Biomedical subjects

M Moriwaki

Publications and source records attributed to M Moriwaki.

At least 19 recordsLinked to original sources

PubMed2007

Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: Type 1A diabetes results from autoimmune destruction of pancreatic beta cells. We examined the involvement of TNF-alpha and IL-1beta, as well as of T cells, macrophages and dendritic cells, in the destruction of beta cells in patients with recent-onset type 1 diabetes. MATERIALS AND METHODS: We obtained pancreatic biopsy specimens from six patients with recent-onset type 1 diabetes and analysed these by immunohistochemistry. RESULTS: T cell infiltration was less common in islets without beta cells (12.5 [0-33.3]%) than in those with beta cells (46.0 [17.4-83.3]%), while macrophages and dendritic cells showed a similar extent of infiltration into islets both with or without beta cells. TNF-alpha was detected in 25.0 (4.3-46.9)% of macrophages and 11.8 (0-40.0)% of dendritic cells infiltrating the islets in samples from each patient, but not at all in T cells. IL-1beta was detected in 1.8 (0-11.3)% of T cells infiltrating the islets with beta cells, while it was found in 19.2 (0-35.3)% of macrophages or 10.7 (0-31.3)% of dendritic cells infiltrating the islets in samples from each patient (all values median [range]). CONCLUSIONS/INTERPRETATION: Macrophages and dendritic cells infiltrate the islets and produce inflammatory cytokines (TNF-alpha and IL-1beta) during the development of type 1A diabetes.

Adolescent↗

PubMed2006

Acid-suppressive effects of rabeprazole: comparing 10mg and 20mg twice daily in Japanese Helicobacter pylori-negative and -positive CYP2C19 extensive metabolisers.

BACKGROUND: Rabeprazole 10mg b.i.d. is often administered as therapy for eradication of Helicobacter pylori (H. pylori) and is also proposed as therapy for refractory gastro-oesophageal reflux disease. However, there has not been a comprehensive assessment of its acid-suppressive effects. AIMS: To compare the acid-suppressive effects of rabeprazole 10mg b.i.d. with 20mg b.i.d. considering H. pylori status. SUBJECTS: Thirteen H. pylori-negative and eleven H. pylori-positive Japanese CYP2C19 extensive metabolisers (<35 years). METHODS: Intragastric pH was measured for 24h three times in a randomised manner; on day 7 of the repeated administration of rabeprazole 10mg b.i.d. or 20mg b.i.d., or a placebo. RESULTS: In median intragastric pH value and percent time of pH>3.0, >4.0, >5.0, >6.0, and >7.0 for 24h, no significant differences were observed between the two doses in either H. pylori-negative or H. pylori-positive subjects. At either dose, these parameters were significantly higher in H. pylori-positive subjects than in H. pylori-negative subjects. Nocturnal acid breakthrough occurred in seven and two of the thirteen H. pylori-negative subjects and one and two of the eleven H. pylori-positive subjects at each dose, respectively. CONCLUSIONS: The effects of rabeprazole 10mg b.i.d. were equal to those of 20mg b.i.d. in H. pylori-positive subjects; whereas in H. pylori-negative subjects, 20mg b.i.d. was superior for prevention of nocturnal acid breakthrough.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2005

Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment.

AIMS/HYPOTHESIS: We have previously reported that fulminant type 1 diabetes is characterised by an absence of diabetes-related antibodies and a remarkably abrupt onset. However, little is known about the mechanism of beta cell destruction in this diabetes subtype, and to obtain insights into the aetiology of the disease, we investigated residual endocrine cells and the expression of Fas and Fas ligand in fulminant type 1 diabetes. METHODS: Residual beta and alpha cells were morphologically assessed in pancreatic tissue obtained by biopsy from five patients with recent-onset fulminant type 1 diabetes and five patients with recent-onset typical autoimmune type 1 diabetes. In addition, the expression of Fas and Fas ligand was evaluated by immunohistochemistry. RESULTS: In fulminant type 1 diabetes, beta and alpha cell areas were decreased significantly, compared with autoimmune type 1 diabetes and control subjects. In contrast, the alpha cell area was not decreased significantly in autoimmune type 1 diabetes, compared with that in control subjects. No Fas expression in islets and Fas ligand expression in CD3(+) cells in the exocrine pancreas were found in the fulminant type 1 diabetic patients who underwent this evaluation. CONCLUSIONS/INTERPRETATION: Our study showed that beta and alpha cells are damaged in fulminant type 1 diabetes. In addition to the lack of Fas and Fas ligand expression, the results suggest that the mechanism of beta cell destruction in fulminant type 1 diabetes is different from that in autoimmune type 1 diabetes.

