Variant-specific effects of GBA1 mutations on dopaminergic neuron proteostasis.

Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non-motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α-synuclein by affecting the cross-talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α-synuclein via the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α-synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome-lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α-synuclein in iPSC-derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α-synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations.

Effect of Different Concentrations of Fructose and Glycerol in Tris Citric Acid Extender on Postthaw Quality and Fertility of Buffalo Bull Spermatozoa.

BACKGROUND: Fructose is considered a vital energy source for metabolic events occurring naturally in the seminal plasma of buffalo spermatozoa. OBJECTIVE: To explore the effect of different concentrations of fructose and glycerol in tris citric acid extender on post thaw quality and in vivo fertility of buffalo spermatozoa. MATERIALS AND METHODS: Semen was collected from three bulls through artificial vagina (42 °C). Two ejaculates were collected from each bull per collection day and were evaluated initially for consistency, volume, motility and concentration, followed by dilution in five extenders with supplements (Treatment 1: F0.1,G7 = fructose 0.1 % + glycerol 7 %; T2: F0.2,G7= fructose 0.2 % + glycerol 7 %; T3: F0.4,G6.5 = fructose 0.4 % + glycerol 6.5%; T4: F0.8,G6 = fructose 0.8 %, glycerol 6 %; T5: F1.0,G5 = fructose 1 % + glycerol 5 %). The experiment was replicated four times and the data were assessed with ANOVA. RESULTS: The results showed that percent progressive motility, plasma membrane integrity and supra-vital plasma membrane integrity of spermatozoa was significantly higher (P < 0.05) in extender supplemented with T5 than T1 and T2. Spem hypo-resistivity, acrosome integrity and DNA integrity were significantly higher in extender supplemented with T5 than T1. Moreover, sperm in vitro quality was significantly higher in T5 than T1 during 30 and 60 min of incubation at 37 ºC. Sperm in vivo fertility was significantly higher in extenders supplemented with T5 (57.3%) as compared to T1 (41.3%). CONCLUSION: It is concluded that extender supplemented with T5 improved post thaw semen quality and in vivo fertility of buffalo bull.

Evaluation of offline analysis of archived three-dimensional volume datasets in the diagnosis of fetal brain abnormalities.

OBJECTIVE: To retrospectively evaluate the reliability of offline manipulation of archived three-dimensional (3D) ultrasound volumes in the assessment of the normal fetal brain and the diagnosis of fetal brain abnormalities. METHODS: Seventy-nine 3D volume datasets, archived at the time of scanning, from women attending a tertiary center, were analyzed. They comprised 52 cases with brain abnormalities and 27 normal controls. Postnatal magnetic resonance imaging or postmortem examination confirmed the final diagnosis in all cases with brain anomalies. Offline analysis of the 79 anonymized 3D volume datasets was carried out by three fetal medicine experts, examiner one (E1), examiner two (E2) and examiner three (E3), using 4D View software. The experts were blinded to any prior diagnosis or history. Data were collected on a specially designed data sheet and entered into a specialized database for analysis. Results were compared between examiners, with the initial two-dimensional (2D) diagnosis and with the final definitive diagnosis by calculation of percentage agreement and kappa coefficients. RESULTS: Of the 52 cases with brain anomalies, the correct diagnosis was reached in 88.5% (46/52), 98.1% (51/52) and 92.3% (48/52) of cases on analysis of the 3D volumes by E1, E2 and E3, respectively, whereas only 82.7% (43/52) of cases were correctly diagnosed on the initial 2D examination when compared with the definitive diagnosis. Fetuses without brain anomalies were identified as such by the three experts with 100% agreement. There was good agreement between the initial 2D examination and the analysis of 3D volumes by each of the experts: 86.1% for E1 (κ = 0.7), 89.9% for E2 (κ = 0.79) and 88.6% for E3 (κ = 0.76). CONCLUSIONS: 3D volume datasets are an appropriate and reliable format for storing data from examination of the fetal brain. Offline analysis of 3D datasets is a reliable method that can be used to help in the assessment of brain anomalies and could be a useful adjunct to realtime 2D ultrasonography.

Anaesthetic management of pregnant patients with cardiac implantable electronic devices: case reports and review.

Heart disease is a leading cause of maternal mortality and morbidity. Pregnant women with structural, conduction or degenerative cardiac disease who require rhythm control or who are at high risk of sudden cardiac death may carry a cardiac implantable electronic device or may occasionally require the insertion of one during their pregnancy. These women are now encountered more frequently in clinical practice, and it is essential that a multidisciplinary approach, beginning from the early antenatal phase, be adopted in their counselling and management. Contemporary cardiac rhythm control devices are a constantly evolving technology with increasingly sophisticated features; anaesthetists should therefore have an adequate understanding of the principles of their operation and the special considerations for their use, in order to enable their safe management in the peripartum period. Of particular importance is the potential adverse effect of electromagnetic interference, which may cause device malfunction or damage, and the precautions required to reduce this risk. The ultimate goal in the management of this patient subgroup is to minimise the disruption to cardiovascular physiology that may occur near the time of labour and delivery and to control the factors that impact on device integrity and function. We present the ante- and peripartum management of two pregnant women with an implantable cardioverter-defibrillator, followed by a review and update of the anaesthetic management of parturients with cardiac implantable electronic devices.

