Combination of low-dose total skin electron beam therapy and subsequent localized skin electron beam therapy as a therapeutic option for advanced-stage mycosis fungoides.

Electron beam therapy (EBT) is an established treatment for mycosis fungoides (MF), but evidence for the use of EBT in advanced cutaneous conditions is limited, and optimal scheduling of the regimen for such conditions remains unclear. We report the case of a 44-year-old woman diagnosed with MF with widespread cutaneous lesions, including multiple huge tumours in the craniofacial area. Low-dose total skin (TS)EBT and subsequent localized skin (LS)EBT achieved striking improvements in eruptions. Oral etretinate was also administered during therapy. Our experience implies that combined TSEBT and LSEBT may be worth attempting when a patient presents with both widespread lesions and prominent tumours, even when the tumours are extremely large.

Identification of factors contributing to phenotypic divergence via quantitative image analyses of autosomal recessive woolly hair/hypotrichosis with homozygous c.736T>A LIPH mutation.

BACKGROUND: Autosomal recessive woolly hair/hypotrichosis (ARWH/H) is caused by mutations in LIPH. Homozygotes for the LIPH c.736T>A (p.C246S) mutation, the most prevalent genotype in Japanese patients, present varying degrees of hair loss; however, determinants of this phenotypic diversity remain elusive. OBJECTIVES: To establish methodologies for quantitative assessment of clinical severity and provide a detailed characterization to elucidate the factors contributing to phenotypic divergence. METHODS: Digital image analyses were conducted to convert clinical severities into numerical values. Eight patients with ARWH/H were classified into three groups (mild, severe, very severe), based on severity scores. Dermoscopic images were collected and assessed for total hair numbers and hair thickness for intergroup comparisons. RESULTS: The image analysis detected a difference in hair thickness but not in total hair numbers, between mild and severe cases. A marked decrease in total hair number was noted in an atypical very severe case. Histopathologically, a patient with a mild case demonstrated hair miniaturization and a high telogen/anagen ratio without a decrease in total hair count, endorsing dermoscopic observations. Two children demonstrated spontaneous improvement without an increase in total hair numbers, and two adults responded well to topical minoxidil with increased total hair numbers and hair thickness. CONCLUSIONS: The difference in the frequency of underdeveloped hairs may be a major factor contributing to the clinical diversity of hair sparseness in LIPH c.736T>A homozygotes with ARWH/H. Hence, pharmacological modification to thicken existing fine hairs may provide a therapeutic strategy.

Potential treatments for genetic hearing loss in humans: current conundrums.

Genetic defects are a major cause of hearing loss in newborns. Consequently, hearing loss has a profound negative impact on human daily living. Numerous causative genes for genetic hearing loss have been identified. However, presently, there are no truly curative treatments for this condition. There have been several recent reports on successful treatments in mice using embryonic gene therapy, neonatal gene therapy and neonatal antisense oligonucleotide therapy. Herein, we describe state-of-the-art research on genetic hearing loss treatment through gene therapy and discuss the obstacles to overcome in curative treatments of genetic hearing loss in humans.

Skin lesions in a patient with IgG4-related disease.

IgG4-related disease (IgG4-RD) is a newly recognized condition that is characterized by raised levels of serum IgG4, tissue infiltration of IgG4-positive plasma cells and presence of fibrosis. It affects multiple organs, including the pancreas, bile duct, and lacrimal and salivary glands. Skin lesions have rarely been reported, and those that have were described as distributed mainly in the head and neck region. We report a case of IgG4-RD with autoimmune pancreatitis and skin lesions on the trunk and limbs. The skin lesions responded well to oral prednisolone (PSL); however, tapering of PSL to 5 mg/day resulted in recurrence. At present, the skin disease is well controlled at a dose of 7 mg/day. Interestingly, IgG4 levels fluctuated with changes in the PSL dose but did not coincide with the severity of the skin disease, implying that the raised levels of IgG4 did not directly influence the skin symptoms.

