Skin injuries and joint contractures of the upper extremities in Rett syndrome.

OBJECTIVES: The purpose of this study was to investigate the incidence and type of skin injuries and joint contractures of the upper extremities in individuals with Rett syndrome. METHODS: In 2016, a questionnaire regarding skin injuries and joint contractures was sent to 1016 directors of schools for special needs education and 204 directors of departments of rehabilitation [consisting of 130 facilities for persons with severe motor and intellectual disabilities (SMID), 73 wards for patients with SMID, and the National Hospital Organisation and National Centre Hospital, National Centre of Neurology and Psychiatry] in Japan. Descriptive statistics were used to indicate frequency in each question. RESULTS: Information was acquired from 216 cases (3-53 years old) with Rett syndrome. Skin injuries and joint contractures of the upper extremities were observed in 41% and 49% of individuals with Rett syndrome, respectively. Most of the skin injuries were observed on the hands (19%) and fingers (29%). The incidence of skin injuries was not affected by age or disease severity. Many joint contractures were observed in the shoulder (33%) and elbow (29%) joints. Joint contractures tended to occur in individuals aged over 10 years or with severe locomotor impairment. CONCLUSION: Almost half of the Rett syndrome subjects assessed in the present study had skin injuries and joint contractures. Especially, the incidence of joint contractures was affected by age and disease severity. Thus, it is important that medical staff attempt to prevent the occurrence of skin injuries and joint contractures in this patient population.

The successful treatment of rapidly progressive idiopathic membranoproliferative glomerulo-nephritis Type 1 in a 4-year-old male pediatric patient.

A multivariate analysis [4] revealed that the presence of crescent formation on initial biopsy irrespective of type of membranoproliferative glomerulonephritis (MPGN) was independently associated not only with end-stage renal disease but also with post-transplantation recurrence. In this study, we reported on a 4-year-old male pediatric patient requiring hemodialysis due to rapidly progressive idiopathic MPGN Type 1 with severe nephrotic syndrome and extensive cellular crescent formation on initial biopsy. The patient had been treated intravenously (i.v.) with 9 pulses of methylprednisolone, followed by daily prednisolone, resulting in the withdrawal of dialysis within 1 month. However, since active lesions in the second renal biopsy such as cellular crescents still remained and nephrotic range proteinuria had persisted for more than 2 months, the patient received additional 3 i.v. pulses of methylprednisolone, followed by combinations of alternate-day prednisolone, mizoribine, dipyridamole and warfarin, which lead to complete remission in a short-period of time. The patient has been off the combination therapy for 10 months because the third biopsy prior to the termination of this regimen showed decreased inflammatory activity. There is currently no established protocol for children with crescentic MPGN due to a rarity of its clinicopathological presentation. This case report indicates that early treatment with multiple pulses of methylprednisolone followed by the short-term combination therapy may be of benefit for children with rapidly progressive idiopathic MPGN Type 1, even when both diffuse crescentic changes and nephrotic syndrome are present at onset.

The role of inflammatory markers and calculated osmotic pressure in the classification of febrile seizures.

OBJECTIVE: Systemic inflammatory response may contribute to the onset of febrile seizures (FSs). The neutrophil-to-lymphocyte ratio (NLR) has been reported to be useful for differentiating simple and complex FSs in children with a first FS. This study aimed to determine whether easily measurable inflammatory markers were useful for distinguishing between the types of FSs in children with FSs not limited to the first FS. PATIENTS AND METHODS: We conducted a retrospective study of children aged 6-60 months who were presented to the Atsugi City Hospital in Japan for the treatment of FSs between December 2018 and February 2020. A complex FS was defined as a seizure with multiple seizures during the same febrile illness, prolonged seizures and/or focal seizures. A simple FS was defined as a seizure without the characteristics of complex FS. We assessed complete blood count, C-reactive protein, and calculated osmotic pressure. RESULTS: A total of 205 children with FSs (simple, 139; complex, 66) fulfilled the inclusion criteria. None of the inflammatory markers, including NLR, could predict the FS type. The median osmotic pressure was 279.0, 278.8, 283.3, and 278.3 mOsm/kg H2O for children with simple, multiple, prolonged, and focal seizures, respectively. Children with prolonged seizures had a significantly higher calculated osmotic pressure than those with simple FSs (p<0.001) and multiple seizures during the same febrile illness (p=0.004). CONCLUSIONS: Easily measurable inflammatory markers, including NLR, were not useful for distinguishing between types of FSs in children. Large multicenter studies are needed to evaluate the association between osmotic pressure and FS.

