Demographic characterization of Brazilian patients enrolled in the Fabry Registry.

Fabry disease (FD) is an X-linked inborn error of metabolism caused by alpha-galactosidase A deficiency. The Fabry Registry is an ongoing observational database that compiles clinical data on patients with FD. We analyzed the Fabry Registry data of patients enrolled in Brazil to characterize the demographic and baseline clinical characteristics of this patient population. As of October 2010, 126 Brazilian patients were enrolled in the Registry (61 males, 65 females). The median age at onset of symptoms in males was 9.8 years, compared to 11.4 years in females. Males were diagnosed at a median age of 31.9 years and females at 27.1 years. The median time between the onset of first symptoms and diagnosis was 20.3 years in males and 14.3 years in females. Neurologic pain was the presenting symptom most frequently reported by both genders. Renal events were the most common clinical events reported in males, while cardiac events were the most common events in females. The results of these analyses indicate that Brazilian patients were frequently not diagnosed with FD until many years after the onset of symptoms. Many Brazilian Fabry Registry patients report experiencing neurological pain, and many Brazilian women with FD exhibit substantial signs and symptoms. The prevalence of neurological pain as a presenting symptom among Brazilian Registry patients is consistent with previous reports from the overall Registry population. FD is treatable, and earlier diagnosis will allow for prompt initiation of appropriate treatment that may avert irreversible damage that could occur during the time from symptom onset to diagnosis.

Neurophysiological patterns of ulnar nerve neuropathy in leprosy reactions.

BACKGROUND: Leprosy neuropathy, despite being primarily demyelinating, frequently leads to axonal loss. Neurophysiological examination of the nerves during Type 1 (T1R) and Type 2 reactions (T2R) may give some insight into the pathophysiological mechanisms. METHODS: Neurophysiological examinations were performed in 28 ulnar nerves during a clinical trial of steroid treatment effectiveness, 19 patients with T1R and nine with T2R. The nerves were monitored during a period of 6 months; there were eight assessments per nerve, for a total of 224 assessments. Nine neurophysiological parameters were assessed at three sites of the ulnar nerve. The compound motor action potential amplitudes elicited at wrist, elbow and above, as well as the conduction velocity and temporal dispersion across the elbow, were chosen to focus on the changes occurring in the parameters at the elbow tunnel. RESULTS AND CONCLUSION: Neurophysiological changes indicating axonal and demyelinating processes during both T1R and T2R were detected across the elbow. Changes in demyelination, i.e. a Conduction Block, as a primary event present during T2R, occurring as an acute phenomenon, were observed regularly; in T1R Temporal Dispersion, a subacute phenomenon, was seen. During treatment remyelination occurred after both types of reactions.

Utility of measuring serum levels of anti-PGL-I antibody, neopterin and C-reactive protein in monitoring leprosy patients during multi-drug treatment and reactions.

OBJECTIVE: To verify the validity of measuring the levels of Mycobacterium leprae-specific anti-phenolic glycolipid (PGL)-I antibody, neopterin, a product of activated macrophages, and C-reactive protein (CRP), an acute phase protein, in serial serum samples from patients for monitoring the leprosy spectrum and reactions during the course of multi-drug treatment (MDT). METHODS: Twenty-five untreated leprosy patients, 15 multi-bacillary (MB) and 10 paucibacillary (PB), participated. Eight patients developed reversal reaction and five developed erythema nodosum leprosum (ENL) during follow-up. The bacterial index (BI) in slit-skin smears was determined at diagnosis and blood samples collected by venipuncture at diagnosis and after 2, 4, 6 and 12 months of MDT. PGL-I antibody and neopterin were measured by enzyme-linked immunosorbent assay, whereas the CRP levels were measured by the latex agglutination method. RESULTS: The levels of PGL-I antibodies and neopterin were higher in the sera of MB than PB patients, which correlated with the patients' BI. The serum levels of CRP did not differ significantly between the MB and PB patients. The serum levels of PGL-I and neopterin were no higher in reactional patients than non-reactional patients prone to such reactions. However, ENL patients had higher serum CRP levels than non-reactional MB patients. The serum PGL-I antibody levels declined significantly during MDT, in contrast to neopterin and CRP levels. CONCLUSION: Measuring the serum levels of PGL-I antibodies and neopterin appeared to be useful in distinguishing MB from PB patients, whereas monitoring the levels of PGL-I antibodies appeared to be useful in monitoring MB patients on MDT. Measuring serum CRP, although not useful in monitoring the patients, has limited significance in detecting ENL reactional patients.

Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan.

Mutations in the genes for nuclear envelope proteins of emerin (EMD) and lamin A/C (LMNA) are known to cause Emery-Dreifuss muscular dystrophy (EDMD) and limb girdle muscular dystrophy (LGMD). We compared clinical features of the muscular dystrophy patients associated with mutations in EMD (emerinopathy) and LMNA (laminopathy) in our series. The incidence of laminopathy was slightly higher than that of emerinopathy. The age at onset of the disease in emerinopathy was variable and significantly older than in laminopathy. The initial symptom of emerinopathy was also variable, whereas nearly all laminopathy patients presented initially with muscle weakness. Calf hypertrophy was often seen in laminopathy, underscoring the importance of mutation screening for LMNA in childhood muscular dystrophy with calf hypertrophy. The clinical spectrum of emerinopathy is actually wider than previously known including EDMD, LGMD, conduction defects with minimal muscle/joint involvement, and their intermittent forms. Pathologically, no marked difference was observed between emerinopathy and laminopathy. Increased number and variation in size of myonuclei were detected. More precise observations using electron microscopy is warranted to characterize the detailed nuclear changes in nuclear envelopathy.

Impact of natural IRS-1 mutations on insulin signals: mutations of IRS-1 in the PTB domain and near SH2 protein binding sites result in impaired function at different steps of IRS-1 signaling.

Insulin receptor substrate-1 (IRS-1) is one of the major substrates of insulin receptor tyrosine kinase and mediates various insulin signals downstream. In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. All the cell lines expressing mutant IRS-1 showed a significant reduction in [3H]thymidine incorporation compared with WT. Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. Cells expressing P170R and M209T showed slight but significant decreases in PI 3-kinase activity (17 and 14%, respectively; both P < 0.05) and in binding of p85 (22 and 16%, respectively; both P < 0.05) and a greater decrease in mitogen-activated protein kinase activity (41 and 43%, respectively; both P < 0.005) compared with WT. After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85.

Patterns of failure and survival in locally advanced carcinoma of the uterine cervix treated with high dose-rate intracavitary irradiation system.

We retrospectively analyzed 71 patients with locally advanced carcinoma of the uterine cervix treated by irradiation using high dose-rate intracavitary brachytherapy between 1978 and 1985. Seven patients were Stage IIIa, 46 Stage IIIb, and 18 Stage IVa. Five-year survivals for Stage IIIa, IIIb, and IVa were 71.4, 60.9, and 16.7%, respectively. An analysis of patterns of failure demonstrated that loco-regional recurrences were observed in 1 (14.3%) for Stage IIIa, 6 (13.0%) for Stage IIIb, and 9 (50.0%) for Stage IVa. The incidence of recurrence outside the pelvis observed in Stage IIIb patients (7 para-aortic nodes, 5 distant metastases) was much higher than that of local recurrence. Five patients (7.0% of the total: 1 with Stage IIIa, 3 with Stage IIIb, 1 with Stage IVa) required surgery to manage the complications. These data suggest that a high dose-rate intracavitary irradiation system is an effective tool for the treatment of cervical cancer. Further efforts to control metastatic lesions outside the pelvis are required for patients with Stage IIIb. To increase a loco-regional control rate for patients with Stage IVa disease, it is important to give additional treatment such as chemotherapy in conjunction with radiation therapy.

Renal lesions in leprosy: a retrospective study of 199 autopsies.

