Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time.

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.

Assessing the non-motor symptoms of Parkinson's disease: MDS-UPDRS and NMS Scale.

BACKGROUND AND PURPOSE: Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I - Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). METHODS: To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland-Altman plot. RESULTS: As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (r(S) > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high (r(S) = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60-64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland-Altman plot; LCCC < 0.60 for severe patients). CONCLUSIONS: (i) MDS-UPDRS Part I (nM-EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant.

Prediction of early- and late-onset pregnancy-induced hypertension using placental volume on three-dimensional ultrasound and uterine artery Doppler.

OBJECTIVES: To determine whether uterine artery (UtA) Doppler findings and three-dimensional (3D) ultrasound measurement of placental volume during the first trimester allowed prediction of early- and late-onset pregnancy-induced hypertension (early PIH and late PIH). METHODS: Subjects with singleton pregnancy who underwent an ultrasound scan at 11-13 weeks' gestation and delivered between 2011 and 2013 were enrolled prospectively into the study. The UtA Doppler indices and placental volume on 3D ultrasound at 11-13 weeks' gestation in cases that developed early PIH (< 34 weeks) or PIH later in pregnancy (≥ 34 weeks) were compared with values in unaffected pregnancies. RESULTS: Ten cases of early PIH, 67 cases of late PIH and 1285 unaffected pregnancies were analyzed. The UtA pulsatility index (PI) was higher in cases of early PIH than that in unaffected pregnancies (median, 2.35 vs. 1.79; P = 0.043) but did not differ between cases of late PIH and unaffected pregnancies. Placental volume was smaller in cases of early PIH than that in unaffected pregnancies (median, 43 cm3 vs. 62 cm(3) ; P = 0.003) but did not differ between cases of late PIH and unaffected pregnancies. The area under the receiver-operating characteristics curve for the prediction of early PIH, by combining UtA-PI and placental volume, was 0.832 (95% CI, 0.742-0.921), with this combination providing a detection rate for early PIH of 67.5% for a 5% false-positive rate. CONCLUSIONS: High UtA-PI and small placental volume were observed more often in cases of early PIH compared with unaffected pregnancies, but not in cases of late PIH. These results may indicate that there are differences in pathophysiology between early PIH and late PIH.

Relationship between the MDS-UPDRS domains and the health-related quality of life of Parkinson's disease patients.

BACKGROUND AND PURPOSE: The Movement Disorder Society sponsored version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson's disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. METHODS: An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire - eight items (PDQ-8). Spearman's rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. RESULTS: The participants' age was 66.71 ± 10.32 years (51.5% men). PD duration was 8.52 ± 6.14, and median HY was 2 (range 1-5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from -0.46 (Part IV) to -0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. CONCLUSIONS: The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living.

Aqueous-phase photochemical formation of peroxides in authentic cloud and fog waters.

Gas-to-drop partitioning of hydrogen peroxide and its precursor, the hydroperoxyl radical (HO2.), has been considered the predominant or sole source of hydrogen peroxide in atmospheric water drops. However, atmospheric water can absorb solar ultraviolet radiation, which initiates the photoformation of peroxides (primarily hydrogen peroxide). Measurements of peroxide photoformation rates in authentic atmospheric water samples demonstrate that aqueous-phase photochemical reactions are a significant, and in some cases dominant, source of hydrogen peroxide to cloud and fog drops. This additional source could significantly change the current understanding, and hence, the models, of sulfuric acid deposition because hydrogen peroxide is the limiting reagent in the dominant pathway for the oxidation of sulfur dioxide to sulfuric acid in the troposphere over eastern North America.

Placenta previa with early opening of the uterine isthmus is associated with high risk of bleeding during pregnancy, and massive haemorrhage during caesarean delivery.