Reversal of freshening trend of Antarctic Bottom Water in the Australian-Antarctic Basin during 2010s.

The Antarctic continental margin supplies the densest bottom water to the global abyss. From the late twentieth century, an acceleration in the long-term freshening of Antarctic Bottom Waters (AABW) has been detected in the Australian-Antarctic Basin. Our latest hydrographic observations reveal that, in the late 2010s, the freshening trend has reversed broadly over the continental slope. Near-bottom salinities in 2018-2019 were higher than during 2011-2015. Along 170° E, the salinity increase between 2011 and 2018 was greater than that observed in the west. The layer thickness of the densest AABW increased during the 2010s, suggesting that the Ross Sea Bottom Water intensification was a major source of the salinity increase. Freshwater content on the continental slope decreased at a rate of 58 ± 37 Gt/a in the near-bottom layer. The decadal change is very likely due to changes in Ross Sea shelf water attributable to a decrease in meltwater from West Antarctic ice shelves for the corresponding period.

Mycophenolate mofetil therapy for childhood-onset steroid dependent nephrotic syndrome after long-term cyclosporine: extended experience in a single center.

BACKGROUND: Mycophenolate mofetil (MMF) is being used increasingly in children with steroid-dependent nephrotic syndrome (SDNS). However, there is limited information on the optimal therapeutic range for mycophenolic acid (MPA), the active metabolite of MMF, in these patients. METHODS: 26 patients with SDNS (mean age 13.1 years, 19 with minimal change disease and 7 with focal segmental glomerulosclerosis) who had received MMF for at least 6 months after longterm cyclosporine (CsA, mean 56 months) at Saitama Children's Medical Center between September 2002 and August 2008 were analyzed. MMF was introduced at an initial dose of 250 mg/12 h, adjusted to maintain target predose MPA at greater than 2 microg/ml (maximum 1 g twice daily) gradually over 4 weeks. After the introduction of MMF, the dosages of both CsA and prednisolone (PSL) were tapered off if possible. RESULTS: The mean MMF dose required was 34 +/- 6 mg/kg, which maintained the mean predose MPA levels of 3.1 mg/ml. In 26 patients, treatment with MMF for a mean follow-up period of 19 months (range 7 - 42), resulted in a reduction of the mean PSL dose from 0.33 +/- 0.23 to 0.17 +/- 0.11 mg/kg per day (p < 0.01) and mean CsA dose from 3.2 +/- 1.7 to 1.3 +/- 1.8 mg/kg per day (p < 0.01). The mean 12-monthly relapse rates decreased from 2.5 +/- 1.4 to 0.8 +/- 1.2 episodes (p < 0.01). In 20 patients treated with MMF (77%), the dose of PSL and/or CsA was successfully tapered with a reduction in the relapse rates. In 6 patients, however, CsA therapy was reintroduced or its dose was increased because of treatment failure. The patients whose average predose MPA levels were less than 3 microg/ml were significantly likely to have treatment failure (p < 0.05). 2 patients reduced the MMF dosage because of anemia or herpes labialis. However, no severe gastrointestinal discomfort was seen in any patients. Despite long-term CsA therapy, marked tubulointerstitial fibrosis developed during MMF therapy in surveillance biopsies of only one of these five patients. CONCLUSIONS: Therapy with MMF based on the predose MPA levels can be a less toxic alternative to CsA or in some cases a useful additional medication to allow for a reduction in the CsA and/or PSL dosage.