In the present work, 199 patients with leprosy who underwent autopsy between 1970 and 1986 were retrospectively studied to determine the prevalence, types, clinical characteristics, and etiologic factors of renal lesions (RLs) in leprosy. Patients were divided into two groups: 144 patients with RLs (RL+) and 55 patients without RLs (RL-). RLs observed in 72% of the autopsied patients were amyloidosis (AMY) in 61 patients (31%), glomerulonephritis (GN) in 29 patients (14%), nephrosclerosis (NPS) in 22 patients (11%), tubulointerstitial nephritis (TIN) in 18 patients (9%), granuloma in 2 patients (1%), and other lesions in 12 patients (6%). AMY occurred most frequently in patients with lepromatous leprosy (36%; nonlepromatous leprosy, 5%; P < 0.01), recurrent erythema nodosum leprosum (33%; P < 0.02), and trophic ulcers (27%; 0.05 < P < 0.10). Ninety-seven percent of AMY was found in patients with lepromatous leprosy, 88% showed recurrent trophic ulcers, and 76% presented with erythema nodosum leprosum. NPS was found in older patients with arterial hypertension, neoplastic diseases, infectious diseases, and vasculitis associated with GN. Most patients with AMY presented with proteinuria (95%) and renal failure (88%). The most frequent causes of death were renal failure in patients with AMY (57%), infectious diseases in patients with GN (41%) and TIN (45%), and cardiovascular diseases in patients with NPS (41%). No difference in survival rates was observed among RL- patients and those with AMY, GN, NPS, or TIN.

Sudden death in calves associated with Strongyloides papillosus infection.

In recent years, a total of 152 calves have died suddenly on three farms in the southern part of Japan which used sawdust as litter. Calves often died within a few minutes of a violent fall without showing previous clinical signs. On necropsy of these cases, only a slight lesion was observed, although all showed heavy infection with Strongyloides papillosus (SPL). They appeared to have not only a large number of SPL eggs in the faeces, together with many adult SPL worms in the intestine, but also many migratory SPL larvae in tissues such as the lung and muscle. These outbreaks ceased following medication with thiabendazole or ivermectin. It is concluded that 'sudden death' is associated with heavy infection with SPL.

Sudden death of calves by experimental infection with Strongyloides papillosus. II. Clinical observations and analysis of critical moments of the disease recorded on videotape.

Four calves experimentally infected with different doses of Strongyloides papillosus were examined for changes of body temperature and other clinical parameters. Also, the critical moments of death, which were recorded on videotape, were analyzed in detail. The first clinical signs included initial accelerated respiration. In general, body temperature was almost normal; however, one calf showed a slight increase after 2 or 3 days of infection, and two calves a gradual increase 7 days after infection. Vocal noises and general spasms were observed 5-14 times during the course of death. Initial vocal noises were heard between 0:50 and 1:30 (minute:second) after the appearance of the initial clinical signs. The final spasm, preceding death, occurred between 3:05 and 3:40 after the appearance of the initial clinical signs.

Sudden death of calves by experimental infection with Strongyloides papillosus. I. Parasitological observations.

Recently, an unknown disease, 'sudden death', in calves has been found in Japanese beef production farms. A previous study conducted by Taira and Ura indicated that sudden death can be effected in calves by hyperinfection of Strongyloides papillosus (SPL) and that the disease is possibly caused by SPL infection. In the present work, an experimental infection of SPL in calves was conducted to confirm the field occurrence. Fifteen Holstein Friesian calves, ranging from 45.5 to 85.6 kg in body weight, were divided into six groups. Calves of Groups A, B, C, D, E and F were infected once at the rate of 100,000, 320,000, 1,000,000, 3,200,000, 10,000,000 and 32,000,000 SPL larvae per 100 kg of body weight, respectively. Five calves were assigned to Group B, while two calves were assigned to the other groups. After showing no premonitory signs, sudden death of ten calves took place. The survival time of these calves was 27.4 and 16.8 days (Group B), 14.8 and 14.8 days (Group C), 13.3 and 14.2 days (Group D), 11.0 and 11.1 days (Group E) and 11.6 and 10.8 days (Group F). Three calves of Group B did not exhibit sudden death. The results of this study demonstrate that strongyloidiasis was the cause of sudden death.

Sudden death of calves by experimental infection with Strongyloides papillosus. IV. Electrocardiographic and pneumographic observations at critical moments of the disease.

Electrocardiographic and pneumographic observations at critical moments were carried out on five calves that died suddenly following experimental infections with Strongyloides papillosus. Time which elapsed during these critical moments was calculated from the time of observation of ventricular flutter (VF) to the appearance of accelerated respiration and cessation of respiration. The beginning of accelerated respiration ranged from -19 to 41 s after VF. Time (minutes:seconds) of cessation of respiration ranged from 2:10 to 3:50 after VF. The results of the experiment suggested sudden cardiac death as the cause of death in calves following infection with Strongyloides papillosus.