Acidosis↗

PubMed2001

Hepatocyte growth factor promotes epithelial morphogenesis and occludin linkage to the cytoskeleton in cultured retinal pigment epithelial cells.

BACKGROUND: Although hepatocyte growth factor (HGF) is also known as scatter factor, it induces epithelial morphogenesis in cultured bovine retinal pigment epithelial (RPE) cells. To elucidate the mechanism of epithelial morphogenesis, we investigated the influence of HGF on occludin, a major component of tight junctions. METHODS: RPE cells were plated on collagen type 1-coated chamber slides or dishes, 20 ng/ml HGF was added and the cells were incubated for 1 week. Cells were harvested at several time-points, and occludin expression was examined by immunohistochemistry. Detergent extraction protocols to identify the intensity of occludin linkage to the cytoskeleton were also used. Occludin expression was determined semiquantitatively by Western blotting. RESULTS: Fluorescence microscopy revealed that HGF treatment increased the levels of insoluble occludin at the cell borders after detergent extraction. These level of insoluble occludin and the associated epithelial morphology were maintained for more than 3 weeks after withdrawal of HGF, whereas cells not treated with HGF had a fibroblastic appearance. Western blotting also showed that insoluble occludin was more abundant in HGF-treated cells. Furthermore, immunoreactive bands of insoluble occludin were somewhat larger than those of soluble occludin, suggesting that insoluble occludin may be modified in comparison to soluble occludin. CONCLUSION: Our results suggest that HGF promotes linkage of occludin to the cytoskeleton. HGF may become a therapeutic candidate in physiological recovery of RPE cells and in preparation of RPE monolayers for transplantation.

Animals↗

PubMed2001

Fundus autofluorescence in patients with pseudoxanthoma elasticum.

PURPOSE: To characterize changes in fundus autofluorescence in patients with pseudoxanthoma elasticum (PXE). Fundus autofluorescence intrinsically derives from lipofuscin, and the degree of autofluorescence is thought to indicate the degree of retinal pigment epithelium (RPE) metabolic activity. METHODS: Twelve eyes of 6 patients (2 men, 4 women) with PXE were studied with a confocal scanning laser ophthalmoscope. Patient age ranged from 42 to 62 years. The autofluorescence of abnormal retinal areas was compared digitally with that of neighboring, presumed healthy control areas. When the average gray level of a fundus region was 2 SDs above or below the average gray level of a control area, autofluorescence of the fundus region was considered abnormal. RESULTS: In all 12 eyes, some segments of the angioid streaks showed decreased fundus autofluorescence, and other segments of the streaks showed normal autofluorescence. Areas of peripapillary chorioretinal atrophy seen in 2 eyes and of disciform scarring seen in 3 eyes showed decreased autofluorescence. Solitary or multiple drusen-like spots showed increased autofluorescence in all 12 eyes. CONCLUSION: Atrophic and degenerative RPE regions showed decreased fundus autofluorescence in areas of chorioretinal atrophy and in some segments of the angioid streaks. Some drusen-like spots showed increased autofluorescence. The characteristic changes in autofluorescence that we observed in PXE patients suggest that the content of the drusen-like substance differs from that of senile drusen and that the drusen-like lesions are similar to the sub-RPE deposits seen in macular dystrophy.

Adult↗

PubMed2001

[The new experimental ulcerative colitis model in rats induced by subserosal injection of acetic acid].