OBJECTIVE: To demonstrate the relationship between the timing of opening of the uterine isthmus and bleeding during pregnancy and caesarean section in patients with placenta previa. METHODS: A prospective observational study was conducted at a single perinatal centre. All patients with placenta previa, diagnosed between 20 and 22 weeks of gestation, who were followed up at the study hospital and underwent caesarean section were enrolled. The condition of the uterine isthmus was examined every 2 weeks. The timing (in gestational weeks) of complete opening of the uterine isthmus was determined. Patients were divided into two groups: patients in whom the uterine isthmus opened before 25 weeks of gestation (EO-previa), and patients in whom the uterine isthmus opened after 25 weeks of gestation (LO-previa). The frequency of bleeding during pregnancy and the amount of intra-operative bleeding were compared between the two groups. RESULTS: Forty-four cases of EO-previa and 55 cases of LO-previa were analysed. Complete placenta previa at delivery was observed more frequently in the EO-previa group than in the LO-previa group (88.6% vs 47.3%, p<0.001). An emergency caesarean section due to active bleeding was performed more frequently in the EO-previa group (48%) than in the LO-previa group (25%) (p=0.021). The frequency of massive haemorrage (>2500ml) during caesarean section was higher in the EO-previa group than in the LO-previa group (25% vs 9%, p=0.033). CONCLUSION: Placenta previa was associated with a high risk of bleeding leading to emergency caesarean section during pregnancy, and massive haemorrhage during caesarean section in patients in whom the uterine isthmus opened before 25 weeks of gestation.

[Neuropsychological study of 12 patients with pure degenerative cerebellar disease]. / Evaluación cognitiva en 12 pacientes con enfermedad cerebelosa degenerativa pura.

INTRODUCTION: The cerebellum has been traditionally associated with motor control learning and performance. However, since 1970 a growing body of clinical and experimental evidences has suggested that the cerebellum may be involved in nonmotor cognitive functions as well. OBJECTIVE: To explore the presence of eventual cognitive impairment in non-demented patients with isolated degenerative cerebellar diseases. PATIENTS AND METHODS: Twelve patients with the diagnosis of selective degenerative cerebellar disorders, either inherited or sporadic, were selected (mean age: 40.42 +/- 13.49 years; mean education level: 9.92 +/- 3.99 years; duration of illness: 12.13 +/- 11.27 years, MMSE: 26.75 +/- 1.5) and evaluated through a standardized neuropsychological tests battery. Normalized Z scores were estimated and compared against 0, employing the t test for one sample. RESULTS: Significant cognitive deficits were found in the following domains: executive, visuo-spatial, memory and attention functions. Performance on the Wisconsin test showed a significative number of perseverative errors. Memory deficits included verbal learning and free recall difficulties, with good recognition of the material presented. CONCLUSIONS: The findings of this study are consistent with the role of the cerebellum as modulator of mental functions. The cognitive deficits resulting from cerebellar pathology may be related with the disruption of cerebello-cortical connexions involving a complex network which includes the prefrontal region, suggesting that the cerebellum may process cortical information coming from different areas linked with the control of cognition.

A structure-based model for cytochrome P450cam-putidaredoxin interactions.

Putidaredoxin (Pdx) is a Fe2S2 ferredoxin which acts as the physiological reductant of cytochrome P-450cam (CYP101). A model for the solution structure of oxidized Pdx has been determined using NMR methods (Pochapsky et al (1994) Biochemistry 33, 6424-6432). 1H-15N correlations and redox-dependent amide exchange rates have also been described (Lyons et al (1996) Protein Sci 5, 627-639). Data obtained from mutagenesis and kinetic measurements concerning the interactions of Pdx and CYP101 are summarized. A model for the structure of the homologous ferredoxin adrenodoxin (Adx) is also described, and data concerning Adx activity are discussed in relation to this structure. The structures of Pdx and CYP101 were used as starting points for molecular modeling and molecular dynamics simulations. Close approach between the metal centers of the two proteins and interaction between aromatic residues on the surfaces of the proteins are premised. The resulting complex exhibits three intermolecular salt bridges, five intermolecular hydrogen bonds and a 12 A distance between the metal centers. The first direct observations of interaction between Pdx and CYP101 (by two-dimensional NMR of 15N-labeled Pdx in solution with CYP101) are described. The results of the NMR experiments indicate that conformational gating of the electron transfer complex between CYP101 and Pdx may be important.

