Major orthopaedic surgeries for haemophilia with inhibitors using rFVIIa

Summary. Between 2000 and 2008, 11 major orthopaedic surgeries for 7 congenital haemophilia patients with inhibitors were performed by the first author as the primary doctor using recombinant activated factor VII (rFVIIa). Orthopaedic surgical treatments were performed for six surgeries for four high‐responder haemophilia A patients, three surgeries for two high‐responder haemophilia B patients and two surgeries for one low‐responder haemophilia B patient. This low‐responder patient is allergic to factor IX products, so he usually uses rFVIIa as a haemostatic agent. All of the surgeries were major, such as joint arthroplasty, arthroscopic synovectomy, and a combination of both, and excellent surgical results were achieved. Seven cases were controlled by bolus infusion of rFVIIa, and the other four cases were controlled by combined bolus and continuous infusion of rFVIIa. An anti‐fibrolytic agent was used for all cases. There were no thrombogenic adverse effects, only two bleeding episodes. As for haemostatic control, nine surgeries were excellent, one was good and one was fair. This report is the largest clinical report on major orthopaedic surgeries at a single institute. We have concluded that the combination of bolus and continuous infusion of rFVIIa is safe and effective, and more convenient to administer than simple bolus infusion therapy to achieve haemostasis at peri‐operative periods. In addition, our data also concurs with the data of several previous reports which showed that orthopaedic surgery for haemophilia patients with inhibitors by means of rFVIIa is safe and effective.     

Increased urinary excretion of human cytomegalovirus in children with malignancy: Detection by polymerase chain reaction

Human cytomegalovirus (HCMV) is one of the most important agents causing opportunistic infections in immunocompromised hosts. In this study, we examined the urinary excretion of HCMV in children with malignancy using polymerase chain reaction (PCR). Urine samples were collected from on-therapy, off-therapy patients with malignancy, and healthy controls. A simple DNA extraction method using glass powder was employed, and inhibitory effect of urine on PCR was prevented. For PCR, a pair of primers from the HCMV major immediate early gene sequence was used. Among patients who received intensive chemotherapy, 52.0% had urinary HCMV excretion after the chemotherapy course. In contrast, off-therapy patients and healthy controls showed a lower incidence of urinary HCMV excretion (20.4 and 8.7%, respectively). The incidence of HCMV urinary excretion in the on-therapy group was significantly higher than healthy controls (P < 0.05). In the on-therapy group, the total white blood cell count of the virus excreters was lower than that of non-excreters. The incidence of HCMV excretion was high in on-therapy patients. Most of the virus excreters were seropositive, so their viruria was thought to be caused by reactivation. Repeated monitoring of virus excretion by this rapid and simple method may be useful to detect HCMV infection early and to control it in such patients.     

Species differences and mechanism of the epimerization of a new MAO-A inhibitor

1. (5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-methoxymethyl2-oxazolidinone (E2011) has two chiral centers in its structure. In vivo optical inversion of the hydroxy group at one of the chiral centers converts E2011 to a diastereoisomer (ER-20593). Pharmacokinetic parameters of E2011 and ER-20593 were determined after administration of E2011 to rat at 10?mg/kg, and the plasma concentration ratios of E2011 to ER-20593 were almost constant after T_max of the plasma concentrations. 2. E2011 and ER-20593 were separately administered orally to six species in addition to rat, and the species differences in both directions of epimerization (i.e. from E2011 to ER-20593 and from ER-20593 to E2011) were studied by measuring the plasma concentrations of both compounds. In mouse, guinea pig, dog, and squirrel monkey, the epimerization of E2011 to ER-20593 did not occur, but the epimerization of ER-20593 to E2011 did. In rat, pig and rhesus monkey, the inversion of E2011 to ER-20593 occurred, but the ratios of this inversion were smaller than those for the inversion in the opposite direction. E2011 underwent about 15% inversion to ER-20593inrat,which was the largest inversion in the seven species examined. 3. To study the mechanism of the epimerization, deuterium-labelled E2011 and ER20593 (created by substituting the proton at the chiral center of the parent compounds for deuterium) were orally administered (separately) to rat and dog, and the concentration ratios and molecular weights of E2011 and ER-20593 in the plasma were determined by hplc and FAB(+)-mass spectrometry respectively. The results indicated that the major mechanism of the epimerization was oxidation to the carbonyl form followed by reduction to the original epimer and or the other epimer. 4. The carbonyl form of E2011 (CO-E2011) was reduced to E2011 and ER-20593 (alcohol forms) by liver cytosol and microsomes from rat and dog in vitro with NADH or NADPH. The resultant epimeric ratios (E2011:ER-20593) were consistent with the in vivo results in rat and dog. 5. In conclusion, species differences in the epimerization of E2011 would result from product stereoselectivity of the reductase activity with the carbonyl intermediate.     

