Does the addition of oxaliplatin to preoperative chemoradiation benefit cT4 or fixed cT3 rectal cancer treatment? A subgroup analysis from a prospective study.

BACKGROUND: Whether there is any benefit derived from adding oxaliplatin to fluoropyrimidine-based preoperative chemoradiation is currently unknown in cases of advanced cT3 or cT4 tumours. Our aim was to evaluate this issue by analysing a randomized trial, which compared two schedules of preoperative treatment (chemoradiation vs. 5 × 5 Gy with 3 cycles of consolidation chemotherapy) for cT4 or fixed cT3 rectal cancer. PATIENTS AND METHODS: Delivery of oxaliplatin was mandatory to the first part of the study. For the second part, its delivery in both treatment-assigned groups was left to the discretion of the local investigator. We analysed a subgroup of 272 patients (136 in the oxaliplatin group and 136 in the fluorouracil-only group) from institutions that had omitted oxaliplatin in the second part of the study. RESULTS: Circumferential resection margin negative (CRM-) status rate was 68% in the oxaliplatin group and 70% in the fluorouracil-only group, p = 0.72. The pathological complete response rate (pCR) was correspondingly 14% vs. 7%, p = 0.10. Following multivariable analysis, when comparing the CRM- status in the oxaliplatin group to the fluorouracil-only group, the odds ratio was 0.79 (95 CI 0.35-1.74), p = 0.54; there being no interaction between concomitant chemoradiation and 5 × 5 Gy with consolidation chemotherapy; pinteraction = 0.073. For pCR, the corresponding results were 0.47 (95 CI 0.19-1.16), p = 0.10, pinteraction = 0.84. CONCLUSION: No benefit was found of adding oxaliplatin in terms of CRM nor pCR rates for either concomitant or sequential settings in preoperative radiochemotherapy for very advanced rectal cancer.

Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study.

BACKGROUND: Improvements in local control are required when using preoperative chemoradiation for cT4 or advanced cT3 rectal cancer. There is therefore a need to explore more effective schedules. PATIENTS AND METHODS: Patients with fixed cT3 or cT4 cancer were randomized either to 5 × 5 Gy and three cycles of FOLFOX4 (group A) or to 50.4 Gy in 28 fractions combined with two 5-day cycles of bolus 5-Fu 325 mg/m(2)/day and leucovorin 20 mg/m(2)/day during the first and fifth week of irradiation along with five infusions of oxaliplatin 50 mg/m(2) once weekly (group B). The protocol was amended in 2012 to allow oxaliplatin to be then foregone in both groups. RESULTS: Of 541 entered patients, 515 were eligible for analysis; 261 in group A and 254 in group B. Preoperative treatment acute toxicity was lower in group A than group B, P = 0.006; any toxicity being, respectively, 75% versus 83%, grade III-IV 23% versus 21% and toxic deaths 1% versus 3%. R0 resection rates (primary end point) and pathological complete response rates in groups A and B were, respectively, 77% versus 71%, P = 0.07, and 16% versus 12%, P = 0.17. The median follow-up was 35 months. At 3 years, the rates of overall survival and disease-free survival in groups A and B were, respectively, 73% versus 65%, P = 0.046, and 53% versus 52%, P = 0.85, together with the cumulative incidence of local failure and distant metastases being, respectively, 22% versus 21%, P = 0.82, and 30% versus 27%, P = 0.26. Postoperative and late complications rates in group A and group B were, respectively, 29% versus 25%, P = 0.18, and 20% versus 22%, P = 0.54. CONCLUSIONS: No differences were observed in local efficacy between 5 × 5 Gy with consolidation chemotherapy and long-course chemoradiation. Nevertheless, an improved overall survival and lower acute toxicity favours the 5 × 5 Gy schedule with consolidation chemotherapy. CLINICAL TRIAL NUMBER: The trial is registered as ClinicalTrials.gov number NCT00833131.

Watch and wait policy after preoperative radiotherapy for rectal cancer; management of residual lesions that appear clinically benign.