Mechanism of oral absorbent AST-120 in lipid abnormalities in experimental uremic rats.

BACKGROUND: We have reported that oral sorbent AST-120 (AST) is effective in delaying the induction of dialysis in patients with chronic renal failure (CRF) because of its effect on lipid metabolism. To clarify the precise mechanism of AST in lipid abnormalities in CRF, we examined the effect of AST on plasma lipid profile, total bile acids (TBA), and lipoprotein lipase (LPL) activity in experimental uremic rats. METHODS: Uremic rats were prepared using male Wistar rats by ligating 5/6 of the renal artery. Uremic rats were randomly divided into two groups as follows: a control group in which rats were maintained on the standard diet and an AST group in which rats were maintained on a diet containing 5 g of AST per 100 g of standard diet for 10 weeks. Plasma LPL activity was measured as free fatty acid (FFA) generation after intravenous administration of heparin. RESULTS: Plasma creatinine at 1.5 +/- 0.1 mg/dl was lower in the AST group than the 1.9 +/- 0.5 mg/ml level in the control group. AST significantly decreased plasma total cholesterol from 192 +/- 29 to 142 +/- 25 mg/dl, triglycerides from 198 +/- 71 to 99 +/- 38 mg/dl, and TBA from 19.6 +/- 2.6 mumol/liter to 8.8 +/- 3.5 mumol/ml. Plasma LPL activity at 0.22 +/- 0.01 mumol FFA/min/hr was significantly higher in the AST group than 0.15 +/- 0.03 mumol FFA/min/hr in the control group. CONCLUSIONS: These results suggest that AST may improve plasma lipid abnormalities by binding to bile acids in the intestinal lumen and preventing their reabsorption and inhibiting the reduction of LPL activity in experimental uremic rats.

Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys.

We recently reported that the serum levels of indoxyl sulfate, a dietary protein metabolite, are increased in both uremic rats and patients, and that the administration of indoxyl sulfate to uremic rats accelerates the progression of glomerular sclerosis. Thus, we hypothesize that the overload of protein metabolites such as indoxyl sulfate on nephrons promotes the progression of chronic renal failure (CRF). Recent studies revealed that tubulointerstitial injury is of equal or greater importance than glomerular sclerosis in determining whether progressive renal dysfunction will ensue in various renal diseases. In the present study, to clarify the role of indoxyl sulfate in the progression of CRF, the expressions of genes related to tubulointerstitial fibrosis such as transforming growth factor (TGF)-beta 1, tissue inhibitor of metalloproteinases (TIMP-1) and pro-alpha 1(I) collagen were examined in the renal cortex of 5/6-nephrectomized uremic rats given indoxyl sulfate. In the first experiment, the administration of indoxyl sulfate for five weeks significantly increased the mRNA levels of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in the uremic rats given indoxyl sulfate compared with the control uremic rats, accompanied by a significant decline in renal function and worsening of glomerular sclerosis. In the second experiment, the administration of indoxyl sulfate for 2.5 weeks also increased the expression of the mRNA levels with no significant decline in the renal function. In conclusion, these findings indicate that the overload of the protein metabolite indoxyl sulfate on remnant nephrons is involved in the increased bioactivity of TGF-beta 1 in uremic kidneys, which enhances the renal expression of TIMP-1 and type 1 collagen, leading to the progression of CRF.

Indoxyl sulfate stimulates renal synthesis of transforming growth factor-beta 1 and progression of renal failure.