Acute Gastric Mucosal Lesion in the Aged

Abstract: Over a period of 3 years between August 1985 and July 1988, 110 patients (male/female ratio, 64: 46, age range 22–89 years, mean 48.1 years) were diagnosed endoscopically as having acute gastric mucosal lesion (AGML). These patients were divided into an elderly group (60 years or more, 26 patients) and a younger group (less than 60 years, 84 patients). The chief complaint, the precipitating factors, the location of the lesion, the disease type, the background gastric mucosa and the state of bleeding were compared between the groups. AGMLs in elderly patients were found to have the following characteristic features. The chief complaints included hematemesis and melena, and oral drugs were the precipitating factor in many patients. The lesion often occurred in the body or whole area of the stomach, and was found to be relatively rare in the vestibule. An acute gastric ulcer was the most frequent clinical finding. The background gastric mucosa was rated C-II or more severe in most cases. Overt bleeding was present in many cases, requiring endoscopic hemostasis.     

Successful high-dose methotrexate chemotherapy in a patient with acute lymphocytic leukemia who developed acute renal failure during the initial treatment

Methotrexate (MTX) is a key drug in the chemotherapy for childhood acute lymphocytic leukemia (ALL). It is essential in the treatment of such areas as the central nervous system (CNS) and reproductive organs. High-dose chemotherapy is applied for this purpose to obtain an effective plasma concentration in the target organs.There are three major mechanisms of nephrotoxicity related with MTX. One is that induced by allergic reaction, which usually appears as interstitial nephritis. In this case MTX is contraindicated. Another is direct pharmacological toxicity against renal tubules. The third is precipitation of MTX, which plugs the renal tubules. The latter two are consequently dose dependent, and are usually associated with high-dose chemotherapy. To prevent these nephrotoxicities, hydration and alkalinization of the urine are performed to accelerate the urinary excretion and avoid the precipitation of MTX.     

Nocturnal enuresis and overactive bladder in children: An epidemiological study

AIMS: To investigate the prevalence and characteristics of nocturnal enuresis (NE) and to examine the prevalence of overactive bladder (OAB) symptoms in primary schoolchildren. METHODS: After conducting an anonymous questionnaire survey about voiding habits and bowel habits in primary schoolchildren, a total of 6917 schoolchildren belonging to 11 primary schools were randomly enrolled in the survey. According to the International Continence Society, we defined NE as any involuntary loss of urine during sleep, occurring more frequently than once per month. Children with NE were subdivided into two groups, monosymptomatic NE (MNE) and enuretic syndrome (ES). To evaluate the characteristic differences of MNE and ES, we assessed the relationships between NE and voiding habits, and episodes of cystitis and constipation. Overactive bladder was defined as increased daytime frequency and/or urge urinary incontinence, and its prevalence was investigated. RESULTS: The response rate to the questionnaire was 76.4%. The prevalence of NE was 5.9% and was inversely related to increasing age. Monosymptomatic NE comprised 59.4% of NE cases. The annual spontaneous resolution rate of MNE was higher than that of ES. Increased daytime frequency, a history of cystitis and infrequent bowel habits were not related to MNE, but were significantly related to ES. The prevalence of OAB was 17.8%. Children with a history of cystitis had a significantly higher rate of OAB than children without it. CONCLUSIONS: Overall, NE and OAB were detected in 5.9% and 17.8% of primary schoolchildren, respectively. The link between NE and OAB symptoms, urinary tract infections and constipation deserves more attention.     