BACKGROUND: During an ongoing phase II observational study on watch and wait policy in rectal cancer, a substantial number of patients presented residual lesion after radiotherapy with a clinical benign appearance. This article aims to discuss the clinical significance of such findings. MATERIALS AND METHODS: Main entry criteria were age ≥70 years and small tumour (≤5 cm and ≤60% of circumferential involvement) located in the low rectum. Patients received chemoradiation (50 Gy, 2 Gy per fraction concomitantly with a 5-Fu bolus and leucovorin) or 5 × 5 Gy if considered unfit for chemotherapy. Patients with clinical complete response (cCR) were observed. Those with persistent tumours underwent transanal endoscopic microsurgery [TEM] if the baseline tumour was ≤3 cm and cN0 or total mesorectal excision. RESULTS: The watch and wait procedure was used in 11 out of the total 35 patients (31%) with a cCR; 17 patients (49%) with residual tumours that appeared clinically malignant were referred for TEM or abdominal surgery. In the remaining seven (20%), the residual tumour clinically appeared benign. Of these, there were two invasive cancers, four high-grade dysplasias and one low-grade dysplasia. The five patients with dysplasia, underwent local lesion resection without recurrence within a median of 11 months follow-up. CONCLUSIONS: The majority of lesions that appeared clinically benign after radio(chemo)therapy were also benign on pathological examination. Thus, local excision of such lesions should be considered.

Combined Therapies for Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) is a group consisting of over 50 disorders caused mostly by dysfunctions of lysosomal proteins and resultant accumulation of particular compounds inside cells and extracellular volumes in affected organisms. Genetic diseases are among the most difficult targets for medical treatment. Nevertheless, understanding of molecular bases of LSDs made it possible to develop novel procedures of treatment, employing molecular medicine. Although various therapeutic approaches have been proposed, and some of them were introduced into clinical practice, none of them was found to be effective in correcting all symptoms in treated patients. Central nervous system and skeleton appear to be the most difficult targets to be improved. Therefore, a proposal appeared that perhaps no single therapeutic procedure may be fully effective in treatment of LSD patients, and only combination of two or more approaches could be a successful therapy. In this review, we present and discuss current stage of various combination therapies for LSDs, based on already available published data.

Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments.

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history. We hypothesize that this discrepancy could be due to differences in open field habituation and home cage behaviour. Eight-month-old wild-type and MPS IIIB mice were tested in a 1-h open field test, performed 1.5 h after lights on, and a 24-h home cage behaviour test performed after 24 h of acclimatization. In the 1-h test, MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and reduced immobility time. No differences in anxiety were seen. Over the course of the test, differences became more pronounced with maximal effects at 1 h. The 24-hour home cage test was less reliable. There was evidence of increased hyperactivity in MPS IIIB mice, however, immobility was also increased, suggesting a level of inconsistency in this test. Performance of open field analysis within 1-2 h after lights on is probably critical to achieving maximal success as MPS IIIB mice have a peak in activity around this time. The open field test effectively identifies hyperactive behaviour in MPS IIIB mice and is a significant tool for evaluating effects of therapy on neurodegeneration.

The prevalence of leptotrichia amnionii in cervical swabs of HPV positive and negative women.

UNLABELLED: The aim of the present study was to determine the prevalence of Leptotrichia amnionii in cervical swabs of women and its possible correlation with HPV infection and the stage of cervical cancer. MATERIAL AND METHODS: A total of 139 cervical swabs from healthy women with normal cytology, with dysplastic changes and with cervical cancer were tested for the presence of L.amnionii and high-risk HPV DNA by PCR methods. RESULTS: L. amnionii was found in normal vaginal flora and in women with bacterial vaginosis (BV), which suggests that it may be oportunistic pathogen. L. amnionii infection was diagnosed in 13.7% (19/139). Statistical analysis showed that there was positive association (p < 0.01) between the presence of L.amnionii in women with cervical cancer (38.5%) and its presence in women without cancer (11.1%). On the other hand, there was no statistically significant association between L.amnionii and HPV infections. CONCLUSION: The data presented in this study show for the first time the prevalence of L. amnionii infection in cervical specimens collected from 2004-2006 in Poznan and Lublin, Poland, and its association with HPV infection and the stage of carcinogenesis of the cervix.