We recently demonstrated that the administration of indoxyl sulfate (dietary protein metabolite) to 5/6-nephrectomized rats accelerated the progression of chronic renal failure by increasing the transforming growth factor (TGF)-beta 1 synthesis in the kidneys, which enhanced the renal expressions of tissue inhibitor of metalloproteinase (TIMP)-1 and type 1 collagen, leading to renal fibrosis. The aim of the present study was to clarify the mechanism by which the administration of indoxyl sulfate increases TGF-beta 1 in the kidneys of uremic rats. Since infiltrative monocytes are suggested to be an important source of TGF-beta 1 in tubulointerstitial fibrosis, we examined the effect of indoxyl sulfate administration to uremic rats on the renal gene expression of intercellular adhesion molecule (ICAM)-1, which is involved in the infiltration of monocytes to kidneys. Indoxyl sulfate administration was observed to enhance the mRNA levels of ICAM-1 as well as those of TGF-beta 1, TIMP-1 and pro alpha 1 (I) collagen in the renal cortex of 5/6-nephrectomized uremic rats. In addition, we demonstrated in vitro that the addition of indoxyl sulfate significantly increased the synthesis of TGF-beta 1 in cultured proximal tubular cells. Thus, the overload of indoxyl sulfate in uremic kidneys increased the infiltration of monocytes and directly increased the synthesis of TGF-beta 1 in proximal tubular cells.

Modulation of rhythmical slow activity, long-term potentiation and memory by muscarinic receptor agonists.

We investigated the cholinergic modulation of hippocampal rhythmical slow activity (or theta activity), long-term potentiation and a behavioral memory task. The intravenous administration of the muscarinic receptor agonists, AF102B ((+/-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3') quinuclidine hydrochloride hemihidrate) and oxotremorine, induced rhythmical slow activity at doses of 1.0 mg/kg and 0.01 mg/kg, respectively. Long-term potentiation of population spike amplitude in the hippocampal CA1, which was induced by tetanic stimulation to the Schaffer collateral/commissural fiber, was increased by AF102B (1.0 mg/kg i.v.) and oxotremorine (0.01 mg/kg i.v.). Oral administration of AF102B and oxotremorine improved scopolamine-induced memory deficits in a passive avoidance task in mice at doses of 1.0 mg/kg and 0.2 mg/kg, respectively. The correspondence of the effective doses of muscarinic receptor agonists in these three experiments suggested the cholinergic correlation of rhythmical slow activity, long-term potentiation and memory.

Dietary protein loading and the oral adsorbent AST-120 in the progression of chronic renal failure in the rat.

Excess protein intake enhances the progression of renal failure. The oral carbonaceous adsorbent, AST-120, was found experimentally and clinically to retard the progression of renal failure. This study was designed to determine whether deterioration of renal function by dietary protein loading can be prevented or mitigated by this oral adsorbent. Rats with uremia induced by partial renal infarction were fed a normal or high-protein diet for 70 days with or without AST-120, in which the inorganic phosphate content was adjusted to the same level. The survival rate deteriorated with the high dietary protein, but was improved from 30% to 100% with AST-120. Dietary protein loading reduced renal function, based on creatinine clearance. AST-120 improved renal function and renal histopathology not only in the normal diet group but in the high-protein group as well. The progression of renal failure induced by protein loading is thus shown to be prevented by oral AST-120. The mechanism for its action remains to be clarified.

[Refractory multiple myeloma preceded by extramedullary plasmacytoma of lymph node--a case report and review of the literature].

It has been reported that extramedullary plasmacytoma (EMP) tends to be characterized by an indolent clinical course and lower incidence of progression to multiple myeloma. Primary plasmacytoma of lymph nodes is extremely rare and details of its clinical picture remain unclarified. We recently encountered an unusual case of EMP of lymph nodes that progressed to refractory multiple myeloma only 18 months later. A 74-year-old woman was admitted to our hospital because of a painless swelling in the right inguinal region. A tumor was removed surgically, and a histological diagnosis of EMP of the lymph nodes was made. Bence Jones protein (BJP) was detected in the urine, but there was no other evidence of systemic myelomatosis. The patient received local irradiation, which resulted in the elimination of BJP. Eighteen months later, however, a tumor developed in her right stemo-clavicular joint. A bone survey revealed multiple osteolytic lesions, and many atypical plasma cells were observed in the bone marrow, indicating multiple myeloma. The patient deteriorated despite several regimens of combination chemotherapy, and died four and a half years after the initial diagnosis of EMP.