Successful gonadotrophin treatment of hypogonadism in postoperative patients with macroprolactinoma and persistent hyperprolactinaemia

We report on two males with prolactinoma in whom hyperprolactinaemia and hypogonadism persisted for several years postoperatively despite the administration of a dopamine agonist or bromocriptine. In these patients, a GnRH test revealed no response in the levels of serum LH or FSH. An hCG stimulation test provoked no response in the serum levels of testosterone. Case 1, who was 28 years old at the first visit, received parenteral testosterone and appreciable virilization of the genitalia was noted within a few months. When he married and desired to father a child, the treatment was switched to hCG/hMG combined therapy and spermatozoa appeared subsequently in the ejaculate, although their numbers were low. His wife conceived and delivered a healthy baby girl. Case 2 was a single young man who presented with hypogonado-trophic hypogonadism and hyperprolactinaemia. He was started on hCG injections three times per week and the maturation of his genitalia was advanced rapidly. Semen analyses showed sperm concentration and motility to be within the normal range. Post-treatment GnRH test revealed no improvement in gonadotrophin responses for LH or FSH. In both cases, the hCG test repeated after the gonadotrophin treatment showed normal basal and stimulated testosterone levels. During the course of gonadotrophin treatment in these cases, serum prolactin levels remained elevated, and it is suggested that, in the two cases, the hypothalamo-pituitary function was disturbed by the tumour or its manipulation and the capacity of the pituitary gland to secrete gonadotrophin was impaired. Under such circumstances with persisting hyperprolactinaemia, hCG and/or hCG/hMG combination treatment can induce normal virilization and advance spermatogenesis sufficiently to achieve fertility.     

Computerized electroencephalogram in untreated schizophrenics: A comparison between disorganized and paranoid types

Abstract Computerized electroencephalogram (CEEG) data were obtained from 30 patients with the disorganized type and 20 patients with the paranoid type of acute untreated schizophrenia and compared with data from age- and sex-matched controls. All patients with acute untreated schizophrenia exhibited more pronounced delta, theta, alpha₁ and beta₁ activity and less prominent alpha₂ activity than the control subjects. These findings support previous studies, and indicate the coexistence of cerebral hypofunction and excitability in acute schizophrenic patients. Compared with the controls, patients with disorganized type schizophrenia had significant increases in theta and beta₁ and decreases in alpha₂ activities; but a significant increase in delta and alpha₁ activities in the posterior regions and beta₂ activity in the frontal regions of the brain. Patients with paranoid type schizophrenia showed significantly increased delta activity in the posterior regions, increased alpha₁ activity in the anterior regions and decreased alpha₂ activity in both these regions. In the paranoid type, however, there was no significant finding for the theta, beta₁ and beta₂ activities. Disorganized type schizophrenics exhibited more increased theta and decreased alpha₂ activity than patients with paranoid type schizophrenia. The CEEG differences between the disorganized and the paranoid types appear to reflect different clinical entities and may help to differentiate both schizophrenias.     

Induction of human IgE synthesis in B cells by a basophilic cell line, KU812

Induction of human IgE synthesis in B cells requires, in addition to IL-4 or IL-13, a second signal provided by CD40 ligand (CD40L) on activated Th2-type CD4⁺ T cells that do not or weakly express Fas ligand (FasL). Mast cells and basophils also produce IL-4 or IL-13 and express CD40L after immunologic or pharmacologic stimulation, although it is unknown whether these cells express FasL. This study investigated the capacity of KU812 cells, a human basophilic cell line, to produce IL-4 and IL-13, to express CD40L and FasL, and to induce IgE and IgG4 synthesis in human normal B cells. Upon stimulation of KU812 cells with either phorbol myristate acetate (PMA) or ionomycin (Iono), IL-4, but not IL-13, was produced in response to Iono, while IL-13, but not IL-4, was inducible by PMA. Moreover, both the time courses of IL-4 and IL-13 production and their amounts secreted were different; IL-4 production was transient, IL-13 production gradually increased, and IL-13 was heavily secreted as compared with IL-4. The combination of PMA and Iono (PMA/Iono) induced higher production of IL-4 or IL-13 than did Iono or PMA alone. KU812 cell-derived IL-4 and IL-13 had the ability to cause CD23 expression on B cells. PMA/Iono also up-regulated CD40L expression and induced a very low level expression of FasL. KU812 cells that had been activated by PMA/Iono followed by fixation could induce IgE and IgG4 synthesis in B cells in the presence of recombinant IL-4 or IL-13. This contact-dependent induction of IgE was completely abrogated by adding anti-CD40L MoAb or soluble CD40, whereas anti-FasL antibody did not significantly affect IgE production. These results indicate that activated KU812 cells produce biologically active IL-4 and IL-13, express functional CD40L, and exhibit weak induction of FasL, thereby supporting sufficient IgE production by B cells.