ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) can occur as a result of mutations in the subunits that form the ATP-sensitive potassium channel (K+ATP) in pancreatic beta-cells which play a major role in modulating insulin secretion from the beta-cells. Mutations have been shown in the genes for these subunits, namely for the plasma membrane sulfonylurea receptor (SUR1), ABCC8, and its associated inwardly rectifying potassium channel (KIR6.2) KCNJ11. Drugs which act on K+ATP channels, such as diazoxide, seem to need intact ABCC8 to be able to show their effects. Thus, it would be desirable to know the exact locus of the abnormality in the beta-cell to be able to choose the right therapeutic agent or to perform early pancreatectomy. The aim of this study was to search for the correlation between the mutations of the K+ATP channel and the outcome of therapeutic measures in patients with PHHI followed for a duration of 4 months to 7.3 years. Thirteen patients (5 F, 8 M) with PHHI with a median age of 2.5 months (8 days-12.1 years) were included in the study. Therapy for PHHI was initiated either with diazoxide (n = 9) or with calcium channel blocker (n = 4) as the agent of first choice. Three patients unresponsive to drugs underwent 95% pancreatectomy. Mutation analysis was performed by polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) in DNA samples extracted from patients' peripheral leukocytes. The PCR products were directly sequenced. Screening of ABCC8 and KCNJ11 for mutations revealed abnormalities in the ABCC8 gene in three patients out of 13: homozygosity for the 155del1 mutation, compound heterozygosity for T267-->G/A4612-2-->G, and compound heterozygosity for G4310-->A/ R1494Q. No mutations in the KCNJ11 gene were identified. Of the three patients who underwent pancreatectomy, two had identified mutations and one did not have any known mutation. In two patients in whom hyperinsulinism recurred after surgery and in the rest of the children, therapy with either diazoxide or calcium channel blocker proved to be effective in controlling hypoglycemia over the follow-up period. Thus it may be concluded that mutations in the ABCC8 gene were not predictive of the response to drugs. Unidentified mutations in the K+ATP channels other than those screened or other functional abnormalities in these channels may account for the different therapeutic responses.     

Expression of brain-derived neurotrophic factor and tyrosine kinase B receptor proteins in glioneuronal tumors from patients with intractable epilepsy: colocalization with N-methyl-D-aspartic acid receptor

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) and its tyrosine kinase B (TrkB) receptor, in addition to promoting neuronal survival and differentiation, modulates synaptic transmission by increasing N-methyl-D-aspartic acid receptor (NMDAR) activity. Overexpression of BDNF may, then, interfere with normal brain function, causing increased excitability. We have examined the immunohistochemical expression of BDNF, full-length TrkB receptor and the NMDAR subunit 1 and subunit 2A/B proteins (NMDAR1 and NMDAR2A/B) in glioneuronal tumors (gangliogliomas, GG, n = 40; dysembryoplastic neuroepithelial tumors, DNT, n = 15), from patients with chronic intractable epilepsy. The great majority of tumors studied were positive for all markers examined, supporting the high level of neurochemical differentiation of these lesions. BDNF and TrkB immunoreactivity (ir) was mainly observed in the neuronal component of the tumors. In GG, more than 90% of tumors contained very intense BDNF-ir ganglion cells. Double labeling confirmed the presence of BDNF-ir and TrkB-ir in neurons which contained NMDAR1. NMDAR2A/B intensely labeled abnormal neurons in both GG and DNT and co-localized with NMDAR1. The presence of BDNF and its receptor in the neuronal component of GG and DNT may suggest a role for this neurotrophin in the development of these lesions, preventing the death of abnormal neuronal cells. In addition, since these neurons contain both NMDAR1 and NMDAR2A/B subunits, the BDNF-TrkB pathway may also contribute through a modulation of glutamatergic transmission to the intrinsic epileptogenicity of glioneuronal tumors.     