We have developed a new experimental ulcerative colitis model in rats. Topical pathological change of a round or a ellips shape was induced by subserosal injection of acetic acid (20%, 0.02 ml) into the middle colon of rats. The size of the induced ulcer could directly be measured using a caliper gauge, and the result was expressed as the ulcer area (mm2). We determined the concentration of leukotriene B4 (LTB4), which is one of important clinical factors, in the ulcer region and found that the quantity of LTB4 was well correlated with the size of the ulcer area. Histopathological studies of the ulcer region demonstrated that there were some morphological similarities to the human form of ulcerative colitis, characterized by edema, necrosis, inflammatory cell infiltration, crypt abscess and granulation tissue formation. Effects of 5-aminosalicylic acid and sodium prednisolone phosphate were investigated by intrarectal administration in this colitis model. The predominant improvement of colitis was obtained from both treatments in the ranges of the clinical doses of each drug. In conclusion, we suggest that this colitis model provides a new way for quantitative evaluation of the efficacy of new therapeutic agents for ulcerative colitis.

Acetic Acid↗

PubMed2001

Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes: close correlation between serological markers and histological evidence of cellular autoimmunity.

To better understand the pathogenesis of type 1 diabetes, we have developed pancreatic biopsy under laparoscope for recent-onset type 1 diabetic patients. The patients included 29 acute-onset type 1 diabetic patients, 5 latent-onset type 1 diabetic patients, and 1 type 2 diabetic patient. Their median age was 28 years, and the duration of diabetes at the time of biopsy was approximately 3 months. In 31 of 35 patients, we could obtain the pancreas tissue by punching. No serious complications, such as heavy bleeding, peritonitis, or pancreatitis, have been experienced. Pneumoderma was observed in two patients, and abdominal dull pain had continued for 2 days in two patients. However, special treatment was not necessary for these complications. T-cell-predominant infiltration to islets (insulitis) and hyperexpression of major histocompatibility complex class I antigens on islet cells were the two major findings and were observed in 17 of 29 recent-onset type 1 diabetic patients. These findings could be regarded as evidence of immune attack against beta-cells, and their presence was closely correlated with the presence of either anti-GAD or anti-IA-2 antibodies (P = 0.02). In conclusion, pancreatic biopsy under laparoscope is a safe procedure without serious complications, according to our findings, for detecting in situ autoimmune phenomenon in recent-onset type 1 diabetic patients.

Adolescent↗

PubMed2000

Inadvertent corneal burn by using indirect wide-field contact lenses and different laser beam delivery systems during experimental fundus photocoagulation.

BACKGROUND AND OBJECTIVE: At fundus photocoagulation by using a wide-field indirect contact lens, the laser radiant exposure may be increased at the anterior segment of the eye. We examined the likelihood of producing inadvertent corneal burn by using parfocal and sharped edge defocus laser delivery systems with various indirect contact lenses. STUDY DESIGN/MATERIALS AND METHODS: The two laser delivery systems were used with four lenses of different viewing angles during fundus photocoagulation in a total 44 eyes of rabbits. RESULTS: By using the lenses, the parfocal system increased corneal radiant exposure more than did the sharped edge defocus system. By using the Widefield PRP 165 lens of the widest viewing angle, there was no difference between the two systems in the corneal burns produced. CONCLUSION: Some indirect contact lenses used in combination with the parfocal system caused inadvertent corneal burns more readily than did the same lenses in combination with the sharped edge defocus system.

Animals↗

PubMed2000

Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion.

Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC has a physiologically important role in the endocrine pancreas. In this study, we examined the in vivo effect of recombinant human BTC (rhBTC) on glucose intolerance and pancreatic morphology using a new mouse model with glucose intolerance induced by selective alloxan perfusion. RhBTC (1 microg/g body wt) or saline was injected subcutaneously every day from the day after alloxan treatment. The intraperitoneal glucose tolerance test revealed no difference between rhBTC-treated and rhBTC-untreated glucose-intolerant mice at 2-4 weeks. However, glucose tolerance was significantly improved and body weight was significantly increased in rhBTC-treated mice compared with untreated mice at 8 weeks. Islet-like cell clusters, consisting mainly of beta-cells, were increased in the pancreas and were localized in contact with the ductal lining cells and sometimes with acinar cells. In conclusion, administration of rhBTC improved glucose tolerance in this mouse model by increasing beta-cell volume, primarily through accelerated neogenesis from ductal lining cells.