Cloning and functional expression of a cDNA encoding a mouse type 2 neuropeptide Y receptor.

A cDNA clone homologous with the human neuropeptide Y (NPY)-Y2 receptor has been isolated from a mouse brain cDNA library. Analysis of the predicted amino-acid sequence indicates that the polypeptide encoded by this cDNA is 94% homologous to the human NPY-Y2 receptor. In Chinese hamster ovary (CHO) cells expressing the mouse NPY-Y2 receptor, an increase in intracellular Ca2+ and inhibition of forskolin-induced cAMP accumulation were observed due to stimulation with NPY, NPY-(13-36) and peptide YY, but not with pancreatic polypeptide or [Leu31, Pro34]NPY. The fact that the NPY-induced increase in intracellular Ca2+ and inhibition of forskolin-induced cAMP accumulation were eliminated by pretreatment with pertussis toxin suggests that the NPY-Y2 receptor couples to PTX-sensitive G-protein(s), probably Gi/Go, in CHO cells.

CD34high+ CD38(low/-) cells generated in a xenogenic coculture system are capable of both long-term hematopoiesis and multiple differentiation.

CD34+ cells isolated from human umbilical cord blood (HUCB) are thought to have potential in clinical applications such as transplantation and gene therapy. Recently, we developed a xenogenic coculture system involving HUCB-CD34+ cells and murine bone marrow stromal cells, HESS-5 cells, in combination with human interleukin-3 and stem cell factor. Under these xenogenic coculture conditions, the numbers of CD34high+ cells and primitive progenitor cells, such as CD34high+ CD38(low/-) cells and high proliferative potential colony-forming cells (HPP-CFCs), increased dramatically by a factor of 102.1, 66.5 and 104.9, respectively. In the present study, we used a secondary culture of B progenitor cells and long-term culture (LTC)-initiating cells to characterize and compare the progenitor capability of re-isolated CD34high+ CD38(low/-) cells, which have been identified as one of the most primitive progenitor cells, with that of freshly isolated CD34high+ CD38(low/-) cells. Compared with freshly isolated CD34high+ CD38(low/-) cells, the re-isolated CD34high+ CD38(low/-) cells were equally as capable of proliferating and differentiating into myeloid and B progenitor cells. No significant differences were observed in the frequency of LTC-initiating cells in the re-isolated CD34high+ CD38(low/-) cells compared with that in freshly isolated CD34high+ CD38(low/-) cells. Furthermore, the re-isolated CD34high+ CD38(low/-) cells were capable of long-term reconstitution and multiple differentiation in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice). The results demonstrate that this xenogenic coculture system can be used for successful in vitro expansion of HUCB-progenitor cells that possess the capability for both long-term hematopoiesis as well as multipotent differentiation into myeloid and lymphoid cells both in vivo and in vitro.

Retroviral vector-mediated gene expression in human CD34+CD38- cells expanded in vitro: cis elements of FMEV are superior to those of Mo-MuLV.

A novel murine stromal cell line, HESS-M28, was established, which supports the expansion of human CD34+CD38- cells more than 300-fold in vitro in the presence of human IL-3 and SCF. These cells were used in an attempt to evaluate cis-acting elements of retroviral vectors in human primitive hematopoietic cells. Cord blood cells were cultured on top of the mixed cell layers of the stromal cell line, HESS-M28, and retroviral vector-producing cells. The FMEV-type vector SF/Lyt contained the spleen focus-forming virus U3 and the MESV primer-binding site (PBS), while MO3/Lyt contained the U3 region and PBS from Mo-MuLV. After transduction by the FMEV-type and Mo-MuLV-based vectors, expression of the marker gene murine CD8 (mCD8) was examined in CD34-, CD34+, and CD34+CD38- cells. In CD34+ and CD34+CD38- cells, expression of mCD8 was higher with the FMEV-type vector, SF/Lyt, compared with the cells transduced by the Mo-MuLV-based vector MO3/Lyt, although the expression was comparable in CD34- cells. Expression of marker genes was also confirmed in long-term culture-initiating cells (LTC-ICs) and SCID-repopulating cells (SRCs).

