Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Use of laparoscopic sleeve gastrectomy and adjustable gastric banding for suboptimally controlled diabetes in Hong Kong.

Bariatric surgery has recently been considered as an option for treatment of type 2 diabetes mellitus (T2DM). We assessed the effect of laparoscopic gastric banding and laparoscopic sleeve gastrectomy in a cohort of 39 T2DM Chinese patients with body mass index (BMI) over 30 kg/m(2) . Their mean body weights and BMI before surgery were 108 kg and 40 kg/m(2) , respectively, and 18 patients (46%) had suboptimal diabetic control (HbA1c >7%). After a mean follow-up of 27 months, 4 of 11 insulin-dependent patients (36%) were able to stop their insulin therapy, and 18 patients (46%) achieved remission of T2DM (HbA1c <6.5% without the use of medication). Glycaemic control remained poor in only nine other patients (27%). Logistic regression analysis showed that a short history of T2DM and high BMI could predict remission of diabetes after restrictive procedures. Our results suggest that restrictive surgery can significantly improve glycaemic control in obese T2DM patients.

Comparing respiratory polygraphy with pulse transit time analysis versus overnight polysomnography in the diagnosis of obstructive sleep apnoea in children.

OBJECTIVE: Obstructive sleep apnea syndrome in children is associated with significant morbidity. Polysomnography is the main diagnostic tool but is time consuming and requires skilled manpower to supervise the patient overnight and hence long referral to diagnosis time. However, there are limitations and underestimation of the apnoea hyponea index (AHI) with alternative home sleep apnoea testing (HSAT), such as type 3 respiratory polygraphy (RP). Prior studies have demonstrated pulse transit time (PTT) to be a reliable indicator of cortical arousals. In this study, the use of PTT together with RP will be studied to determine whether the derived AHI is comparable to that of PSG. METHOD: Forty-five patients with suspected OSA met the inclusion criteria underwent PSG in the sleep laboratory for analysis. The raw data for either PSG or RP analysis were allocated separately to two different accredited sleep technicians. The primary outcome AHI derived from PTT with RP was compared to the AHI derived from PSG. Secondary outcomes compared were obstructive apnoea index (OAI), total hypopnoea index (THI) and arousal index (AI). Bland Altman analysis was used to compare the agreement of AHI derived from the 2 modalities and demonstrate whether RP is non inferior or equivalent to the gold standard for diagnosing OSAS. RESULTS: The patients studied had a median age of 8.8 years (range 3-17 years). The patients were not limited to certain spectrum of severity OSA and had AHI results spread from mild to severe OSA (AHI 0.4/hr to 72.2/hr). The RP with PTT-derived AHI was strongly correlated to the PSG derived AHI as seen on the Spearman plot (r = 0.98). The Bland Altman plot showed no evidence of underestimation of the AHI due to missed arousal related hypopneas. The difference of AHI derived from RP and PSG results were clinically insignificant. The differences between the PSG and RP total hypopnoea index (THI) and arousal index (AI) were also statistically insignificant. CONCLUSION: The study shows that RP with PTT can be considered a reliable diagnostic alternative compared with PSG. The role of PTT incorporated with RP was to minimize underestimation of AHI due to missed arousal associated hypopnea events. The results were apparent across mild to severe severity of OSA. There are advantages of RPs particularly in paediatrics. Overall this study offers promising preliminary insights that RP incorporated with PTT can be further explored as an acceptable home diagnostic tool for diagnosing OSA in children.

Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Central nervous system abnormalities, including cognitive and brain impairments, have been documented in adults with type 2 diabetes who also have multiple co-morbid disorders that could contribute to these observations. Assessing adolescents with type 2 diabetes will allow the evaluation of whether diabetes per se may adversely affect brain function and structure years before clinically significant vascular disease develops. METHODS: Eighteen obese adolescents with type 2 diabetes and 18 obese controls without evidence of marked insulin resistance, matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index and waist circumference, completed MRI and neuropsychological evaluations. RESULTS: Adolescents with type 2 diabetes performed consistently worse in all cognitive domains assessed, with the difference reaching statistical significance for estimated intellectual functioning, verbal memory and psychomotor efficiency. There were statistical trends for executive function, reading and spelling. MRI-based automated brain structural analyses revealed both reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular, but there was no obvious grey matter volume reduction. In addition, assessments using diffusion tensor imaging revealed reduced white and grey matter microstructural integrity. CONCLUSIONS/INTERPRETATION: This is the first report documenting possible brain abnormalities among obese adolescents with type 2 diabetes relative to obese adolescent controls. These abnormalities are not likely to result from education or socioeconomic bias and may result from a combination of subtle vascular changes, glucose and lipid metabolism abnormalities and subtle differences in adiposity in the absence of clinically significant vascular disease. Future efforts are needed to elucidate the underlying pathophysiological mechanisms.