[Successful treatment with CPT-11 and adriamycin for hemophagocytic syndrome associated with intravascular lymphomatosis].

A 75-year-old man was admitted because of non-Hodgkin's lymphoma (histology undetermined) of the rib. A complete remission was achieved after CHOP therapy and irradiation. One year later, high fever, thrombocytopenia and liver dysfunction developed. Bone marrow aspirate revealed a hypoplastic marrow with hemophagocytic histiocytes, and a diagnosis of hemophagocytic syndrome (HPS) was made. Although no lymphomatous lesions were detected, HPS due to relapsed lymphoma was strongly suspected. The patient received MEVP therapy including etoposide and prednisolone, but without any improvement. Soon after the initiation of CPT-11 and adriamycin (ADM) therapy, all symptoms of HPS disappeared. This combination chemotherapy was repeated over a three-week span, and the patient remained in partial remission for the next 10 months. In November 1997, a tumor developed in the paranasal sinus, and the patient died three months later. The autopsy disclosed many B lymphoma cells filling the small vessels of almost all organs, and a final diagnosis of intravascular lymphomatosis (IVL) was made. These findings indicate that combination CPT-11 and ADM therapy is effective for cases of IVL accompanied by HPS that are refractory to conventional chemotherapies.

[Effect of oral adsorbent (AST-120) in the rat model of chronic renal failure induced by adriamycin].

The effect of AST-120 was examined in the rat model of CRF induced by adriamycin (ADM), which is known to induce focal glomerular sclerosis (GS). ADM (2mg/kg) was injected intravenously twice at a 3-wk interval. After 14 wks, rats were paired with control (C) and AST-120 (A) groups according to levels of BUN and proteinuria. Then, the rats were fed regular rat chow with (A, n = 10) or without (C, n = 10) AST-120. After 28 wks, there were more GS in C. Averaged sclerosis index (SI, 0-4 scale) in C was 1.97 (0.94-3.22), while 1.61 (0.60-2.97) in A. When GS was advanced in C (SI > 2.0), largely ameliorated SI was noted in A (2.61 vs. 1.97, C vs. A, p < 0.05 by paired W-test, n = 5 each). Also, in these rats, BUN, serum creatinine and Ht were all improved in A (p < 0.05). Thus, AST-120 was effective in CRF rats induced by ADM when uremia was advanced. The data also indicates that a reduction of uremic toxins could improve glomerular histology and renal function in CRF.

[Pathological study on the effect of oral adsorbent AST-120 on chronic renal failure in rats].

In order to evaluate the direct or indirect effect of AST-120 on chronic renal failure (CRF) in rats, histological and electron microscopical examinations were performed. A total of 30 Sprague-Dawley rats (aged 11 weeks and weighing 226 to 229 gm) with CRF induced by 5/6 nephrectomy were prepared. Rats were fed by a commercial diet (CE-2, Japan Kurea) and were divided into two groups: A (16 rats) and B (14 rats). AST-120 (5% content) was only administered to group B. After two months, kidneys were removed and prepared for the histological and electron microscopical examinations. On histological examination, group A kidneys showed severe glomerular hyalinization (more than 80%) and frequent crescents, as well as tubulo-interstitial fibrosis and many protein casts. In contrast, segmental glomerular lesions were identified in group B kidneys. Tubulo-interstitium were also well preserved. Furthermore, the ultrastructural findings of group B were milder than that of group A. The preservation of renal tissue in group B revealed the beneficial effect of AST-120 on CRF rats' kidneys. In conclusion, this beneficial effect is provided by the removal of the serum toxic metabolite (uremic toxin) and the precursor substance of the toxin by orally administered AST-120.

[Effect of oral adsorbent AST-120 in rats with chronic renal failure--mechanism of progression of renal failure by dietary protein].