Alcohol dependence syndrome and Before-Discharge Intervention Method (BDIM)--No. 5. Patients' evaluation of BDIM by questionnaire survey]

One (A.I) of the authors has developed BDIM (Before-Discharge Intervention Method) for the purpose of making alcoholics aware of their drinking problems. 153 patients were treated by BDIM. After the practiced BDIM, the patients underwent a 52 month observational period. 82 patients (53.6%) continued with either treatment as outpatient or inpatients, or attendance of a self-help group. We administered these 82 patients our questionnaire that asked for their assessment about the therapeutic effects of BDIM. 76 patients (49.7%) completed our questionnaire. Regarding the impression of family members' letters in BDIM, 70 patients (92.1% of 76) answered that the letter have had a positive impression on them. 52 patients (68.4% of 76) answered that they have had very strong or strong impressions. The numbers of patients who have [very strong or strong] impression are significantly more in the abstinence group than in the drinking group. Also, we asked patients about which messages of spouses, daughters and sons in BDIM gave the strongest impression to these patients. The result showed that their daughter gave the strongest impression to many patients. We believe that their children, especially the patients' daughter's messages, have therapeutic effects as impact messages even though alcoholics have cognitive or memory disorder. Patients positively assessed that BDIM strengthened motivation for treatment or attendance of self-help group meetings, for abstinence and for the consequence to their lives. Many patients assessed that BDIM has effect on awareness of their drinking problems. But the ratio of positive answers about motivation of awareness of drinking problem is smaller than the ratio of positive answers about other questions. As a result, we surmised that BDIM will have the effect of empowerment, including the effect of awareness.     

Randomized phase I study of standard-fractionated or accelerated-hyperfractionated radiotherapy with concurrent cisplatin and vindesine for unresectable non-small cell lung cancer: a report of Japan Clinical Oncology Group Study (JCOG 9601).

BACKGROUND: We attempted dose escalation of standard-fractionated and accelerated-hyperfractionated radiotherapy combined with concurrent cisplatin and vindesine to improve local control and survival in unresectable non-small cell lung cancer. METHODS: Twenty-one patients were enrolled between June 1996 and August 1997. There were 19 males and two females and their median age was 65 years (range 45-74 years). Performance status was 0 in 10 cases and 1 in 11 cases. Disease stage was IIIA in three cases and IIIB in 18 cases. The cases were randomized to a standard-fractionated arm (n = 10) or an accelerated-hyperfractionated radiotherapy arm (n = 11) with two or three cycles of concomitant cisplatin 80 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1 and 8 every 4 weeks in both arms. Dose escalation from 60 Gy/30 fractions/6 weeks to 70 Gy/35 fractions/7 weeks was planned in the standard-fractionated radiotherapy group and from 54 Gy/36 fractions/3.6 weeks to 60 Gy/40 fractions/4 weeks and then 66 Gy/44 fractions/4.4 weeks in the accelerated-hyperfractionated radiotherapy group. RESULTS: Grade 3 or 4 hematological toxicities were observed as follows: in the standard-fractionated/accelerated-hyperfractionated radiotherapy group, leukocytopenia 9/10, anemia 2/3 and thrombocytopenia 0/2. Grade 3 non-hematological toxicity consisted of esophagitis 0/3, increased serum total bilirubin 2/0 and hypoxia 0/1. Two patients died of radiation pneumonitis in the standard-fractionated radiotherapy group. Dose-limiting toxicity was observed in four of the 10 and seven of the 11 patients at initial dose level of standard-fractionated radiotherapy, 60 Gy/30 fractions/6 weeks, and of accelerated-hyperfractionated radiotherapy, 54 Gy/36 fractions/3.6 weeks, respectively. Thus, we failed to escalate the dose of radiotherapy in both arms. The overall response rate in the standard-fractionated group and the accelerated-hyperfractionated radiotherapy group was 70 and 73% and the 1-year survival rate was 70 and 64%, respectively. CONCLUSIONS: We concluded that these schedules of radiotherapy with concurrent cisplatin and vindesine were unacceptable for use in patients with unresectable non-small cell lung cancer. Further modifications of the schedule for radiotherapy and evaluation of combination with new chemotherapy are warranted.     