Single cell reporter assay using cell surface displayed Vargula luciferase.

Reporter genes such as firefly luciferase are common tools to monitor gene expression in various systems. As reporter gene represents the expression level of the gene of interest with its enzyme activity, firefly luciferase is most frequently used because its luminescent activity is highly sensitive and less time consumable for assay. However, since firefly luciferase is expressed internally in the cell, lysis of the cell is a critical step, and thus it is difficult to monitor the gene expression level continuously. In this report, we utilized secretive Vargula hilgendorfii luciferase modified to cell surface displayed one by fusing with human EGFR transmembrane sequence. This modified Vargula luciferase was expressed on cell surface without losing its bioluminescent activity. Co-transfection with secretive alkaline phosphatase showed that the behaviors of cell surface displayed Vargula luciferase and secretive alkaline phosphatase are comparable to each other. Furthermore, the luminescence of a single cell expressing cell surface displayed Vargula luciferase can be monitored by using photon counting CCD camera, which indicates that this reporter gene can monitor gene expression in a single cell without cell lysis.

Larvicidal effects of several chemicals on Strongyloides infective larvae.

The larvicidal effects of 11 anthelmintics, 7 pesticides and 4 disinfectants were evaluated with infective larvae of Strongyloides papillosus (SPL) and Strongyloides venezuelensis (SVZ). The lethal concentrations against SPL and SVZ were found to be similar. Three chemicals (dichlorvos, levamisole and trichlorfon) showed highest larvicidal effects. The 50% lethal concentration (LC(50)) values for the three compounds against SPL larvae were 0.08, 0.24, and 0.59 ppm, respectively.

Sudden death of calves by experimental infection with Strongyloides papillosus. III. Hematological, biochemical and histological examinations.

Nine calves infected percutaneously with graded doses of Strongyloides papillosus (SPL) were examined for hematological, biochemical and histological changes during the infection. Six of the calves infected with the highest larval doses died suddenly and the three calves given lower doses survived. No changes were observed in blood cell counts except for a transient eosinophilia. Parameters of the blood coagulation system and blood gas remained normal. A decrease in blood glucose was observed in four of the calves that died after the prepatent period of the parasite. However, endotoxic shock could be ruled out as a cause of death because of normal platelet counts, no intravascular coagulation and low levels of serum endotoxin. A transient increase of creatine kinase was observed in three of the calves that died; however, myocardial infarction or myocarditis were not observed. No lesions were observed except for minor inflammatory changes in the lungs and slight cellular infiltrations in the heart. In the absence of any consistent hematological, biochemical or histological changes in the calves that died, the present study failed to demonstrate mechanisms underlying sudden death due to SPL infection.

Sudden cardiac death in calves with experimental heavy infection of Strongyloides papillosus.

For obtaining the preliminary data on the pathogenesis of sudden death in calves naturally heavily infected with Strongyloides papillosus, we monitored 8 Holstein calves experimentally infected with the larvae on electrocardiographic and pneumographic changes. Six calves died suddenly on days 11 to 17 after infection. Sinus tachycardia had been recorded continuously since 1 to 6 days before death. Heart rates increased gradually until death. Since 1 or 2 days before death, various patterns of tachyarrhythmia and bradyarrhythmia had been observed among patterns of sinus tachycardia. Arrhythmias included serious ventricular premature beat, paroxysmal ventricular tachycardia, complete atrioventricular block and so on. The terminal pattern observed suddenly in all of the cases was ventricular arrhythmias consisting of serial ventricular tachycardia, flutter and fibrillation, which were followed by respiratory arrest. Abnormal pneumograms were not obtained before the terminal ventricular fibrillation. Two of 8 calves recovered from the infection, only one of which showed sinus arrest and the second degree of atrioventricular block transiently. We concluded that calves heavily infected with the larvae died due to sudden cardiac arrest.

Dermatophytosis: association between ABO blood groups and reactivity to the trichophytin.