Progression of renal insufficiency was evaluated in partially nephrectomized Sprague-Dawley rats at the age of 10 weeks, fed on the low (6%), usual (20%), and high (36%) protein diet (group 6C, 20C, and 36C). Effects of oral adsorbent AST-120 on these experimental uremic models were also examined (group 6A, 20A, 36A). All the rats underwent paired feeding, and survived during the experimental period of 3 weeks. GFR (inulin clearance) and RPF (para-amino hippurate clearance), as well as Ccr was measured before the sacrifice. Initial serum creatinine and Ccr were 1.7 mg/dl and 0.27 ml/min. The rats of group 36C showed progressive elevation of serum creatinine level and decrease in Ccr. At the end of the study, GFR was significantly lower in group 36C than in group 6C and 20C (0.19, 0.68, 0.87 ml/min respectively). Significant elevation of filtration fraction in group 36C suggested that the decrease in GFR mainly resulted from low RPF. Even in group 36C, no glomerular sclerosis was histologically demonstrated in the remnant kidney, and the mean planar area of the remnant glomeruli was significantly small, which might reflect low RPF. Tubulo-interstitial changes like dilatation of the urinary space and tubular epithelial flattening were prominent in group 36C. Beneficial effect of AST-120 was obvious in high protein diet groups. GFR and RPF were rather well preserved in group 36A (0.36 and 0.78 ml/min) with normal filtration fraction. Tubulo-interstitial damage was evidently mild in group 36A. These data suggested the presence of some humoral factors, which can be adsorbed by AST-120 in gastrointestinal tract, and responsible for the deterioration of renal function and tubulo-interstitial damage induced by high protein diet in the uremic condition. Besides hyperfiltration and glomerular hypertrophy, such humoral factors as suggested in this study may contribute to the progression of chronic renal failure to some extent.

Three-quarters nephrectomy in rats as a model of early renal failure.

To produce a compatible model of early renal failure easily, we prepared three-quarters nephrectomized animal. 20 Sprague-Dawley rats were divided into the following two groups: 10 rats which received three-quarters nephrectomy (Nx group), assuming the weight of both kidneys to be equal, and another 10 rats which underwent sham operations (S group). The levels of creatinine clearance in Nx group and S group were 286.5 +/- 33.5 vs. 431.1 +/- 55.9 microliters/min/100 g BW (P less than 0.001) on week 2, and 233.0 +/- 16.7 vs. 562.3 +/- 62.9 microliters/min/100 g BW (P less than 0.001) on week 10, respectively. The indirect and direct systolic blood pressure (SBP) values of Nx group and S group at the 10th week were 154.5 +/- 5.5 vs. 131.1 +/- 3.6 mmHg (P less than 0.01), and 148.2 +/- 4.8 vs. 130.7 +/- 6.6 mmHg (P less than 0.01), respectively. Significant changes in the levels of urinary protein excretion, urinary sodium output, urinary epinephrine, urinary norepinephrine and plasma renin activity between both groups were recognized on the 10th week. The planar area of Nx group was significantly increased as compared to that of S group (11.0 +/- 0.3 vs. 7.2 +/- 0.1 x 10(-3) mm2, P less than 0.001). It is concluded that this model resembles early renal failure in humans because slow progression of renal dysfunction occurred with mild elevation of SBP, and that it is adequate for evaluating the influence of glomerular hypertrophy, resulting in glomerulosclerosis.

Effect of an oral adsorbent (AST-120) in rats with daunomycin-induced chronic renal failure.

The effect of an oral adsorbent (AST-120) was examined in rats with daunomycin-induced chronic renal failure. Sixteen pairs of daunomycin rats which had similar levels of proteinuria at 4 weeks after being injected with daunomycin were selected. One rat of each pair served as a control and was fed on a standard diet, while the other rats were fed on a diet containing AST-120. The blood creatinine and blood urea nitrogen (BUN) were significantly lower in the rats fed with AST-120 than in the controls. Moreover, the life span of the rats fed with AST-120 was significantly prolonged as compared to that of the control rats. These findings suggest that oral administration of AST-120 may help to prevent rapid deterioration of renal function in experimental chronic renal failure induced by daunomycin in rats.