Nephrotic syndrome as first manifestation of a bronchopulmonary malignancy. A case report.

We present two cases of a bronchopulmonary tumor with paraneoplastic nephrotic syndrome as initial manifestation. After surgical resection of the tumor, regression of the nephrotic syndrome occurred.

Efficacy and safety of a new ready-to-use recombinant human growth hormone solution.

We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency (GHD) that were paramount to the development of a new recombinant human GH (rh- GH, somatropin), approved as the first 'biosimilar' in Europe. Study 1 consisted of 3 parts performed in 89 children. The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [Somatropin Powder (Sandoz)] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [Somatropin Solution (Sandoz)] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution. Study 2 was performed in 51 children and designed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential; rhGH was given sc at a daily dose of 0.03 mg/kg. Primary [body height, height SD score (HSDS), height velocity, and height velocity (HV) SD score (HVSDS)] and secondary [IGF-I and IGF binding protein 3 (IGFBP-3)] efficacy endpoints and safety parameters were assessed regularly. In study 1, all treatments showed comparable increases in growth. The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was -0.20 cm/yr (95% confidence interval (CI) [-1.34;0.94]) and in mean HVSDS was 0.76 (95% CI [-0.57;2.10]) after 9 months. These very small differences demonstrate comparable therapeutic efficacy between the two treatments. The results of study 2 were consistent with those seen in study 1. Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated. The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations.

Smokers with airway obstruction are more likely to quit smoking.

BACKGROUND: Chronic obstructive pulmonary disease (COPD), usually caused by tobacco smoking, is one of the leading causes of morbidity and mortality. Smoking cessation at an early stage of the disease usually stops further progression. A study was undertaken to determine if diagnosis of airway obstruction was associated with subsequent success in smoking cessation, as advised by a physician. METHODS: 4494 current smokers (57.4% men) with a history of at least 10 pack-years of smoking were recruited from 100 000 subjects screened by spirometric testing for signs of airway obstruction. At the time of screening all received simple smoking cessation advice. 1177 (26.2%) subjects had airway obstruction and were told that they had COPD and that smoking cessation would halt rapid progression of their lung disease. No pharmacological treatment was proposed. After 1 year all subjects were invited for a follow up visit. Smoking status was assessed by history and validated by exhaled carbon monoxide level. RESULTS: Nearly 70% attended a follow up visit (n = 3077): 61% were men, mean (SD) age was 52 (10) years, mean (SD) tobacco exposure 30 (17) pack-years, and 33.3% had airway obstruction during the baseline examination. The validated smoking cessation rate in those with airway obstruction was 16.3% compared with 12.0% in those with normal spirometric parameters (p = 0.0003). After correction for age, sex, nicotine dependence, number of cigarettes smoked daily, and lung function, success in smoking cessation was predicted by lower lung function, lower nicotine dependence, and lower tobacco exposure. CONCLUSIONS: Simple smoking cessation advice combined with spirometric testing resulted in good 1 year cessation rates, especially in subjects with airway obstruction.

[Effects of spirometric screening in the community on smoking cessation]. / Wplyw wczesnego srodowiskowego wykrywania POCHP na ograniczenie nalogu palenia tytoniu.

UNLABELLED: In the years 1998-2000 in the Centre of COPD and Respiratory Failure in Bydgoszcz a group of tobacco smokers at risk of COPD (over 40 years of age, with smoking history of more than 10 packyears) were studied. Every patient filled-in a simple questionnaire on clinical signs of COPD and tobacco habit, had a spirometry performed according to ATS standards and received a short antitobacco counseling together with a booklet on how to quit smoking. Out of 1072 patients studied in 1998, airway obstruction was found in 200. Eighty seven of these were current smokers (studied group-S). Another 90 current smokers with normal spirometry served as a control group-C. Both groups of smokers were invited in 1999 and 2000 to perform spirometry. Changes in smoking habit were recorded at each yearly visit. After one year 13 patients (15%) from the S group and 4 (4.5%) from the C group permanently stopped smoking. In 2000 24 patients (28%) in S group and 13 (14.7%) in C group permanently quit smoking. CONCLUSION: Spirometric screening in smokers at risk of COPD together with a minimal antismoking intervention seems to be a promising method of smoking cessation.

