Development of mucosal immune function in man: potential for Gl disease states

The human mucosal immune system is structurally mature and has all the necessary cellular components to generate an immune response at birth. However, in the absence of dietary antigens and bacterial flora, there are no secondary follicles in the Peyer's patches and virtually no immunoglobulin A plasma cells in the lamina propria. Reactive follicle centers develop after birth but it takes 2 years for mucosal IgA plasma cell density to reach adult levels. T cells are present in the epithelium and lamina propria at birth, albeit at a lower frequency than later in life and there are major differences in phenotype between T cells in fetal intestine and postnatal intestine. There is no information on the impact of the massive antigenic challenge at birth on the mucosal immune system. Well-documented deficiencies in the ability of the blood T cells of the neonate to produce interleukin-4 and interferon-gamma may also occur in the intestine. It is still an open question whether it is better to try to prevent immunological sensitization of the newborn by avoiding potential allergens (i.e. cow's milk), or whether early exposure (as happens when premature infants are given formula feeds) might tolerize the infant. Hydrolysed cow's milk formulae are probably less antigenic than whole cow's milk and have been widely used in the treatment of cow's milk allergy. Some thought is now being given as to whether the prophylactic use of hydrolysates can reduce cow's milk allergy in ‘at-risk’ infants.     

Complete structure of eclosion hormone of Manduca sexta

The locations of the three disulfide bonds of eclosion hormone (EH) isolated from Manduca sexta were assigned by sequence analysis of thermolysin fragments and by comparison of a key heterodimeric fragment to regiospecifically synthesized parallel and antiparallel isomers. We elucidated the complete structure of Manduca EH as a 62-residue peptide which has three disulfide bonds between Cys¹⁴-Cys³⁸, Cys¹⁸-Cys³⁴, and Cys²¹-Cys⁴⁹.     

Changes in hepatic lymph vessels in endotoxaemia.

This study was undertaken into rats to investigate changes in the hepatic lymph vessels and the space of Disse in endotoxaemia and to examine their relationship with the development of endotoxin-induced hepatic injury. Lymph stasis, namely dilatation of the lymph vessels and oedema, developed rapidly in the medium-sized portal canals, the large portal canals, and the liver hilum after endotoxin injection, but not in the small portal canals. Such changes reached their maximum 4-8 h after endotoxin injection and had recovered markedly by 16 h after the injection. The space of Disse remained within normal limits during this period. These findings suggest that the intrahepatic lymph stasis in endotoxaemia may be caused by a reduction in the pumping activity of the extrahepatic and the intrahepatic large lymph vessels rather than by an increase of lymph formation in the liver lobules. There was no evidence suggesting a direct relationship between the disturbance of hepatic lymph flow and the development of hepatic injury in endotoxaemia.     

Employment, medical absenteeism, and disability perception in Parkinson's disease: A pilot double-blind, randomized, placebo-controlled study of entacapone adjunctive therapy.

The objective of this study was to test the impact of entacapone (ENT) addition to levodopa with a decarboxylase inhibitor (LD) in full-time-employed patients with Parkinson's disease (PD), focusing on retirement rates, medical absenteeism, self-perception of disability, as well as motor assessments of parkinsonism, motor fluctuations, and dyskinesias. Thirty full-time-employed PD patients (disease onset before age 60 years) and on optimized monotherapy with LD exhibiting minor motor fluctuations or dyskinesias were entered into a 2-year randomized double-blind placebo-controlled study of ENT adjunctive therapy. The outcome measures were the number of full-time-employed patients at study end, cumulative days of medical absenteeism, patient-completed disability assessments, diary records, and the Unified Parkinson's Disease Rating Scale-based measures of motor fluctuations and dyskinesias. LD + ENT treatment was associated with a lower retirement rate (2 [17%] of 12 vs. 6 [50%] of 12; P = 0.12), lower absenteeism rate (21.5 vs. 43.5 days; P < 0.0001), improved self-perception of disability progression over 2 years (change score 1.0 vs. 4.5; P < 0.0001), and lower scores for both motor fluctuations and dyskinesia assessments compared to LD monotherapy. In this pilot study, LD with ENT adjunctive therapy positively influenced employment rate over 2 years; this effect was associated with reduced motor complications and patient perceptions of stabilized disability.     