Variation in CO2 assimilation rate induced by simulated dew waters with different sources of hydroxyl radical (*OH) on the needle surfaces of Japanese red pine (Pinus densifora Sieb. et Zucc.).

The hydroxyl radical (*OH) is generated in polluted dew on the needle surfaces of Japanese red pine (Pinus densiflora Sieb. et Zucc.). This free radical, which is a potent oxidant, is assumed to be a cause of ecophysiological disorders of declining trees on the urban-facing side of Mt. Gokurakuji, western Japan. Mists of *OH-generating N(III) (HNO2 and NO2-) and HOOH + Fe + oxalate solutions (50 and 100 microM, pH 5.1-5.4) simulating the dew water were applied to the foliage of pine seedlings grown in open-top chambers in the early morning. Needles treated with 100 microM N(III) tended to have a greater maximum CO2 assimilation rate (Amax), a greater stomatal conductance (g(s)) and a greater needle nitrogen content (Nneedle), suggesting that N(III) mist acts as a fertilizer rather than as a phytotoxin. On the other hand, needles treated with 100 microM HOOH + Fe + oxalate solution showed the smallest Amax, g(s), and Nneedle, suggesting that the combination of HOOH + Fe + oxalate caused a decrease in needle productivity. The effects of HOOH + Fe + oxalate mist on pine needles were very similar to the symptoms of declining trees at Mt. Gokurakuji.

Efficacy of agar-plate culture in detection of Strongyloides stercoralis infection.

Agar-plate culture of feces using a modified petri dish proved to be highly efficient in the detection of Strongyloides stercoralis infection. Furrows left by S. stercoralis on the agar plate were distinguished readily in size from those left by Necator americanus.

Efficacy of ivermectin against Strongyloides stercoralis in humans.

Okinawa Prefecture is an endemic area of Strongyloides stercoralis infection. Since treatment of this infection remains unsatisfactory, we evaluated the efficacy of ivermectin. Twenty-three patients were treated with a single oral dose of ivermectin (mean +/- SD, 105.5 +/- 20.8 mcg/kg of body weight), followed by a second dose two weeks later. The rate of cure was 85.7% at 2 weeks after the first treatment, and 90.5% at 2 weeks after the second treatment. Side effects occurred in 2 patients (8.7%), but they were mild and transient. The results indicate that ivermectin might be useful and relatively safe for the therapy of Strongyloides stercoralis infection as an alternative to thiabendazole or mebendazole.

[New trial with thiabendazole for treatment of human strongyloidiasis].

Okinawa prefecture is well known as an endemic area of Strongyloides stercoralis infection, and its recent infection rate was reported 6.2%, which was investigated by a new technique to detect S. stercoralis, agar plate method. Traditional treatment with thiabendazole was temporarily effective for S. stercoralis, but the recurrence rate was extremely high. We tried the new treatment for the purpose of complete eradication of the parasite. The patients were divided into two groups, who were given 500 mg of thiabendazole three times daily for 5 days and not medicated for the following 9 days. The medication was repeated 3 times in group 1 which consisted of 92 patients and 4 times in group 2 which consisted of 70 patients. Obtained results were as follows: 1) Six months after treatment, the cure rate was 89.5% in the only one course treatment, and 100% in more than 2 course treatments. 2) Side effects such as nausea, vomiting, anorexia or general fatigue were noted in 67.5% of all the patients after initial treatment, and 45.1% of the patients were dropped out of this trial. The dose of the drug was reduced in 32.1% of the patients, and only 22.8% were treated with full course of the regimen. 3) The elevation of S-GPT was observed in 33.8% of all patients. After initial treatment the rate was only 8.1%, but after 3 or 4 repeated course of treatments the rate was elevated to 39.0% and 45.4%, respectively. The liver injury was closely related to the total dose of thiabendazole and the period of the medication.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical study on ivermectin against Strongyloides stercoralis].