[A test for early detection of COPD]. / Próba wczesnego srodowiskowego wykrywania POChP.

Free spirometry was offered to inhibitants of Bydgoszcz who presented with chronic cough. 1072 subjects were investigated, 638 males and 433 females, mean age 54 years. Eighty percent were smokers or exsmokers. In 78.6% subjects spirometry was normal. 200 persons (18.7%) had spirometric signs of airway obstruction, 19.5% mild, 51.5% moderate and 29% severe. Mass spirometry of smokers with chronic cough is a good screenings method for detection of COPD.

[Early detection of COPD by high risk population spirometric screening]. / Wczesne wykrywanie POChP badaniem spirometrycznym grup wysokiego ryzyka.

UNLABELLED: COPD is the most frequent chronic lung disease in Poland. The disease is however under-diagnosed, especially at the early stages. The aim of the study was to assess the efficacy of spirometric screening for COPD in middle aged smokers. Informations on causes and symptoms of COPD were disseminated in mass media in 14 large cities. Subject aged over 39 and with smoking history of > 10 packyears were invited for a free spirometry in local chest clinic. However, everyone attending had the spirometry performed. Spirometry was performed according to ATS recommendations. Airway obstruction (AO) was diagnosed when FEV1/FVC < 85% of N and categorised as mild (FEV1 > 70% of N), moderate (FEV1 50-69% of N) or severe (FEV1 < 50% of N). Spirometry was accompanied by an antismoking advice. RESULTS: 12.781 subjects were screened (mean age 52 +/- 12 years, 57% males). In 8.269 subjects who complied with inclusion criteria AO was diagnosed in 29.8% (mild in 10.9%, moderate in 12% and severe in 6.9%). In smokers < 40 years of age and a history of < 10 packyears AO was found in 8.8% (mild in 6.0%, moderate in 1.8% and severe in 1.0%). CONCLUSION: Mass spirometry is an effective and easy method for early detection of COPD.

[The range of antagonistic effects of Lactobacillus bacterial strains on etiologic agents of bacterial vaginosis]. / Zakres antagonistycznego dzialania bakterii z rodzaju Lactobacillus na czynniki etiologiczne waginozy bakteryjnej.

Bacterial vaginosis is caused by uncontrolled sequential overgrowth of some anaerobic bacteria: Gardnerella vaginalis, Prevotella bivia, Bacteroides spp., Peptostreptococcus spp., Mobiluncus sp. usually occurring in stable numbers in the bacterial flora of healthy women. On the other hand, different species of bacteria belonging to the genus Lactobacillus, most frequently L. plantarum, L. rhamnosus and L. acidophilus, form a group of aerobic bacteria dominating in the same environment. The diversity and density of their populations depend on the age and health conditions. Thanks to their antagonistic and adherence properties bacteria of the genus Lactobacillus can maintain a positive balance role in this ecosystem. The aim of this study was to assess the antagonistic properties of Lactobacillus strains isolated from the vagina of healthy women against most common agents of bacterial vaginosis. It was found that nearly all of the tested Lactobacillus strains exerted distinct antagonistic activity against anaerobic bacteria: Gardnerella vaginalis, Prevotella bivia and Peptostreptococcus anaerobius and quite a number also against Gram-negative rods, while only some of them were able to inhibit Gram-positive aerobic cocci as Enterococcus faecalis or Staphylococcus aureus.

The influence of prenatal dexamethasone treatment on urinary excretion of adrenocortical steroids in newborns.