Animals↗

PubMed1999

Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus.

AIMS/HYPOTHESIS: To determine whether the clinical heterogeneity observed in the development of Type I (insulin-dependent) diabetes mellitus correlates with immunohistochemical differences observed at diagnosis. METHODS: Patients (n = 17) with recent-onset diabetes clinically considered to be insulin dependent (Type I), underwent pancreatic biopsy for immunohistological analysis. These patients were divided into two groups based on the presence or absence of islet immunological abnormalities (insulitis or hyperexpression of MHC class I antigens or both). The patients were also HLA typed and tested for islet cell antibodies and antibodies to glutamic acid decarboxylase (GAD-Ab). All patients were followed monthly for 2 years and their fasting plasma glucose, haemoglobin A1c and daily insulin doses were recorded. The clinical course of patients with islet immunological abnormalities was compared with that of patients without those abnormalities. RESULTS: Patients with and without islet immunological abnormalities did not differ with regard to HLA type or islet cell antibodies. Antibodies to glutamic acid decarboxylase correlated with the presence of insulitis and MHC class I hyperexpression. These local immunological abnormalities were also associated with higher haemoglobin A1c values (p < 0.05) and a trend towards greater insulin requirements. Further, patients with the islet abnormalities had higher fasting plasma glucose concentrations 2 years after the biopsy than at the time of the biopsy (p < 0.05). CONCLUSION/INTERPRETATION: The heterogeneous clinical course observed following diagnosis in patients with Type I diabetes correlates with islet immunological abnormalities. Insulitis and hyperexpression of MHC class I correlate with deteriorating glycaemic control.

Adolescent↗

PubMed1999

Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus.

AIMS/HYPOTHESIS: Type I (insulin-dependent) diabetes results mainly from T-cell-mediated autoimmune destruction of pancreatic beta cells. Cytotoxic T lymphocytes destroy target cells via a perforin-based or Fas-based mechanism. Our previous study indicated that the Fas-Fas ligand (FasL) pathway is required for the development of autoimmune diabetes in the NOD mouse. We now investigated whether or not the Fas-FasL system is involved in the beta-cell destruction in human Type I diabetes. METHODS: We immunohistochemically analysed pancreas biopsy specimens of 13 recent-onset patients. RESULTS: Pancreatic islets were identified but showed various degrees of reduction in beta-cell volume in all patients. Out of 13 patients 6 had insulitis. In these 6 patients Fas was expressed in both the islets and infiltrating cells but not in either cell type in the 7 other patients without insulitis. Double immunostaining showed that Fas was positive in 92.2 to 97.7 % of beta cells but only in 17.6 to 46.7 % of alpha cells in Fas-positive, insulin-remaining islets. We found FasL was expressed exclusively in islet-infiltrating cells in patients with insulitis. Double immunostaining revealed that the most prevalent phenotype of FasL-positive cells was CD8, which was followed by macrophages and CD4. CONCLUSION/INTERPRETATION: The interaction between Fas on beta cells and FasL on infiltrating cells might trigger selective apoptotic beta-cell death in inflamed islets, leading to immune-mediated Type I diabetes. [Diabetologia (1999) 42: 1332-1340]

Adolescent↗

PubMed1999

Suppressed phenylalanine ammonia-lyase activity after heat shock in transgenic Nicotiana plumbaginifolia containing an Arabidopsis HSP18.2-parsley PAL2 chimera gene.