Human sperm telomere-binding complex involves histone H2B and secures telomere membrane attachment.

Telomeres are unique chromatin domains located at the ends of eukaryotic chromosomes. Telomere functions in somatic cells involve complexes between telomere proteins and TTAGGG DNA repeats. During the differentiation of germ-line cells, telomeres undergo significant reorganization most likely required for additional specific functions in meiosis and fertilization. A telomere-binding protein complex from human sperm (hSTBP) has been isolated by detergent treatment and was partially purified. hSTBP specifically binds double-stranded telomeric DNA and does not contain known somatic telomere proteins TRF1, TRF2, and Ku. Surprisingly, the essential component of this complex has been identified as a specific variant of histone H2B. Indirect immunofluorescence shows punctate localization of H2B in sperm nuclei, which in part coincides with telomeric DNA localization established by fluorescent in situ hybridization. Anti-H2B antibodies block interactions of hSTBP with telomere DNA, and spH2B forms specific complex with this DNA in vitro, indicating that this protein plays a role in telomere DNA recognition. We propose that hSTBP participates in the membrane attachment of telomeres that may be important for ordered chromosome withdrawal after fertilization.

Solution structure of the epithelial cadherin domain responsible for selective cell adhesion.

Cadherins are calcium-dependent cell adhesion molecules containing extracellular repeats of approximately 110 amino acids. The three-dimensional structure of the amino-terminal repeat of mouse epithelial cadherin was determined by multidimensional heteronuclear magnetic resonance spectroscopy. The calcium ion was bound by a short alpha helix and by loops at one end of the seven-stranded beta-barrel structure. An exposed concave face is in a position to provide homophilic binding specificity and was also sensitive to calcium ligation. Unexpected structural similarities with the immunoglobulin fold suggest an evolutionary relation between calcium-dependent and calcium-independent cell adhesion molecules.

Survival prediction in patients with chronic obstructive pulmonary disease following a pulmonary rehabilitation programme in Hong Kong.

BACKGROUND AND OBJECTIVE: Pulmonary rehabilitation programme (PRP) is an important component in the management of chronic obstructive pulmonary disease (COPD). However, to date so far there has been limited literature on the survival outcomes of patients with COPD after a PRP in Hong Kong. This study aimed to investigate the outcomes of a pulmonary rehabilitation programme on the survival rates of a retrospective cohort of patients with COPD. METHODS: This was a retrospective study that included subjects who participated in the PRP in a rehabilitation hospital from the year 2003 to 2015. A total of 431 patients with chronic obstructive pulmonary disease were identified from the electronic record system of the hospital. The dataset were split into two age groups for reporting and analysis using the mean age of 72 as the cut-off. Their median survival times were calculated using Kaplan-Meier analysis. Cox-proportional regression model was used to explore factors that predicted better survival. The most significant predictors were used as strata, and their respective effects on survival functions were analysed with Kaplan-Meier analysis again. RESULTS: The overall median survival of the cohort was 4.3 years. The median survival times of the younger patient group (aged <72) and the older patient group (aged ≥72) were 5.3 and 3.6 years, respectively. For the patients, aged <72 years old, Moser's Activities of Daily Living class and the pulmonary rehabilitation programme completion rate were the most significant survival predictors. For the patients aged ≥72 years old, Monitored Functional Task Evaluation score was the most significant survival predictor. CONCLUSION: Moser's Activities of Daily Living class ≥2 and non-completion of PRP for younger group, low exercise capacity with Monitored Functional Task Evaluation score <17 for older group were identified as significant predictors of poor survival. The findings of this study helped identifying those patients with COPD who have the needs to be more intensively treated and closely monitored.

Laparoscopic adjustable gastric banding for the treatment of morbidly obese patients: early outcome in a Chinese cohort.