Partnering to improve infant immunizations: The Arizona Partnership for Infant Immunization (TAPII).

The Arizona Partnership for Infant Immunization (TAPII) is a public-private partnership intended to achieve the year 2000 goal of 90% infant immunizations. Created in 1992 as a means to develop a statewide approach to improving infant immunization rates, TAPII is a broad-based partnership that includes public health departments, managed care plans, professional organizations, medical organizations, pharmaceutical companies, businesses, the faith community, the media, and many others. TAPII's organizational structure includes a steering committee and five subcommittees: advocacy and policy, community awareness, provider awareness, survey and assessment, and strategic planning. A key accomplishment of TAPII has been the development of a statewide infant immunization registry known as the Arizona Statewide Immunization Information System (ASIIS). This registry will facilitate up-to-date immunizations of children and improve statewide immunization assessment capability. Since the advent of TAPII, infant immunization rates within private managed care plans have increased. However, significant improvement in statewide rates will require long-term strategic efforts in provider and community awareness and a fully operational statewide registry, ASIIS, which is set to begin in January 1998. TAPII has been a successful partnership for a number of reasons: private sector participation, a single and measurable goal, vision and leadership, a strong emphasis on assessment, a broad-based membership, community ownership, Governor's Office participation, health plan involvement, and full-time project staffing. As resources to improve the health of communities diminish, public-private partnerships such as TAPII can effectively consolidate resources and expertise to improve the health of populations.

Comparative study of symptoms and neuroendocrine-immune network mediator levels between rheumatoid arthritis patients and healthy subjects.

OBJECTIVE: In order to understand the disturbances in the neurophysiological, endocrine (including the hypothalamic-pituitary-adrenal axis), and immune systems objectively and in detail, we measured and compared various test items in the peripheral blood which were considered to reflect the state of these systems, in patients with rheumatoid arthritis and in control subjects. METHODS: The levels of beta-endorphin, methionine-enkephalin, epinephrin, norepinephrin (NE), dopamine, corticotropin releasing factor (CRF), adrenocoricotropic hormone (ACTH), cortisol, CD4/CD8 ratio, CD57, NK cell activity and IL-6 in the peripheral blood, which are considered to reflect the activity of this neuroendocrine-immune network, were measured and compared between 49 patients with rheumatoid arthritis (RA) and 54 healthy control subjects. The face scale (to measure mood) and the Cornell medical index (CMI) health questionnaire were administered to both groups, and pain scores were measured using a visual analog scale in the RA group. RESULTS: The serum levels of NE, dopamine, IL-6 and CD4/CD8 ratio were higher, whereas the levels of beta-endorphine, ACTH and NK cell activity were lower in the RA subjects than in the control subjects. On the other hand, the serum levels of Met-enk, epinephrin, CRF, cortisol and CD57 were not significantly different between the two groups. In RA patients a positive correlation was observed between the face scale score and the serum cortisol level and between the pain score and the serum IL-6 level. The more severe the pain, the higher the NK cell activity and IL-6 concentrations in the peripheral blood. On the other hand, in healthy females none of the measured items in the peripheral blood were significantly correlated with the face scale results or the responses to the CMI health questionnaire. CONCLUSION: In RA patients the hypothalamic-pituitary-adrenal (HPA) axis is altered and this condition is correlated to a deterioration in symptoms.

[A study of effective administration of recombinant interferon-gamma in renal cell carcinoma regarding immunological influence on peripheral blood lymphocytes].