The activity of phenylalanine ammonia-lyase (PAL; EC 4.3.1.5) after heat shock (HS) in leaves and buds of transgenic Nicotiana plumbaginifolia containing an Arabidopsis HSP18.2 promoter-parsley phenylalanine ammonia-lyase 2 (HSP18.2-PAL2) chimera gene was examined. Immediately after HS treatment at 44 degrees C for 5 h, the PAL activity in both transgenic and normal (untransformed) plants was 35-38% lower than that before HS. At normal temperature (25-26 degrees C), the PAL activity recovered within 5 h of ending the HS treatment in normal plants, but not until 12-24 h in transgenic plants containing the HSP18.2-PAL2 gene. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the presence of parsley PAL2 mRNA in transgenic plants, which remained for 8-12 h following 5-h HS at 44 degrees C; the mRNA was not observed before HS. The content of chlorogenic acid (CGA; 3-caffeoylquinic acid) decreased drastically 8-12 h after HS in transgenic plants, but only slightly in normal plants. Thus, the decrease in PAL activity accompanied by expression of the parsley PAL2 gene after HS treatment corresponded to the decrease in CGA synthesis. These results might be attributed to post-transcriptional degradation of endogenous PAL mRNA triggered by transcription of the transgene.

Journal Article↗

PubMed1999

Age-related scattered hypofluorescent spots on late-phase indocyanine green angiograms.

PURPOSE: Scattered hypofluorescent spots may be seen on indocyanine green (ICG) angiograms of regions that do not show abnormalities when viewed with an ophthalmoscope. Hypofluorescent spots are found in several pathologic conditions, typically in inflammatory diseases. In this report, we describe hypofluorescent spots in normal fundi and show that such spots can be age-related. METHODS: Video-fundus camera ICG angiograms of 115 eyes of 109 patients aged 12 to 85 years with normal fundi or with only age-related maculopathy were reviewed. The relation between age and scattered hypofluorescent spots, and between age-related maculopathy and spots was examined utilising regression analysis. RESULTS: Scattered hypofluorescent spots were seen throughout the posterior pole in 24 eyes of 23 patients and in a portion of the posterior pole in 30 eyes of 29 patients. The hypofluorescent spots were noted between 26 and 37 minutes after dye injection. Patient age ranged from 51 to 80 years, and regression analysis showed that the frequency of hypofluorescent spots increased significantly with aging (p < 0.05). However, age-related maculopathy did not show a significant relation to the spots. CONCLUSION: Scattered hypofluorescent spots seen in the posterior pole during the late-phase of ICG angiograms can apparently be due to aging of the fundus.

Adolescent↗

PubMed1999

Overexpression of the aldose reductase gene induces apoptosis in pancreatic beta-cells by causing a redox imbalance.

To determine the role of the polyol metabolizing pathway under hyperglycemic conditions, the effects of aldose reductase (AR) on the cellular functions of pancreatic beta-cells were examined. Stable transfectants of rat AR cDNA were obtained with a pancreatic beta-cell line, HIT, in which a negligible amount of AR was originally expressed. Overproduction of AR triggered DNA fragmentation, as judged with the TUNEL method and agarose gel electrophoresis. Morphological analysis by electron microscopy also clearly showed apoptosis of the AR-overexpressing HIT cells. Induction by interleukin-1beta of gene expression such as those of an inducible form of nitric oxide synthase (NOS-II) and Mn-superoxide dismutase (Mn-SOD), was much lower in the transfectants than in the control cells, while the expression of constitutively expressed genes such as those for Cu,Zn-superoxide dismutase and insulin was not changed. The susceptibility to interleukin-1beta stimulation of the expression of the NOS II and Mn-SOD genes was due to suppressed NF-kappaB activity, which is essential for the expression of these genes. In addition, the intracellular NADPH/NADP+ ratio was considerably lower in the AR-transfected cells than in control cells. Thus, the overexpression of AR in pancreatic beta-cells induced apoptosis that may be caused by a redox imbalance.

Aldehyde Reductase↗

PubMed1999

Fetal treatment of congenital heart block ascribed to anti-SSA antibody: case reports with observation of cardiohemodynamics and review of the literature.