UNLABELLED: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency suspected in 14 newborns (5 F, 9 M), was treated prenatally with dexamethasone from weeks 7-9 of gestation. The 24 h urinary excretion of selected adrenocortical steroids derived from fetal and definitive adrenal zones was evaluated in these newborns at the age of 3 9 days. Among 11 babies born healthy, in one of six treated until confirmation of male karyotype in gestational weeks 12-17 and in four of five treated until delivery, suppression of fetal adrenal zone steroids was observed, accompanied additionally in three by a diminished excretion of tetrahydrocortisone. In three babies born affected (2 male, 1 female), excretion of 17alpha-hydroxyprogesterone and 21-deoxycortisol metabolites did not differ from 12 affected, age-matched controls, not treated prenatally. However, some influence on suppression of the fetal adrenal zone metabolite 16alpha-hydroxypregnenolone was observed in two newborns treated until delivery. CONCLUSIONS: Heterogeneity in the fetal adrenal response to maternal dexamethasone treatment was confirmed. Suppression of fetal adrenals, especially within the fetal adrenal zone, can be observed in some babies born healthy until at least 1 week after birth.

Thalamic and amygdaloid connections of the auditory association cortex of the superior temporal gyrus in rhesus monkey (Macaca mulatta).

Thalamic and amygdaloid connections of three association auditory areas (AA1, AA2, AA3) of the superior temporal gyrus (STG) were investigated. In order to define the projections of the particular areas, injections of fluorescent tracers were made in three monkeys. Distribution of labeling indicates that area AA1 differs from areas AA2 and AA3 in patterns of both thalamo-cortical and amygdalo-cortical connections. Area AA1 receives its predominant inputs from the ventral and dorsal nuclei of the medical geniculate body (MGB). The amygdaloid projection to the area AA1 originates from the basal nuclei, whereas input from the lateral nucleus was not found. The characteristic thalamic projections to areas AA2 and AA3 originate from the dorsal MGB nucleus and the polymodal nuclei of the posterior thalamus. The density of projections from the dorsal nucleus gradually decreases from area AA1 to area AA3 while projections from the Plm, Sg and Lim nuclei increase in the same direction. Areas AA2 and AA3 are the source of strong connections with the lateral nucleus of amygdala, which density increases progressively when injections shift from area AA2 to AA3. The basal and accessory basal nuclei are the source of a less significant amygdalofugal projections to both cortical areas. Thus, our experimental data indicate that influence of the polymodal thalamic nuclei increases substantially in the direction of the higher order association areas. The strong relation of the same cortical areas with the lateral amygdaloid nucleus might suggest that areas AA2 and AA3, in addition to auditory input are the site of transfer of complex sensory information to the amygdala.

Diversity of connections of the temporal neocortex with amygdaloid nuclei in the dog (Canis familiaris).

Reciprocal connections of amygdaloid nuclei with the temporal neocortex in the dog were investigated. Injections of fluorescent tracers and BDA into particular temporal areas were made in eleven dogs. The topographical arrangement of connections and variations in their density differentiate the temporal neocortex in the dog into a few regions. Among them, the cortex involving the anterior part of the ectosylvian gyrus did not send any amygdalopetal projection. The middle ectosylvian, dorsal zone of the posterior ectosylvian and the anterior part of the Sylvian gyrus were weakly connected with the amygdala. The cortical region involving the ventral zone of the posterior ectosylvian and composite posterior areas, as well as posterior Sylvian gyrus, was characterized by profuse connections with the amygdaloid complex. Cortico-amygdaloid connections originate in the wide cortical area of the auditory cortex of the middle and dorsal part of the posterior ectosylvian gyrus as well as in the auditory association cortex located in the ventral ectosylvian, composite posterior and posterior Sylvian gyri. The connections showed a dorso-ventral gradient of increasing density, in the direction of association fields. The most substantial projection taking rise from the ectosylvian posterior and posterior composite gyri terminated preferentially in the pericapsular sector of the lateral amygdaloid nucleus and, to a lesser degree, in its medial sector. Terminals of connections originating in the Sylvian gyrus occupied preferentially the intermediate part of the lateral nucleus, slightly more medially than that from the ectosylvian and posterior composite areas. Additionally, axonal terminals derived from the composite posterior and Sylvian posterior areas were observed in the basal parvocellular and magnocellular nuclei. Neocortical projections were reciprocated by amygdalofugal connections with two exceptions: the basal magnocellular nucleus was distinguished by a substantial amygdalofugal projection to the temporal neocortex focused on the dorsal Sylvian gyrus, and the central nucleus of the amygdala, in contrast, received an exclusively corticofugal projection.