No association between hearing loss due to bilateral otitis media with effusion and Denver-II test results in preschool children

OBJECTIVE: Otitis media with effusion (OME) is the most common cause of acquired hearing loss in childhood and has been associated with delayed language development and behavioral problems. In this study, children with an evidently recurrent otitis media were investigated. The present study examines the association between hearing loss versus developmental screening test parameters of preschool children. METHODS: Sixteen children with bilateral otitis media were compared with age-matched same number of children with normal hearing (controls). RESULTS: Language and verbal cognitive abilities were not affected significantly as a result of the presence of hearing loss because of OME. Using internationally standardized Denver-II test to evaluate the language development and other developmental screening parameters, no significant difference was found between the patient and control groups. CONCLUSIONS: This study failed to find any association between the hearing loss due to otitis media with effusion and speech and language parameters in preschool children.     

Pulmonary arterial pressure in infants with laryngomalacia

OBJECTIVE: Persistent upper airway obstruction may lead to increased pulmonary arterial pressure in childhood. Laryngomalacia is one of the most common causes of transient upper airway obstruction by laryngeal blockage in infants. The aim of the study is to evaluate the pulmonary arterial pressures in infants with laryngomalacia during infancy period. METHODS: Fifteen infants with laryngomalacia and 30 healthy controls were enrolled into this study. The pulmonary arterial pressures were measured by using Doppler echocardiography. Infants were also evaluated by clinical investigations, telecardiography and electrocardiography. RESULTS: Our results showed that infants with laryngomalacia may have significantly higher pulmonary arterial pressure than healthy subjects. Pressures of patient group were significantly decreased at the end of infancy period. CONCLUSIONS: Increased pulmonary arterial pressure levels due to laryngomalacia are reversible by during developmental process. Therefore, in symptomatic period, evaluation of infants with laryngomalacia by using Doppler echocardiography may be useful for monitoring pulmonary arterial pressure and following up the clinical outcome.     

Lack of association between the glutathione-s-transferase genes (GSTT1 and GSTM1) and nasal polyposis

OBJECTIVES: To evaluate the glutation-S-transferase (GST) polymorphisms (GSTM1 and GSTT1) in nasal polyposis (NP). METHODS: The study population consisted of 102 unrelated healthy individuals and 98 patients with NP (67 without asthma, 31 with asthma). Genotyping of the polymorphism in the GSTM1 and GSTT1 genes was performed using the multiplex polymerase chain reaction (PCR)-based method. RESULTS: GSTM1 and GSTT1 null-genotypes were found in 46.1% and 23.5% of the controls, and in 43.9% and 33.7% of the NP patients, respectively. These differences were not significant (for GSTM1 null odds ratio (OR) = 0.92; 95% confidence interval (CI) = 0.52-1.6 and for GSTT1, OR = 1.65; 95% CI = 0.89-3.07). Although no significant difference for combined GSTM1 and GSTT1 null genotypes between control (8.8%) and NP patients (17.3%) was found, there was a 2.16-fold increased proportion in the NP with the combined GSTM1-null and GSTT1-null genotype (OR = 2.16; 95% CI = 0.91-5.13). CONCLUSION: These results suggest that there is lack of association between GSTM1 and GSTT1 polymorphisms and NP. The GSTM1 or GSTT1 polymorphisms had also no relevant developing effect on NP patients without or with asthma.     

Analysis of puberty and pubertal growth in healthy boys

The aim of this study was to provide normative data for the onset and tempo of puberty in healthy boys. The analyses are based on data that were collected and evaluated biannually on 1112 Turkish school children aged from 8 to 18 years and a subsample of 30 boys who had reached final height (FH). The data were analyzed cross-sectionally in the total group and longitudinally in the subsample. Mean age and height (Ht) at onset of puberty were 11.6 ± 1.2 years and 146.1 ± 7.7 cm, respectively. Peak height velocity (HtV) was 10.1 ± 1.6 cm. Total pubertal height gain was 26.4 ± 4.3 cm. The duration of puberty was 4.9 ± 0.6 years. Height at onset of puberty was positively correlated with FH (p  <  0.0001) and with duration of puberty (p = 0.03). Body mass index at onset of puberty correlated negatively with age at onset of puberty (p < 0.009) and with the duration of puberty (p = 0.05) but not with FH. In conclusion, these results provide normative data for Ht and HtV for each testicular volume stage for boys in puberty. Height at onset of puberty is the most important determinant of FH. There is no secular trend for the onset of puberty. Weight does seem to affect the onset and tempo of puberty but not FH.