OBJECTIVE: To evaluate the efficacy of laparoscopic adjustable gastric banding in the management of morbid obesity in a cohort of Chinese patients. DESIGN. Cohort study. SETTING: University teaching hospital, Hong Kong. PATIENTS: From August 2002 to September 2003, 10 patients (6 male, 4 female) with a median age of 34 years (range, 23-48 years) underwent laparoscopic adjustable gastric banding to treat morbid obesity. Considerable co-existing diseases were present in 90% of the cases. We instituted a team approach that allowed every patient to see our dietitian, physician, psychiatrist (if necessary), and surgeon prior to deciding on the procedure to be used. MAIN OUTCOME MEASURES: Excessive body weight loss, quality-of-life score (SF36), and co-morbidities improvement. RESULTS: The 10 patients had a median weight of 127 kg (range, 115-196 kg) and median body mass index of 47 kg/m(2) (range, 38-67 kg/m(2)). The operation was successful in all patients with a median operating time of 110 minutes (range, 75-240 minutes). The median hospital stay was 3 days (range, 3-4 days) and three of the patients required overnight observation in the intensive care unit because of severe sleep apnoea and asthma. The median follow-up period was 12 months (range, 1-18 months). The mean weight loss at 6, 12, and 18 months was 19.3, 22.4, and 25.9 kg, respectively. Mean percentage of excessive weight loss at 6, 12, and 18 months was 34.9%, 36.5%, and 40.5%, respectively. Unsatisfactory weight loss (<20 kg) occurred in three patients because of poor dietary compliance and non-follow-up. Surgery also considerably improved the patients' co-morbidities (hypertension, diabetes, and obstructive sleep apnoea) and the quality of life. CONCLUSION: In the short term, laparoscopic adjustable gastric banding is certainly an effective procedure for morbid obesity, which results in a substantial weight loss and improvement of co-existing morbidities. Longer follow-up will show whether this weight loss is maintainable.

Purification and spectroscopic characterization of a recombinant amino-terminal polypeptide fragment of mouse epithelial cadherin.

Cadherins are a family of Ca(2+)-dependent cell adhesion molecules containing four extracellular tandem repeats each of 110 amino acids. The most amino-terminal repeat is believed to confer the specificity of cell adhesion. A polypeptide containing the amino-terminal repeat of mouse epithelial cadherin has been over-expressed in E. coli and purified to homogeneity. This polypeptide binds Ca2+ with a dissociation constant of 1.6 x 10(-4) M. CD and NMR experiments indicate that the polypeptide adopts a predominantly beta-sheet conformation and that binding of Ca2+ induces only small conformational changes.

A NMR study of mobility in the histone octamer.

The histone octamer from chicken erythrocytes was studied in 2 M NaCl using 500 mHz 1H NMR spectroscopy. We compared the spectrum of control octamers with that of octamers isolated from trypsinized nucleosome core particles. We observe that the sharp resonances found in the spectrum of the native octamer disappear completely after trypsinization. Therefore, within the time frame of the NMR experiment, all of the mobile amino acid residues in the histone octamer are found in the well defined trypsin sensitive domains. These results indicate that there is a very clear structural demarcation between the random coil N- and C-terminal tails and the globular domains of the histones.

Visualization of focal nuclear sites of DNA repair synthesis induced by bleomycin in human cells.

In this study, we examined DNA repair synthesis in human cells treated with the radiomimetic drug bleomycin, which efficiently induces double-strand breaks (DSBs). Using tyramide-biotin to amplify fluorescent signals, discrete nuclear foci from the incorporation of 5-iododeoxyuridine (IdU) were detected in proliferating human cells treated with bleomycin. We believe this comes from the repair of DSBs. An increase in the number of foci (>5 per nucleus) was detected in a major fraction (75%) of non-S-phase cells labeled for 30 min with IdU 1 h after the end of bleomycin treatment. The fraction of cells with multiple IdU-containing foci was found to decrease 18 h after treatment. The average number of foci per nucleus detected 1 h after bleomycin treatment was found to decrease twofold between 1 and 3.5 h, indicating that the foci may be associated with the slow component of DSB repair. The presence of DSBs in bleomycin-treated cells was confirmed using antibodies against phosphorylated histone H2AX (gamma-H2AX), which is strictly associated with this type of DNA damage. After treatment with bleomycin, non-S-phase cells also displayed heterogeneous nuclear foci containing tightly bound proliferating cell nuclear antigen (PCNA), suggesting an ongoing process of unscheduled DNA synthesis. PCNA is known to be involved in base excision repair, but a fraction of the PCNA foci may also be associated with DNA synthesis occurring during the repair of DSBs.

Dephosphorylation of histone gamma-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A.