Deep brain stimulation for Parkinson''s disease: electropermeabilization and activation

Deep brain stimulation, DBS, is an accepted technique for the treatment of Parkinson's disease. DBS affects the electrical functions of neurons, but exactly how it alters those functions is not clearly explained. An electrical model is determined to simulate treatment with DBS of the sub thalamic nucleus. This model shows the difference in electrical fields between the inside and the outside the neurons. The generated electrical field near the electrodes is high enough to perform an electropermeabilization of the cell membranes, which most likely blockade normal nerve pulses or reduce the nerve impulse speed. Further away from the electrodes activation of large axons is performed.     

Skin cancers and precancerous lesions in Parkinson's disease patients.

Our objective was to evaluate the frequency of neoplastic and preneoplastic skin lesions in Parkinson's disease (PD) patients when compared with an aged-matched population. We performed a cross-sectional survey in PD patients and in an age-matched control group. Patients and controls were examined by a movement disorder specialist and a dermatologist. 150 PD patients and 146 controls were included. Thirty-five PD patients (23.3%) presented skin lesions that could be classified as neoplastic or preneoplastic vs. 20 subjects in the control group (13.7%) (OR 95%, CI 1.92 [1.05, 3.51]). However, this difference lost statistical significance when adjusted for gender (recruitment of controls was matched just for age with an over representation of males in the PD group). Twenty-nine PD patients (19%) presented actinic keratosis and basal cell carcinoma was diagnosed in 4 patients (3%). Although nonconclusive, our results are in agreement with previous studies suggesting an increased risk of skin cancer in PD patients. The frequency of actinic keratosis in PD patients and the associated risk to develop melanoma recommends its screening in future epidemiological studies.     

Rotigotine transdermal patch in early Parkinson's disease: a randomized, double-blind, controlled study versus placebo and ropinirole.

Rotigotine is a new, non-ergot dopamine agonist formulated in a transdermal delivery system. The present study was to investigate the efficacy and safety of the rotigotine transdermal patch in the treatment of early Parkinson's disease. Patients (n = 561) were randomized to rotigotine, ropinirole, or placebo. The titration period was up to 13 weeks, and there was a minimum dose-maintenance period of 24 weeks for ropinirole and 33 weeks for rotigotine. The primary endpoint was the proportion of patients with a minimum of 20% decrease in the combined Unified Parkinson's Disease Rating Scale Part II and Part III scores. The responder rate in the rotigotine group was significantly higher than in the placebo group (52% vs. 30%, P < 0.0001). Transdermal rotigotine at doses < or =8 mg/24 h did not show noninferiority to ropinirole at doses < or =24 mg/day. In a post-hoc subgroup analysis, rotigotine < or =8 mg/24 hours had a similar efficacy to ropinirole at doses < or =12 mg/day. The rotigotine transdermal patch was well tolerated. The most common adverse events were application-site reactions, nausea, and somnolence. Application-site reactions were predominantly mild or moderate in intensity. In conclusion, the rotigotine transdermal patch represents an effective and safe option for the treatment of patients with early Parkinson's disease.     

Interhemispheric and ipsilateral connections in Parkinson's disease: relation to mirror movements.

Mirror movements (MM) occur in early, asymmetric Parkinson's disease (PD). To examine the pathophysiology of MM in PD, we studied 13 PD patients with MM (PD-MM), 7 PD patients without MM (PD-NM), and 14 normal subjects. Cross-correlogram did not detect common synaptic input to motoneuron pools innervating homologous hand muscles in PD-MM patients. Transcranial magnetic stimulation studies showed no significant difference in ipsilateral motor-evoked potentials between PD-MM patients and normal subjects. The MM side of PD-MM patients showed a slower increase in ipsilateral silent period area with higher level of muscle contraction than the non-MM side and normal subjects. There was less interhemispheric inhibition (IHI) at long interstimulus intervals of 20 to 50 ms in PD-MM than PD-NM. IHI reduced short interval intracortical inhibition in normal subjects and PD-NM, but not in PD-MM. IHI significantly increased intracortical facilitation in PD-MM and PD-NM patients, but not in normal subjects. Our results suggest that MM in PD is due to activation of the contralateral motor cortex. PD-MM patients had reduced transcallosal inhibitory effects on cortical output neurons and on intracortical inhibitory circuits compared to PD-NM patients and controls. These deficits in transcallosal inhibition may contribute to MM in PD patients.     

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.     

Autopsy-proven Huntington's disease with 29 trinucleotide repeats.

Huntington's disease (HD) is a neurodegenerative disorder associated with expansion of CAG trinucleotide repeats in the huntingtin gene. A minimum of 36 CAG repeats is usually reported in patients with clinical features of HD; 30 to 35 repeats represent an intermediate range. Here we report a 65-year-old male with autopsy-proven HD and 29 CAG repeats.