Traumatic arteriovenous fistula.

Traumatic arteriovenous fistula in the head and neck may present a difficult problem in management. We present a surgical case of traumatic arteriovenous fistula between the right subclavian artery and internal jugular vein with false aneurysm formation. Traumatic injury of the subclavian artery causing arteriovenous fistula with false aneurysm is a serious surgical emergency with appreciable morbidity and mortality that requires early recognition and prompt surgical intervention.

Venous ulcers in chronic venous insufficiency: King Khalid University Hospital experience.

BACKGROUND: The purpose of this study was to identify the anatomical location of the venous disease in C.V.I. patients presented with venous ulcers in addition to discussing the management. DESIGN: Retrospective study, at King Khalid University Hospital. METHODS: Between January 1991 to January 1997, 90 patients (63 females, 27 males) with CVI were evaluated. The evaluation included history, clinical examination, bidirectional ultrasound continuous wave Doppler, Duplex, ambulatory venous pressure (AVP), ascending and descending venography. RESULTS: Forty eight (48) patients (57 limbs) had Stage III with venous ulcers. Out of these 48 patients, fifteen (15) showed deep venous system involvement with deep vein thrombosis (DVT). Thirty three (33) patients had venous reflux in the superficial or deep systems without occlusion. Out of these 33 patients, 24 patients had superficial system reflux, while the remaining 9 patients revealed deep system reflux with a competent superficial system. CONCLUSIONS: Superficial venous incompetence plays a major role in venous ulcer formation and that location and type of venous disease should be thoroughly investigated as surgical excision of the superficial system leads to a long standing recurrence free period.

Intraoperative balloon angioplasty: a useful adjunct.

Intraoperative balloon angioplasty is a useful adjunct to a bypass procedure where the latter requires obvious enhancement of either inflow or outflow tracts. This retrospective study reviews experience with 62 patients (72 procedures) managed between January 1990 and January 1997 at UBC and KKUH. There were 36 men and 26 women. The indications were severe claudication in 44 (71%) patients and limb salvage in 18 (29%) patients. There were 42 cases of iliac artery (58%), 22 cases SFA (31%), and 8 cases pop/tibial (11%). The initial technical success for iliac balloon angioplasty was 90% (38 out of 42 cases), for SFA 91% (20 out of 22) and for popliteal/tibial 63%, (5 out of 8 cases). There were eight major complications, five of them treated surgically (7%), three patients needing amputations. The followup period ranged from 6 to 54 months with accumulated patency rate of 90% in iliac, 78% in SFA and 60% in pop/tibial in 12 months. Intraoperative angioplasty is a valuable adjunct to vascular surgery either to improve inflow or outflow in association with a reconstructive vascular procedure.

Groin lymphorrhea postoperative nuisance.

Lymphorrhea is defined as the flow of lymph from disrupted lymphatic channels that drains externally or is contained within a wound. It complicates approximately 2% of vascular incisions in the groin. Of 116 patients who underwent different arterial reconstructions involving 186 groin wounds, lymphorrhea developed in 4 patients (3.4%) including 4 groins (2.1%). They have been managed in the Division of Vascular Surgery at King Khalid University Hospital (KKUH) in Riyadh, during a 3-year period ending in February 1996. There were 105 (90.5%) males and 11 (9.5%) females. The ages ranged from 32 to 96 years with a mean age of 63 years. All the 4 cases complicated with lymphorrhea were managed conservatively for a period of three to five weeks. In 2 cases, the lymphatic leak stopped and the patients discharged without other local complications. In the other 2 cases, lymphatic leakage stopped immediately and permanently following direct surgical ligation. The use of isosulphane blue for localization of the site of the lymphatic leak was a simple, reliable and accurate method during wound exploration. Follow-up of all cases for 6 months showed no recurrence, no sepsis and patent vascular graft.

Neurobehavioral effects of carotid endarterectomy.

OBJECTIVE: Nineteen patients with symptomatic carotid stenosis (>70%) were subjected to carotid endarterectomy in a prospective study to evaluate neurobehavioral changes before and 6 months following the operation. METHODS: All patients were subjected to neurobehavioral rating scale one week before and 6 months after the operation. RESULTS: There were no significant changes in the 27 items of this scale before and 6 months following the operation. Some patients showed no difference at all in some items of this scale before and after operation such as suspiciousness excitement, speech and articulation using Mann-Whitney rank test, P values were (> 0.05) as regards to all items of neurobehavioral rating scale. CONCLUSION: Uncomplicated carotid endarterectomy does not seem to be associated with significant long time neurobehavioral impairment following the operation.

Neurobehavioral effects of carotid endarterectomy.

OBJECTIVE: Nineteen patients with symptomatic carotid stenosis (>70%) were subjected to carotid endarterectomy in a prospective study to evaluate neurobehavioral changes before and 6 months following the operation. METHODS: All patients were subjected to neurobehavioral rating scale one week before and 6 months after the operation. RESULTS: There were no significant changes in the 27 items of this scale before and 6 months following the operation. Some patients showed no difference at all in some items of this scale before and after operation such as suspiciousness excitement, speech and articulation using Mann-Whitney rank test, P values were (> 0.05) as regards to all items of neurobehavioral rating scale. CONCLUSION: Uncomplicated carotid endarterectomy does not seem to be associated with significant long time neurobehavioral impairment following the operation.