Immunological effect of recombinant interferon gamma (IFN-gamma) was studied in 18 cases of renal cell carcinoma. Sixteen of them were administered IFN-gamma as post-operative adjuvant therapy. Two of them were administered IFN-gamma for metastatic renal cell carcinoma. All of them were followed for at least 1 year. We divided the patients into two groups. One group subcutaneously received IFN-gamma every other day for 16 days, then 4 weeks later every week for one year (group A), and the other group, received alternate subcutaneous IFN-gamma every other day for 16 days and every week for 4 weeks (group B). For immunological testing, peripheral blood lymphocytes were obtained before treatment on day 1, 2 weeks later, 6 months later and 12 months later. The cells were tested for natural killer activity (NK), antibody dependent cellular cytotoxicity (ADCC), positive lymphocytes of CD3, CD4, CD8 and CD11b. Both ADCC and NK activity were increased after therapy, especially in group B. CD3, CD4 and CD8 positive lymphocytes were increased by means of IFN-gamma. On the other hand, CD11b-positive lymphocytes could not be elicited in group B. Tumor regression was observed in 2 cases of metastatic renal cell carcinomas. When clinical responses were observed, both ADCC and NK were elicited as compared with the pretreatment values. Our findings indicated that ADCC and NK could be elicited in group B.

[Clinical trial of inhalant recombinant interferon-gamma in patients with pulmonary metastasis from renal tumor (preliminary report)].

Recently, we applied inhalation of recombinant interferon (IFN)-gamma, to 4 patients with pulmonary metastatic tumor (3 with renal cell carcinoma and 1 with renal pelvic tumor). Of the patients with renal cell carcinoma 2 had received previous nephrectomy, 1 patient had received embolization alone, 1 subcutaneous IFN-gamma in 1, and 1 systematic chemotherapy. All 4 patients inhaled 1 x 10(6) JR U-2 x 10(6) JR U recombinant IFN-gamma 3 times per day. Additionally, all metastatic renal cell carcinomas received subcutaneous injection of IFN-gamma. One patient with renal cell carcinoma achieved a complete response after inhalation therapy and 2 patients did not respond (NC: 1, PD: 1). A case of metastatic renal pelvic tumor did not respond. Immunohistochemical staining with antibody to Ber-MAC3 (stimulated macrophage) of this case revealed positive cells within the transitional cell carcinoma. According to these results, inhalation of IFN-gamma appears to be applicable as one treatment for pulmonary metastatic tumor of renal cell carcinoma.

[Immunological effect of recombinant interferon-gamma in renal cell carcinoma].

The immunological effect of interferon-gamma (IFN-gamma) was investigated in 18 cases of renal cell carcinoma before and after the operation. In 6 patients, IFN-gamma was administered preoperatively for 21 days (administration group), while 12 patients underwent nephrectomy alone without preoperative treatment (control group). The peripheral immunological effects were measured at before and 12 days after the operation in the administration group and at 11 days in the control group. In the administration group, a marked increase was noted in the test of antibody dependent cell-mediated cytotoxicity (ADCC) activity and natural killer (NK) activity, and slight increase in CD4/8 and CD11b. In low stage cases, no appreciable effect was obtained by the administration of IFN-gamma. However, in high stage cases, IFN-gamma tended to increase the value of ADCC activity and NK activity. Immunohistochemical studies of tumor infiltrating lymphocytes in renal cell carcinoma showed a high incidence of CD8 and CD11b in the administration group. Moreover, the presence of CD8 was higher than that of CD4 in the administration group in contrast to the results of the peripheral blood analysis.

[Clinical effect of new alpha-adrenergic blocker on micturition disturbance of neurogenic bladder and lower urinary tract obstruction].