PROBLEM: Maternal anti-SSA(B) antibody crosses the placenta and causes fetal myocarditis, congenital heart block (CHB), hydrops fetalis, and intrauterine fetal death. The aim of this study was to evaluate corticosteroids' efficacy as a treatment for CHB. METHOD OF STUDY: One fetus with complete CHB and one fetus with incomplete CHB due to anti-SSA(B) antibody received maternal prednisolone (PSL) and dexamethasone (DEXA) treatments. Heart rate, cardiothoracic ratio (CTR), left ventricular fractional shortening (FS), and preload index (PLI) were longitudinally measured by serial fetal echocardiograms. RESULTS: In the former case, after maternal PSL/DEXA administration, improvement of cardiohemodynamics, i.e., the reduction of PLI from 1.7 to 0.4, CTR from 70 to 52%, and FS from 63 to 54% were observed. In the latter case, second degree 2:1 block was converted to 3:2 block/sinus rhythm, resulting in the increase of the fetal heart rate from 65 to 116 beats per minute (bpm). CONCLUSIONS: We disclosed for the first time the beneficial effects of corticosteroids in the fetal cardiohemodynamics and conduction system of affected fetuses with the presence of maternal anti-SSA(B) antibodies.

Adult↗

PubMed1999

Effect of retinoic acid on proliferation and polyamine metabolism in cultured bovine retinal pigment epithelial cells.

Reports regarding the effect of all-trans-retinoic acid (RA) on the cell growth of retinal pigment epithelial cells (RPE) have been contradictory. The aims of this study are to clarify the in vitro effect of RA on RPE cells and to examine polyamine metabolism after RA stimulation. A 4-day incubation of fetal-calf-serum (FCS)-stimulated RPE cells with 10 or 25 microM RA significantly increased both cell number and [3H]thymidine incorporation. RPE cells grown over an extended period for 8 days also increased in number and reached full confluency. However, if the incubation was further extended to 12 days, no further increase in cell number was detected. RA treatment of FCS-stimulated RPE cells shifted the peak of ornithine decarboxylase (ODC) activity from 16 to 4 h. S-adenosylmethionine decarboxylase (SAMDC) activity and spermidine/spermine N1-acetyltransferase (SAT) activity of RA-treated RPE cells were significantly greater until 8 and 16 h after incubation, respectively. The putrescine content was significantly increased in RA-treated RPE cells up until 24 h, while spermidine, spermine and N1-acetylspermidine contents were significantly increased until 16 h. Our findings suggest that RA treatment increases the intracellular polyamine concentration of RPE cells via activation of ODC, SAMDC and SAT and that this results in the promotion of RPE cell growth until the cells reach full confluency.

Adenosylmethionine Decarboxylase↗

PubMed1998

Retinal sensitivity measurement over drusen using scanning laser ophthalmoscope microperimetry.

BACKGROUND: Retinal sensitivity over drusen was examined using a scanning laser ophthalmoscope to confirm a previous report of no change in sensitivity over drusen. METHODS: Microperimetry was performed using a scanning laser ophthalmoscope in 23 eyes of 19 subjects. Subject age ranged from 42 to 86 years (mean 68.5 years). Fifty-four drusen bigger than the diameter of a major retinal vein at the optic disc rim were examined, and drusen were classified as soft drusen and other large drusen. RESULTS: Nine eyes of eight subjects showed a decrease in retinal sensitivity over drusen. The decrease in retinal sensitivity was more than 5 dB less than the sensitivity at a peripheral non-drusen area peripheral to the measurement point. The sensitivity decrease was noted over 15 of 29 large drusen and the decrease was statistically significant (P < 0.02). However, no relationship between the size of the drusen and the amount by which sensitivity decreased was found. Nevertheless, a decrease in retinal sensitivity was not seen over any of 25 soft drusen. CONCLUSION: Large drusen may influence retinal sensitivity and function.

Adult↗

PubMed1998

Acute retinal necrosis late in the second trimester.

PURPOSE: To report treatment of a patient with acute retinal necrosis during pregnancy. METHODS: A 24-year-old woman in her twenty-third week of gestation was diagnosed with acute retinal necrosis. A combination of acyclovir and interferon therapy was started at 25 weeks. Pars plana vitrectomy was performed during the 26th week of gestation. RESULTS: The necrotizing retina became gliotic within 3 weeks of surgery. The patient's visual acuity improved to LE, 20/40. A healthy baby was delivered at 39 weeks of gestation. CONCLUSION: Combination therapy of acyclovir and interferon followed by surgery partially restored the patient's vision without affecting fetal development.

Acyclovir↗