The induction of DNA double-strand breaks (DSBs) by ionizing radiation in mammalian chromosomes leads to the phosphorylation of Ser-139 in the replacement histone H2AX, but the molecular mechanism(s) of the elimination of phosphorylated H2AX (called gamma-H2AX) from chromatin in the course of DSB repair remains unknown. We showed earlier that gamma-H2AX cannot be replaced by exchange with free H2AX, suggesting the direct dephosphorylation of H2AX in chromatin by a protein phosphatase. Here we studied the dynamics of dephosphorylation of gamma-H2AX in vivo and found that more than 50% was dephosphorylated in 3 h, but a significant amount of gamma-H2AX could be detected even 6 h after the induction of DSBs. At this time, a significant fraction of the gamma-H2AX nuclear foci co-localized with the foci of RAD50 protein that did not co-localize with replication sites. However, gamma-H2AX could be detected in some cells treated with methyl methanesulfonate which accumulated RAD18 protein at stalled replication sites. We also found that calyculin A inhibited early elimination of gamma-H2AX and DSB rejoining in vivo and that protein phosphatase 1 was able to remove phosphate groups from gamma-H2AX-containing chromatin in vitro. Our results confirm the tight association between DSBs and gamma-H2AX and the coupling of its in situ dephosphorylation to DSB repair.

Laparoscopic antireflux surgery in the treatment of gastroesophageal reflux in patients with Barrett esophagus.

BACKGROUND: Patients with gastroesophageal reflux and Barrett esophagus may represent a group of patients with poorer postoperative outcomes. It has been suggested that such patients should undergo open rather than laparoscopic antireflux surgery. HYPOTHESIS: The laparoscopic approach to antireflux surgery is appropriate treatment for patients with Barrett esophagus who have symptomatic gastroesophageal reflux disease. METHODS: The outcome of 757 patients undergoing laparoscopic surgery for gastroesophageal reflux disease from January 1, 1992, through December 31, 1998, was prospectively examined. Barrett esophagus was present in 81 (10.7%) of these patients (58 men and 23 women). The outcome for this group of patients was compared with that of patients undergoing surgery who did not have Barrett esophagus. RESULTS: The types of operation performed were similar for the 2 patient groups. The mean +/- SD length of columnar mucosa was 47.4 +/- 43.6 mm. The average +/- SD operation time was 79.0 +/- 33.4 minutes. Conversion to open surgery occurred in 6 patients. Postoperative outcomes were as follows. Esophageal manometry and 24-hour pH studies before and after laparoscopic fundoplication demonstrated a significant increase in lower esophageal sphincter resting and residual relaxation pressures and a significant decrease in distal esophageal acid exposure. Four patients have developed high-grade dysplasia or invasive cancer within 4 years of their antireflux surgery, and all of these have subsequently undergone esophageal resection. CONCLUSIONS: The outcome of laparoscopic antireflux surgery is similar for patients with Barrett esophagus compared with other patients with gastroesophageal reflux disease. This suggests that laparoscopic surgery is appropriate treatment for this patient group.

The influence of esophageal length on outcomes after laparoscopic fundoplication.

BACKGROUND: It has been suggested that laparoscopic antireflux surgery has been associated with an increased incidence of postoperative paraesophageal hiatus herniation, and that this comes (at least in part) from not performing an esophageal lengthening procedure in patients with preoperative esophageal shortening. This study was undertaken to determine whether patients with esophageal shortening have an increased risk of reoperation after laparoscopic antireflux surgery. STUDY DESIGN: All patients who underwent a laparoscopic fundoplication between December 1991 and March 1999, and who had undergone preoperative esophageal manometry in our department were included in this study. Preoperative, operative, and followup data were collected prospectively, and original manometry recordings were reviewed to determine the length of the esophagus (the distance between the midpoints of the upper and lower esophageal sphincters). An index of esophageal length versus height was also calculated by dividing esophageal length by height. Esophageal length and the index were then compared with clinical outcomes. In addition, outcomes for the 50 patients with the shortest index was compared with outcomes of the 50 patients with the longest index. RESULTS: This study included 484 patients from an overall experience of 774 laparoscopic antireflux procedures. Postoperative followup ranged from 3 months to 5 years (median 2 years). Mean esophageal length was 23 cm (range 14 to 30 cm). There was a significant correlation between height and esophageal length (r = 0.44, p < 0.0001). Although patients with large hiatus hernias tended to have a shorter esophagus, preoperative endoscopic esophagitis grading did not influence length. Esophageal length did not influence the overall requirement for further surgical reintervention, although an analysis of esophageal length in patients who developed specific complications demonstrated that postoperative paraesophageal herniation was more likely in patients with a shorter esophagus, and reoperation for a tight esophageal hiatus was less likely in patients with a short esophagus. The incidence of paraesophageal hernia in the 50 patients with the shortest index was 8% versus 2% in the 50 patients with the longest index (p = 0.36). CONCLUSIONS: Although the overall reoperation rate after laparoscopic fundoplication was not influenced by esophageal length, this study did demonstrate an association between esophageal shortening and postoperative paraesophageal herniation. But the increased risk of this problem is small, and for this reason a case cannot be made for patients with a manometrically short esophagus to routinely undergo an esophageal lengthening procedure.

