance seemed to be prolonged by the nutritional education. Thus, a n-3 rich diet in combination with nutritional education specific for Crohn's disease patients is very important for the in maintenance of high compliance and for maintaining nutritional balance.

Medium-chain triglyceride-rich enteral nutrition is more effective than low-fat enteral nutrition in rat colitis, but is equal in enteritis.

BACKGROUND: Although enteral nutrition (EN) therapy for Crohn's disease has been confirmed to be as effective as steroid therapy, the precise mechanism responsible for the effects of EN remains unclear, although some of the therapeutic effects of EN are believed to be due to a low dietary fat content. In order to elucidate the influence of fat in EN, it is important to investigate not only the quantity of fat, but also the source of the fat. METHODS: We compared two enteral nutritional formulae: Elental (Ajinomoto) (elemental diet; ED), which contains only 1.5% fat, provided as long-chain triglycerides (LCT), versus Twinline (Snow Brand Milk Products) (TL), which contains a high percentage of fat (20.4%), provided mainly as medium-chain triglycerides (MCT). These formulae were tested on rat enteritis and rat colitis induced by trinitrobenzene sulfonic acid (TNBS). RESULTS: Both ED and TL reduced the manifestations of enteritis. TL had a stronger anti-inflammatory effect than ED for colitis. TL also had nutritional advantages as compared with ED, as shown by the total serum protein in the TL group being significantly higher than that in the ED group. CONCLUSION: The results indicate that intraluminal MCT is suitable as a fat energy source during intestinal inflammation in rats. We suggest that Twinline may be more useful to improve nutritional status and to reduce the mucosal inflammation in rat colitis, but that Twinline is equal in effect to Elental for rat enteritis.

Cutaneous necrosis after superficial temporal artery-to-middle cerebral artery anastomosis: is it predictable or avoidable?

OBJECTIVE: This study was carried out to determine whether a relationship exists between cutaneous necrosis after superficial temporal artery-to-middle cerebral artery anastomosis and background risk factors or surgical methods, and to determine whether such necrosis is predictable or avoidable. METHODS: Forty-seven patients (a total of 51 sides) with atherosclerotic lesions of the internal carotid artery or middle cerebral artery who underwent superficial temporal artery-to-middle cerebral artery anastomosis at the National Kyushu Medical Center Hospital between September 1, 1994, and August 31, 1999, were reviewed. Each procedure was analyzed to determine whether cutaneous necrosis was present postoperatively around the donor site, whether preexisting risk factors (hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, and arteriosclerosis obliterans) were present, and whether a flap or cutdown method or a single or double anastomosis was performed. RESULTS: Postoperative necrosis was clearly related to arteriosclerosis obliterans (P < 0.003). The tendency for a relationship between necrosis and smoking was noted. Although statistical analysis failed to demonstrate a significant difference, necrosis was found with the flap method but not with the cutdown method. CONCLUSION: Further study is needed using greater numbers to clarify the relationship between the surgical method and the presence of necrosis. To prevent cutaneous necrosis, however, it may be preferable to use the cutdown method in patients with the preexisting risk factors of arteriosclerosis obliterans or in smokers.

Primary peripheral-postthymic T-cell lymphoma in the central nervous system: immunological and molecular approaches to diagnosis.

Primary intracranial T-cell lymphoma is a very rare clinical entity, and only limited biological studies of this disease have been undertaken. A tumor specimen from a patient with a primary leptomeningeal and perivascular presentation of a T-cell lymphoma was analyzed using cellular and molecular techniques. Frozen sections of the sample were examined by immunohistochemical techniques using monoclonal antibodies to phenotypic marker antigens expressed on human lymphoid cells. Intercellular adhesion molecules expressed on the tumor were studied, as was expression of messenger ribonucleic acid (mRNA) transcripts of the T-cell receptor variable alpha and beta chain genes. The immunophenotypical analysis of lymphoma revealed that the tumor expressed CD2, CD3, CD4, CD5, CD25 and HLA-DR. In addition, all of the adhesion molecules studied (ICAM-1, LFA-3, VLA-1, CD11a, CD11b, and CD11c) were detected on the cell surface. Polymerase chain reaction amplification of mRNA from the tumor demonstrated 10 V alpha and three V beta T-cell receptor subfamilies, indicating that this tumor was a low-grade well-differentiated helper type of peripheral T-cell lymphoma of the central nervous system. In addition, the tumor was derived from multiple T-cell lineages.

Endovascular treatment of basilar artery trunk aneurysms with Guglielmi detachable coils: clinical experience with 41 aneurysms in 39 patients.