The authors investigated the relationship between dermatophytosis and ABO blood groups through blood typing, identification of isolated dermatophytes and specific cellular immune response of 40 individuals carriers of this mycosis. They verified that the fungus Trichophyton rubrum, isolated from 54.5% of the patients, was more frequent in individuals belonging to blood group A. The cellular immune response, evaluated through the trichophytin antigen, was positive in 25% of the studied patients; the presence of immediate reactions (30 minutes) was verified in 35%. The blood group distribution among patients with dermatophytosis and control groups was, respectively: 47.5% X 36% in group A, 40% X 50% in group O, 12. 5% X 11% in group B. Even though the authors have found a higher number of patients belonging to blood group A infected by T. rubrum, these results suggest that there is no statistical evidence that these individuals are more susceptible to dermatophytosis.

[Assessment of the Mitsuda reaction in lepromatous patients inactive before and after immunotherapy]. / Avaliação da reação de Mitsuda em pacientes virchovianos inativos antes eapós imunoterapia.

In this study the immunopotentiator levamisole as well as a mixture of BCG/Mycobacterium leprae were investigated in inactive lepromatous leprosy patients by using the Mitsuda reaction as a parameter. Twenty lepromatous patients ten years ago classified as histologically negative for Mitsuda's test were divided into three groups: five patients that were only retested with Mitsuda antigen; eight patients that received oral levamisol and seven patients that received a mixture of alive BCG plus autoclaved M. leprae. The results indicated that: 1) the levamisole did not alter the reactivity to lepromin in any of the patients studied; 2) neither the changes in the reactivity to lepromin by using the mixture (3 cases) nor those that occurred spontaneously (3 cases) were clear. They properly reflected the natural variation of patients with some degree of resistance to Mycobacterium leprae.

Informal complaints procedure in general practice: first year's experience.

OBJECTIVE: To evaluate the first year's experience of an informal patient complaints system that encourages extensive patient participation. DESIGN: Audit of an informal complaints procedure. SETTING: The Marylebone Health Centre, London. SUBJECTS: 39 complaints received over the audit period. MAIN OUTCOME MEASURES: Types of complaints (administrative, about doctors or medical care or both, staff about patients, mixed, other) and resolution of complaints (how complaints were dealt with and their resolution). RESULTS: 37 of the 39 complaints were resolved within two weeks. Two complaints sent direct to the family health services authority were resolved (with patients' agreement) by the informal complaints procedure. CONCLUSIONS: The informal complaints procedure was more cost effective than the family health services authority system and was comparatively straightforward to implement within the practice without major organisational restructuring. The two way process of the procedure ensured patients received a quick response to complaints and helped morale of health centre staff.

[Two adult cases of nemaline myopathy presenting different clinical symptoms and CT findings].

We report herein two cases of nemaline myopathy which showed peculiar muscle involvement and clinical symptoms. Case 1: A 44-year-old woman had developed gradual woresening of muscle weakness. Neurologically, only flexion of her neck was found to be weak. Her muscular CT revealed mild atrophy of four extremities and the sternocleidomastoid muscles. Histological examinations with Gomori-trichrome staining revealed tiny structures whose form was compatible with nemaline rods. Moreover, electronmicroscopic examination demonstrated the lattice pattern of electron-dense structures, and they also appeared to possess structural continuity with the Z-band. Case 2: A 56-year-old woman visited our department because of neck pulsations. Neurological examinations revealed bilateral hearing disturbance, marked atrophy of neck muscles, muscle weakness in four extremities and hypoactive deep tendon reflexes. She also exhibited steppage and waddling gaits. Her muscular CT demonstrated degenerative processes in the neck muscles(splenius muscles and semispinal muscles), trapezius muscles, para-spinal muscles, deltoid muscles and gluteal muscles. Among them, the para-spinal muscles and extensor muscles of the lower limbs showed marked degeneration and had been partly replaced by fatty tissues. A muscle biopsy was performed, and the presence of nemaline rods was confirmed by Gomori-trichrome staining. Although these two cases could be diagnosed as nemaline myopathy, the clinical symptoms and muscular CT findings were not quite the same. Whether these differences might simply indicate different clinical phases during the disease progression or be of further pathogenic significance still remains unclear. Additionally, since long-term follow-up studies of nemaline myopathy are quite rare, further follow-up examinations of these cases are necessary in order to understand the clinical and pathological alterations of nemaline myopathy.