A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design.

Mucopolysaccharidosis type III is a group of four autosomal recessive enzyme deficiencies leading to tissue accumulation of heparan sulfate. Central nervous system disease is prominent, with initial normal development followed by neurocognitive decline leading to death. In order to define outcome measures suitable for gene transfer trials, we prospectively assessed disease progression in MPS IIIA and IIIB subjects >2years old at three time points over one year (baseline, 6 and 12months). Fifteen IIIA (9 male, 6 female; age 5.0±1.9years) and ten IIIB subjects (8 male, 2 female; age 8.6±3years) were enrolled, and twenty subjects completed assessments at all time points. Cognitive function as assessed by Mullen Scales maximized at the 2.5 to 3year old developmental level, and showed a significant age-related decline over a 6month interval in three of five subdomains. Leiter nonverbal IQ (NVIQ) standard scores declined toward the test floor in the cohort by 6 to 8years of age, but showed significant mean declines over a 6month interval in those <7years old (p=0.0029) and in those with NVIQ score≥45 (p=0.0313). Parental report of adaptive behavior as assessed by the Vineland-II composite score inversely correlated with age and showed a significant mean decline over 6month intervals (p=0.0004). Abdominal MRI demonstrated increased volumes in liver (mean 2.2 times normal) and spleen (mean 1.9 times normal) without significant change over one year; brain MRI showed ventriculomegaly and loss of cortical volume in all subjects. Biochemical measures included urine glycosaminoglycan (GAG) levels, which although elevated showed a decline correlating with age (p<0.0001) and approached normal values in older subjects. CSF protein levels were elevated in 32% at enrollment, and elevations of AST and ALT were frequent. CSF enzyme activity levels for either SGSH (in MPS IIIA subjects) or NAGLU (in MPS IIIB) significantly differed from normal controls. Several other behavioral or functional measures were found to be uninformative in this population, including timed functional motor tests. Our results suggest that cognitive development as assessed by the Mullen and Leiter-R and adaptive behavior assessment by the Vineland parent interview are suitable functional outcomes for interventional trials in MPS IIIA or IIIB, and that CSF enzyme assay may be a useful biomarker to assess central nervous system transgene expression in gene transfer trials.

NONO regulates the intra-S-phase checkpoint in response to UV radiation.

The main risk factor for skin cancer is ultraviolet (UV) exposure, which causes DNA damage. Cells respond to UV-induced DNA damage by activating the intra-S-phase checkpoint, which prevents replication fork collapse, late origin firing and stabilizes fragile sites. Recently, the 54-kDa multifunctional protein NONO was found to be involved in the non-homologous end-joining DNA repair process and in poly ADP-ribose polymerase 1 activation. Interestingly, NONO is mutated in several tumour types and emerged as a crucial factor underlying both melanoma development and progression. Therefore, we set out to evaluate whether NONO could be involved in the DNA-damage response to UV radiations. We generated NONO-silenced HeLa cell clones and found that lack of NONO decreased cell growth rate. Then, we challenged NONO-silenced cells with exposure to UV radiations and found that NONO-silenced cells, compared with control cells, continued to synthesize DNA, failed to block new origin firing and impaired CHK1S345 phosphorylation showing a defective checkpoint activation. Consistently, NONO is present at the sites of UV-induced DNA damage where it localizes to RAD9 foci. To position NONO in the DNA-damage response cascade, we analysed the loading onto chromatin of various intra-S-phase checkpoint mediators and found that NONO favours the loading of topoisomerase II-binding protein 1 acting upstream of the ATM and Rad3-related kinase activity. Strikingly, re-expression of NONO, through an sh-resistant mRNA, rescued CHK1S345 phosphorylation in NONO-silenced cells. Interestingly, NONO silencing affected cell response to UV radiations also in a melanoma cell line. Overall, our data uncover a new role for NONO in mediating the cellular response to UV-induced DNA damage.

The 2-min walk test is sufficient for evaluating walking abilities in sporadic inclusion body myositis.

Sporadic inclusion body myositis causes progressive functional loss due to declining muscle strength. Although the underlying cause is unknown, clinical trials are underway to improve strength and function. Selection of appropriate outcome measures is critical for the success of these trials. The 6-min walk test has been the de facto standard for assessing function in neuromuscular disease; however, the optimal walking test has not been determined in this disease. In this study, 67 individuals with sporadic inclusion body myositis completed a battery of quantitative strength and functional tests including timed walking tests, patient-reported outcomes, and other tasks. The 2-min and 6-min walk tests are highly correlated to each other (r=0.97, p<0.001) and to all lower extremity strength, patient-reported, and functional measures in this population. All subjects completed the 2-min walk test, but 7% of subjects were unable to walk the full 6-min of the 6-min walk test due to fatigue. The 2-min walk test demonstrates similar correlation to all outcomes compared to the 6-min walk test, is less fatiguing and better tolerated. Results suggest that the 2-min walk test is a better alternative to tests of longer duration. Further research is needed to determine longitudinal changes on this outcome.