OBJECT: The authors present a retrospective analysis of their clinical experience in the endovascular treatment of basilar artery (BA) trunk aneurysms with Guglielmi detachable coils (GDCs). METHODS: Between April 1990 and June 1999,41 BA trunk aneurysms were treated in 39 patients by inserting GDCs. Twenty-seven patients presented with subarachnoid hemorrhage, six had intracranial mass effect, and in six patients the aneurysms were found incidentally. Eighteen lesions were BA trunk aneurysms, 13 were BA-superior cerebellar artery aneurysms, four were BA-anterior inferior cerebellar artery aneurysms, and six were vertebrobasilar junction aneurysms. Thirty-five patients (89.7%) had excellent or good clinical outcomes; procedural morbidity and mortality rates were 2.6% each. Thirty-six aneurysms were selectively occluded while preserving the parent artery, and in five cases the parent artery was occluded along with the aneurysm. Immediate angiographic studies revealed complete or nearly complete occlusion in 35 aneurysms (85.4%). Follow-up angiograms were obtained in 29 patients with 31 aneurysms: the mean follow-up period was 17 months. No recanalization was observed in the eight completely occluded aneurysms. In 19 lesions with small neck remnants, seven (36.8%) had further thrombosis, three (15.8%) remained anatomically unchanged, and nine (47.3%) had recanalization caused by coil compaction. In one patient (2.6%) the aneurysm rebled 8 years after the initial embolization. CONCLUSIONS: In this clinical series the authors show that the GDC placement procedure is valuable in the therapeutic management of BA trunk aneurysms. The endovascular catheterization of these lesions tends to be relatively simple, in contrast with more complex neurosurgical approaches. Endosaccular obliteration of these aneurysms also decreases the possibility of unwanted occlusion of perforating arteries to the brainstem.

Release of pancreatic secretory trypsin inhibitor from human hepatoblastoma cells on stimulation with cytokines.

To determine whether or not human pancreatic secretory trypsin inhibitor (PSTI) is an acute phase reactant released from hepatocytes, we investigated the effects of various cytokines on the release of PSTI from cultured human hepatoblastoma cells. PSTI was synthesized in human hepatoblastoma cells and released on stimulation with various cytokines: interleukin-1, tumor necrosis factor and interferon-beta.

Elevation of serum pancreatic secretory trypsin inhibitor following serious injury.

Twenty-six of 31 seriously injured patients (84%) showed a marked elevation of serum pancreatic secretory trypsin inhibitor (PSTI) to more than twice the initial level within the first 2 weeks after admission. Serum PSTI rose from the second or third post-traumatic day and reached the maximum at day 5.8 on average. In uneventful cases, it returned to the level on admission within 2 weeks. The maximum serum PSTI in these patients was significantly correlated with the severity of the injury as judged at the time of admission, indicating that the elevation of serum PSTI in these patients was related to the extent of initial damage. In contrast, serum PSTI in patients with serious complications remained at high level even at 2 weeks after trauma, and it was not correlated with the initial severity of the injury.

Protective effect of recombinant neutrophil elastase inhibitor (R-020) on sepsis-induced organ injury in rat.

Severe inflammatory responses after major surgeries, trauma, and infection develop multiple organ dysfunction. In the mechanisms of the pathogenesis of these responses, activated neutrophils are thought to be important in terms of their ability to produce various kinds of proteinases, which can degrade various proteins constructing human tissues. Among their proteinases, neutrophil elastase is the strongest serine proteinase secreted from activated neutrophils. Thus, we examined in this study the inhibitory effect and therapeutic efficacy of newly produced recombinant human Kunitz-type proteinase inhibitor (R-020), which coded the second domain of human urinary trypsin inhibitor. R-020 was effective in significantly improving the survival rate after induction of the rat lethal peritonitis model (cecal ligation and puncture-induced septic shock model). We suggest that various serine proteinases are implicated in the pathogenesis of neutrophil-related multiple organ failure and that recombinant human Kunitz-type proteinase inhibitor might be effective in the treatment of these kinds of organ dysfunction.

Vertebral arteriovenous fistula that developed in the same place as a previous ruptured aneurysm: a case report.

BACKGROUND: Aneurysms of the extracranial vertebral artery (VA) and vertebral arteriovenous fistulas (VAVFs) are relatively rare diseases. The most frequent cause of both diseases is trauma. Atraumatic lesions are less common. Presented here is a case of atraumatic AVF of the extracranial VA that developed in the same location as a previous ruptured aneurysm of the ipsilateral VA that was originally treated by proximal occlusion 11 years earlier. METHODS: A 40-year-old woman presented with a massive hematoma in the upper posterior neck region caused by the rupture of an extracranial VA aneurysm. Proximal occlusion of the VA was performed by use of a detachable balloon. She enjoyed good health for 11 years, then she noticed a pulsatile bruit. Angiograms revealed an AVF between the left VA that was fed by collateral circulation and the paravertebral venous plexus. Incidentally found were soft tissue masses in the left retroauricular and the right suboccipital regions. Also, skull X-ray films showed multiple bony defects. Biopsy of the subcutaneous mass was performed in the hope of obtaining clues as to which pathological processes had weakened the artery. RESULTS: As direct transarterial access to the fistula was out of the question, the fistulous compartment of the paravertebral venous plexus was tightly packed with multiple platinum coils effected by the transfemoral approach. A histological examination of the specimen revealed features of a neurofibroma, and a diagnosis of neurofibromatosis Type 1 was established. CONCLUSIONS: In this case, transvenous embolization of the VAVF was successfully performed. The fragility of the arterial wall, related to neurofibromatosis Type 1, was considered to contribute to the development of the aneurysm and AVF.