Early reoperation following laparoscopic antireflux surgery.

PURPOSE: To assess the outcome for patients undergoing early reoperation following laparoscopic antireflux surgery. METHODS: The outcome was prospectively determined for 28 patients who underwent 30 reoperative procedures within 4 weeks of their initial laparoscopic fundoplication between 1992 and 1998. Follow-up ranged from 3 months to 4 years (median 2 years). Before mid 1994, patients were assessed and managed based on clinical findings (first 192 patients in overall series), whereas subsequently (for the most recent 530 patients) all patients underwent routine early postoperative barium swallow radiography, and laparoscopic exploration during the first postoperative week if problems were suspected. RESULTS: The reoperations were performed for acute paraoesophageal hiatus hernia (8 patients), tight oesophageal hiatus (7), postoperative haemorrhage (3), tight Nissen fundoplication (8), early recurrent reflux (1), and coeliac/superior mesenteric artery thrombosis (1). Two patients required a second operation for persistent dysphagia due to a tight hiatus. Both patients initially underwent loosening of their fundoplication. Before mid 1994, reoperations were usually undertaken by an open approach, whereas subsequently a laparoscopic approach has usually been successful. Laparoscopic reintervention was easily achieved within 7 days of the first procedure whereas subsequent surgery was more difficult and often required open surgery. The change in protocol was associated with an improvement in overall patient satisfaction and dysphagia in the latter part of this experience. CONCLUSIONS: Routine early contrast radiology following laparoscopic fundoplication and a low threshold for laparoscopic reexploration facilitates early identification of postoperative problems at a time when laparoscopic correction is easily achieved. This may result in an improved overall outcome for patients requiring early reintervention following laparoscopic antireflux surgery.

Effect of the chlorinated hydrocarbons heptachlor, chlordane, and toxaphene on retinoblastoma tumor suppressor in human lymphocytes.

Organochlorine use over the past 50 years has resulted in the contamination of soil, water, plant and animal species. This contamination has created a long-lasting environmental problem, as the members of the organochlorine class of pesticides are resistant to degradation and have been labeled as persistent bioaccumulators. Studies have shown certain organochlorines to be tumor promoters, liver toxicants and to induce immune cell dysfunction in rats and mice. Our laboratory has shown that the organochlorines heptachlor and chlordane affect leukocytic gene expression and differentiation. In this study, experiments with CEM x 174 cells, a hybrid of human T and B cells, were performed to investigate the effects of the tumor promoter heptachlor and its congeners chlordane and toxaphene on retinoblastoma (Rb) gene expression. The results indicated that heptachlor, chlordane or toxaphene, in the range of 10-50 microM, were able to reduce Rb protein levels in a concentration-dependent manner. In the case of heptachlor, the reduction could be seen as early as 12 h and was time-dependent. Analysis of Rb mRNA levels revealed no detectable difference over the same concentration range. These results suggest that members of the organochlorine class are able to downregulate Rb expression at the post-transcriptional level, an effect similar to that on p53 tumor suppressor previously reported by our laboratory.

The effect of heptachlor, a chlorinated hydrocarbon insecticide, on p53 tumor suppressor in human lymphocytes.

Previous studies have shown that heptachlor, a chlorinated hydrocarbon insecticide, is a liver tumor promoter in rats and mice and induces tumor promoting-like alterations in human myeloblastic leukemia cells. The nature of tumor promotion is multifaceted and has recently been shown to include suppression of programmed cell death (apoptosis) as a mechanism by which a tumor promoter can prolong cell viability. The ability of tumor promoters to suppress apoptosis prompted us to address the question of whether heptachlor is capable of effecting the expression of genes involved in lymphocyte apoptosis, in particular, the p53 tumor suppressor gene. Experiments with a CEM x 174 cell line, a hybrid of human T and B cells, revealed that heptachlor downregulated p53 gene expression at the post-transcriptional level without changing levels of mRNA in the cells. The heptachlor-induced reduction in the basal levels of expression of this gene was both in a concentration and time-dependent manner.

Massive congenital arteriovenous malformation of the pterygomaxillary space.

A case is presented of a massive congenital, extracranial arteriovenous malformation (AVM). The origins and hemodynamic considerations that led to prior treatment failure are discussed. A sudden accelerated growth in the AVM, caused by an alteration in the hemodynamics of the feeding and draining vessels, mandated further surgical management. The treatment of choice is complete surgical excision at the time of diagnosis, if possible. Ligation of the feeding vessels alone is unsatisfactory and, like other adjunctive treatments, may lead to disastrous complications.