[Follow-up chest radiography in surgical breast cancer patients]. / La radiografia del torace nel controllo delle pazienti operate per neoplasia della mammella.

PURPOSE: We investigated to what extent the diagnostic findings of chest radiography can improve prognosis and treatment in surgical breast cancer patients. We also reviewed the literature and our personal findings to choose the optimal follow-up frequency to meet therapeutical and management needs, including radiation protection. MATERIAL AND METHODS: We retrospectively reviewed 1556 chest radiographs of 195 surgical patients with M0 breast cancer performed January 1990 to December 1996. Patient's history and clinical data were accurately reviewed to investigate the relation between protocol type and results. The maximalist or intensive protocol featured 3 chest radiographs a year, even in the absence of any specific signs; the results were reviewed in terms of early diagnosis and prolongation of life. RESULTS: Only 13% of the examinations had been performed following a specific clinical indication, while 87% had been performed for a generic referral. Recurrences were found in 0.6% only of the latter examinations, which means that radiography provided no diagnostic improvement or important change in treatment in as much as 99.4% of cases. In 1997 radiographic follow-up was made triannual instead of biannual as it used to be. DISCUSSION AND CONCLUSIONS: In the absence of specific clinical indications, chest radiography can be performed in the two projections once a year. More aggressive protocols requiring more frequent examinations are not justified, as the patient's life expectancy is not increased. Yearly examinations permit to meet economic and management needs, with a better use of time, staff and materials. Moreover, the clinical-diagnostic yield is not affected by the skipping of unselected examinations. Finally, another pro is the technical thoroughness of the examination with orthogonal projections and the possibility to use ionizing radiations, which improves the management of clinical risks. Maximum radiologist-oncologist cooperation in clinical practice can improve both diagnostic efficiency and treatment efficacy, by reducing the population dose and rationalizing the use of human, instrumental, structural and financial resources.

Small bowel enteroclysis in surgically treated obesity.

PURPOSE: To define the indications, technical limitations and diagnostic yeld of small bowel transbuccal enema in the follow-up of surgical jejunoileal shunting in patients with complicated severe essential obesity. MATERIAL AND METHODS: Three patients were submitted to surgical diversion: two of them underwent an intestinal bypass after Payne-De Wind (isoperistaltic end-to-side jejunoileostomy) and the other after Scott (end-to-end jejunoileostomy). The latter refers to intestinal recanalization and antiperistaltic lower end-to-side gastroenteric restoration. RESULTS: Radiologic studies are the only means to depict the surgical small bowel. Radiographic follow-up needs barium sulfate administration and therefore cannot be performed any sooner than 30 days postoperatively. In the last three years the classic transbuccal enema has been performed with a Rollandi tube (with a terminal opening and a balloon). Both the anastomosis and the blind loop are difficult to demonstrate. CONCLUSIONS: Jejunoileal bypass can be used to treat severe obsity uncontrollable otherwise, to reduce food absorption. Different severe complications may result and small bowel studies may permit to show late local complications. Small bowel enema is also indispensable in bypass reversal. There are no alternatives to this radiologic examination which is however very difficult to perform, because of the changes made by previous operation(s), and to interpret because the anastomosis, the sutured loop and wall changes are often poorly demonstrated.

[Pancreatic fractures: the role of CT and the indications for endoscopic retrograde pancreatography]. / Fratture del pancreas: ruolo della TC e indicazioni alla pancreatografia retrograda endoscopica.