[Evaluation of prognostic factors and progress of disease in patients with COPD treated with long-term oxygen]. / Ocena czynników rokowniczych i postepu choroby u chorych na POChP leczonych przewlekle tlenem.

Long-term sequential evolution of pulmonary function, blood gas, body mass index (BMI) and oxygen breathing time was observed in 266 COPD patients with advanced airway obstruction (FEV1 = 0.80 L), and severe respiratory failure (PaO2 = 52 mmHg, PaCO2 = 49 mmHg) undergoing LTOT. There were significant differences between survivors and non-survivors at entry and during the treatment. Patients dying during LTOT had at entry lower BMI and more advanced airway limitation than survivors. They did not differ in blood gas values. During the follow-up (between 1-4 years) different trends in evolution of studied variables were observed in survivors (over 4 years on LTOT) and patients dying during LTOT (up to 4 years). Long term stabilization of spirometric and blood gas values as well as in mean oxygen breathing time (14 hours) were observed in survivors. In non-survivors a significant progression in airway limitation and respiratory failure coupled with better compliance with LTOT (oxygen use increased from 15 to 17 hours/ day) was observed especially in the last year before death. In survivors BMI increased significantly during the treatment, whereas in non-survivors no change was observed.

Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma.

Inherited predisposition to phaeochromocytoma is seen in multiple endocrine neoplasia type 2 syndromes, von Hippel-Lindau (VHL) disease, and neuro-fibromatosis type 1. In addition familial phaeochromocytoma alone has been reported. To investigate the genetic basis for familial phaeochromocytoma alone, we screened three affected kindreds for mutations in the RET proto-oncogene and the VHL tumour suppressor gene. We did not detect MEN 2 associated RET mutations in any family, but missense VHL gene mutations (V155L and R238W) were identified in two kindreds with no clinical evidence of VHL disease. Patients with familial, multiple, or early onset phaeochromocytoma should be investigated for germline VHL and RET gene mutations as the molecular diagnosis of multisystem familial cancer syndromes enables appropriate counselling and screening to be provided.

Heterogeneity of urinary steroid profiles in children with adrenocortical tumors.

The excretory patterns of urinary steroids determined by capillary gas chromatography in 11 children (aged 0.8-16.5 years) with adrenocortical tumors were established. In 8 patients the predominant clinical feature was virilization, in 3 others, Cushing's syndrome. In 5 patients (3 carcinoma, 2 adenoma) very high excretion of 3 beta-hydroxy-5-ene steroids was observed. In 2 others (adenomas) only moderately elevated excretion of 11 beta-hydroxyandrosterone was found. In 1 patient (adenoma) pregnanediol dominated in the steroid profile, accompanied by moderately elevated 3 beta-hydroxy-5-ene steroids. Out of 3 Cushingoid patients (1 carcinoma, 2 adenomas), 1 presented an atypical urinary steroid pattern for hypercortisolemia, without 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase deficiencies. Neither the urinary steroid pattern nor tumor size alone were reliable indicators of tumor malignancy, as evaluated by a pathological examination and subsequent metastasis-free survival.

Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome.

Review of 20 patients with glucocorticoid deficiency (three cases also with salt loss) associated with absent tear secretion (19 cases) and achalasia of the cardia (15 cases) revealed neurological abnormalities in 17 including hyper-reflexia, muscle weakness, dysarthria, and ataxia together with impaired intelligence and abnormal autonomic function, particularly postural hypotension. These findings indicate that significant neurological problems are common in this multisystem disorder.