E-643, a newly developed alpha 1-adrenergic blocker with a postsynaptic action, was tried on 17 subjects, 10 patients with neurogenic bladder and 7 patients with lower urethral obstruction. The results of treatment were excellent in 5, good in 7, and poor in 5 of them, the rate of effectiveness therefore being 70.6%. The inhibitory effect of E-643 on the contractility of the detrusor was no stronger than that of other alpha-blockers. The rate of effectiveness for neurogenic bladders was as high as 80% whereas that for lower urethral obstruction was much lower: 57%. Concerning benign prostatic hyperplasia (B.P.H.) alone, this agent was markedly beneficial. In the case of B.P.H the urethra pressure in the prostatic urethra tends to drop and urination is facilitated even without a change in maximum urethral closure pressure, which reduces the amount of residual urine, this sequence of events taking place on condition that the contractility of the detrusor is adequate. According to urodynamic criteria, the underlying causes of the so-called bladder neck contracture can be classified into organic and functional obstruction, but it is mistaken to use this term for functional disturbance of the bladder neck. It seems worthwhile to determine the clinical effect of alpha-blockers on functional urethral obstruction. E-643 produced few if any appreciable signs or symptoms of side effects either subjectively or objectively.

[Immunological effect of recombinant interferon-gamma on tumor infiltrating lymphocytes of renal cell carcinoma--relationship with clinical stage].

We studied the relationship between clinical stage and tumor infiltrating lymphocytes (TIL) in 26 cases of renal cell carcinoma. In 10 patients, interferon-gamma (IFN-gamma) was administered preoperatively (administration group); 5 patients had low stage (Robson < or = I), and the remaining 5 patients had high stage (Robson > or = II) tumors. The other 16 patients underwent nephrectomy alone without preoperative IFN administration (control group); 11 patients had low stage, and the remaining 5 patients had high stage tumors. Immunohistochemical studies of tumor infiltrating lymphocytes in renal cell carcinoma showed a significantly high incidence of CD3, CD8, CD11b and ICAM-1 in the administration group, while CD4, LFA-1 and Ber-MAC3 were increased without significance (p < 0.05). Concerning clinical stage (Robson), a significant increase in CD3, CD8, CD11b and ICAM-1 was observed in the patients with high-stage tumors in the administration group compared to those in the control group (p < 0.05). This suggested that TIL could be changed by preoperative administration of IFN-gamma.

[Tumor volume and percent of gland involvement with tumor as predictors of pathological stage in prostate cancer].

BACKGROUND: It is well recognized that tumor volume correlates with pathological stage, histological grade and progression in prostate cancer. We analyzed the tumor volume and the percent of gland involvement with tumor (%TV/PV) to determine if either or both of these morphometric factors would be good predictors of pathological stage. METHODS: The pathological reviews were retrospectively performed on the basis of the 22 step sectioned prostate specimens removed by radical retropublic prostatectomy for clinical T1c-T2-T3 prostate cancer. The percent of gland involvement with tumor was calculated using the following formula [100 x (tumor volume cc/prostate volume cc)]. When the patients had organ confined disease (OCD) or specimen confined disease (SCD) they were defined as surgically cured patients, whereas the patients with positive surgical margin, seminal vesicle involvement or positive lymph node were defined as not surgically cured patients. RESULTS: The likelihood of OCD was 25% in patients with clinical T1c-T2 disease. No patients with clinical T3 had OCD. Patients with SCD was not observed. The mean tumor volume was 1.3 cc in the surgically cured patients and 6.2 cc in the not surgically cured patients. The tumor volume correlated with pathological stage (r = 0.607, p = 0.0054). The mean %TV/PV was 3.23% in the surgically cured patients and 18.2% in the not surgically cured patients. The %TV/PV also correlated with pathological stage (r = 0.543, p = 0.0129). Both the tumor volume and the %TV/PV in surgically cured patients were less than those in the not surgically cured patients. A correlation between tumor grade and both the tumor volume and the %TV/PV were not observed. CONCLUSION: The tumor volume and the %TV/PV correlated well with the final pathological stage. Multiple regression analysis showed that the tumor volume was the best predictor of pthological stage.