We previously reported the efficacy of ivermectin (IVM) for the treatment of 23 strongyloidiasis patients. We now reported the efficacy and safety of IVM therapy on 54 patients. Fifty-four patients, 28 males and 26 females, received a single oral dose of IVM one hour before breakfast and this treatment was repeated 2 weeks later. The following results were obtained: 1) The cure rate at 2 weeks after the initial treatment was 92.5% (49 of 53 patients) and 2 weeks after the second course was 96.0% (48 of 50 patients). 2) Four patients (7.4%) complained of diarrhea (n = 2 patients), constipation (n = 1), borborygmus (n = 1), dizziness (n = 1), diplopia (n = 1) and peri-anal itching (n = 1) after the first treatment. Three patients (5.6%) complained of borborygmus (n = 1), itching (n = 1) and exanthema (n = 1) after the second treatment. But all symptoms were mild and required no treatment and subsided in a few days. 3) Positive rate of HTLV-1 antibody was 25.9% in the patients. As described above, although side effects occurred in some cases, they were mild and transient. From these results, we concluded that IVM is an effective drug for strongyloidiasis.

[Two case reports of septic shock due to Vibrio vulnificus with liver cirrhosis].

We have recently experienced a case of Vibrio vulnificus septicemia which occurred in a patient with hepatic cirrhosis, and as we were able to give early antibiotic treatment, the patient survived. We would like to report this case here together with another case experienced 2 years ago. Case 1 was a 58-year-old male who was attending our hospital as an outpatient for hepatic cirrhosis. At 5:30 pm on August 8, 1987, he consumed abalone and giant clam and at 9 pm complained of high fever with shaking chills. He was admitted to our department as an emergency case. Cefoperazone was administered resulting in a decline of fever on the following day. During the course of treatment he fell transiently into pre-DIC, but due mainly to the administration of antibiotics his condition was subsided. Case 2 was a 53-year-old male who was under medical care in our hospital for grave hepatic cirrhosis. On October 11, 1985, he consumed sushi and two days later suffered chills and pyrexia. A blood culture revealed Vibrio vulnificus. His condition improved transiently with administration of Cefazolin, but oliguria, hypotension and ascites occurred subsequently, and finally the patient died on the 22nd day.

[Hypopituitarism caused by colonic carcinoma metastasis associated with hypophysial aspergillosis]. / Hipopituitarismo originado por metástasis de carcinoma de colon asociado con aspergilosis hipofisaria.

Pituitary metastases constitute 1% to 8.3% of all metastatic brain tumors. The most frequent localization is in the posterior lobe and diabetes insipidus may be the only symptom of dysfunction. Cerebral aspergillosis is an unusual disease and it has been described complicating an underlying malignancy or following intracraneal surgery. We describe a case of hypopituitarism and hyperprolactinemia in a patient with pituitary metastases of a colon carcinoma and aspergillosis. Two years before a colon adenocarcinoma (Class C1 of Duke) had been resected. There were no clinical signs of hypopituitarism or galactorrea. The laboratory findings showed deficiency of cortocotropin (ACTH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and slight hyperprolactinemia (PRL). Cerebral magnetic resonance image (MRI) revealed an intra and suprasellar mass which extended to the hypothalamus. Chest X-ray film and computed tomographic scanning (TC) confirmed a macronodular mass at the apical segment of the inferior left lung lobule with mediastinal hypertrophic lymph nodes. A non functional pituitary tumor was diagnosed and transphenoidal surgery was carried out. At microscopic examination a malignant proliferation was found suggesting colonic differentiation. Fragments of tumoral pituitary tissue showed hyphae of aspergillus in the form of abscess. Aspergillosis complicating neoplastic disease is more often present in leukemia and lymphoma than in solid tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of multiple jejunal diverticula with strongyloidiasis and malabsorption syndrome].

We reported multiple jejunal diverticula with strongyloidiasis and malabsorption syndrome. To our knowledge, 140 cases including the present one have been reported in Japan. We reviewed these cases in this report.