PURPOSE: To assess the role and the diagnostic yield of CT and of endoscopic retrograde cholangiopancreatography (ERCP) in the study of emergency pancreatic injuries from blunt abdominal trauma. MATERIAL AND METHODS: January, 1992, to December, 1996, eleven subjects with pancreatic trauma were operated on. The patients were 8 men and 3 women (mean age: 28.4 years, range: 15-47 years) with pancreatic traumas of different severity but all with gland fracture and severe ductal injuries. Direct radiography was performed in all cases in different projections: CT with 1 cm slice thickness and feed was also performed. A contrast agent was administered orally in 8/11 patients and i.v. in 11/11. ERCP was performed in supine recumbency within 12 hours of trauma; a hypotonic agent was administered i.v. in 5 cases. The examination was successful in 10 patients. Wirsung duct studies were extended to the biliary tract in 6 cases. RESULTS: Pancreatic traumas were never isolated and usually associated with other abdominal injuries in the liver, spleen, small intestine, kidneys (by frequency) and with injuries in other body regions--the chest in 8/9 cases, limbs in 7/9, the spine in 4/9 and the skull-brain in 3/9 cases. Pancreatic fractures were mostly cervical and 3 of them were bifocal. The radiologic findings of pneumoperitoneum (4 cases), sentinel loop (3), paralytic ileum (11), air-fluid levels (9) were always aspecific. CT had 66.7% sensitivity, with over-all accuracy of pancreatic involvement by trauma in 5/11 cases and specific findings of fracture in 1/11 cases. CT showed associated parenchymal injuries in both the abdomen and other sites. ERCP diagnostic accuracy and sensitivity topped 100% in the demonstration of ductal injuries. DISCUSSION: Pancreatic traumas are usually a rather uncommon event. They are classified as major and minor according to the extent and severity of ductal involvement. Injury site corresponds to the direction of impact force, but the neck is the preferential site for fractures because it is compressed within the spine and extended. Clinical findings are usually aspecific and questionable and diagnostic imaging, especially CT, plays therefore a major role in treatment planning. However, CT provides mainly indirect signs and fails to depict ductal rupture. Despite its difficult technical execution in emergency, ERCP shows ductal injuries with extreme accuracy and specificity, which finding is indispensable for treatment planning. CONCLUSIONS: Both CT and ERCP are necessary tools to diagnose pancreatic fractures: the former because it provides indispensable panoramic findings and the latter because it is the only method showing ductal involvement. Therefore, both techniques should be used for accurate surgical planning, which is a crucial step for the prognosis of these injuries. Cost-effectiveness and safe execution are well balanced.

Evolutional neurologic evaluation of seven year-old children born prematurely.

A sample of 51 children aged 7 with a history of prematurity was compared to 44 age-matched children who were born at term at the HCPA. The premature children had had gestational ages up to 37 weeks and 6 days and were born weighing less than 2,500 g. The control group consisted of children born with gestational age between 38 and 42 weeks and weights above 2,500 g. The evaluation criteria were clinical examination, neurological examination and the evolutional neurological evaluation (ENE). The results pointed out that impulsiveness, aggressiveness, disorganization and enuresis were prevalent symptoms of developmental disturbances in the sample of prematures. Alterations at neurological examination did not discriminate between the two groups, although cerebral palsy occurred only in the group of prematures. The ENE functions which differentiated the two groups studied were dynamic balance, appendicular and trunk-limb coordination and motor persistence.

The incentive plan: an approach for modification of physician behavior.

Blue Shield of Massachusetts undertook a one-year study in 1981 to determine if a group of obstetrician/gynecologists could be motivated to reduce average length of stay (ALOS) for normal deliveries, cesarean sections, and hysterectomies. The group decreased ALOS for all three procedures. Additional studies are required to determine what portion of the decrease in ALOS can be attributed to change in physician behavior.

A report of 1000 cases of minilaparotomy sterilizations in a community hospital.

PIP: Experience with 1000 minilaparotomy sterilizations performed over 6 years in a community hospital in Melrose, Massachusetts are reported. The method used was the Tural (tubouterine resection and ligation) technique. The Tural procedure was developed as a modification of previous surgical techniques. A loop of fallopian tube is grasped with a Babcock clamp and doubly tied with a double 0 chromic catgut. The tied loop is then excised and both free ends are doubly tied separately with double 0 surgilon suture. At the end of the procedure both severed ends of the tubes diverge from each other. In the 1000 case studies, 578 were primary interval sterilizations and 145 were sterilizations performed at the time of cesarean sections. The primary interval patients were done via a minilaparotomy Pfannenstiel incision, and the postpartum patients via a semicircular periumbilical incision. In 1980, the average postpartum hospital stay was 3.4 days. The average postpartum hospital stay with tubal sterilization added was 3.7 days. There was never a need to stop in midprocedure with minilaparotomy or extend the operation because of poor visibility. There was no unusual bleeding, cancelling of the procedure because of adhesions, adherent retroversion, or other pelvic disease. There were no pregnancies, no complications, and no hospital readmissions. Minilaparotomy for tubal sterilization emerged as a safe, economical alternative to conventional laparoscopy. It offers greater operative simplicity and avoids the rare major complications of visceral, vascular, and thermal injuries associated with laparoscopy. Because of disastrous consequences in a small but significant number of cases with laparoscopic electrocautery of the fallopian tubes, a method of nonelectric laparoscopic sterilization was sought by several investigators. A comparative study of female sterilization conducted by the International Research Program revealed the tubal ring was associated with a higher failure rate than electrocoagulation, the Racket clip, or modified Pomeroy technique. An unrecognized bowel injury is 1 of the most serious complications in laparoscopic sterilization. Uchida reported no failures and minimal complications in more than 20,000 minilaparotomies over a 28-year period. The argument that there is more postoperative pain with a minilaparotomy than a laparoscopic procedure was not found in this experience. Some of the positive aspects of minilaparotomy for sterilization are: no shoulder pain secondary to peritoneal insufflation; no contraindication for conditions such as obesity and previous surgery; and thermal injuries to bowel and pelvic organs are prevented.^ieng