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.

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.

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.

Vascular compromise associated with supracondylar fractures in children.

OBJECTIVE: Our aim was to study the significance of persistently absent radial pulse, with monophasic doppler flow after close reduction percutaneous pinning of displaced supracondylar fracture of humerus, and the need of early exploration of brachial artery in such cases. METHODS: Between July 1992 and 1999, 86 children with Grade III supracondylar fracture of humerus were treated at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia The history, physical examination, vascular status of limb before and after close reduction percutaneous pinning of fracture were recorded. All children having persistently absent radial pulse and monophasic flow doppler signals after close reduction percutaneous pinning under went exploration of brachial artery. RESULTS: Of the 86 children with Grade III supracondylar fracture of humerus, 6 had persistently absent radial pulse with monophasic flow doppler signals after close reduction percutaneous pinning. Five children had one warm pink well perfused hand and one cold pale poorly perfused hand. All 6 under went exploration of brachial artery and were found to have entrapped artery at the fracture site. There was an immediate return of radial pulse with triphasic Doppler flow on release of brachial artery. CONCLUSION: Persistently absent radial pulse with objectivity, obtained by doppler ultrasound in the form of absent or monophasic flow in radial artery, is a reliable indicator of vascular compromise. Surgical exploration of brachial artery by a competent surgeon is to be carried out to avoid early and late complication, of pulseless limb in children with displaced supracondylar fracture of humerus.

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.

Effect of arteriovenous fistula for hemodialysis on limb circulation.

The number of patients with end-stage renal disease maintained on chronic hemodialysis is increasing progressively. Arteriovenous fistula (AVF) is a common vascular access for hemodialysis, however, its effect on limb distal circulation has not been studied well. Palpation of pulse at the wrist is a crude method of clinical assessment. Over one year period, 26 AVFs were created; 16 at the wrist (61.5%) and ten fistulas at the elbow (38.5%). Six of the latter were through the brachio-basilic approach while the other four were performed by basilic vein transposition. Doppler measurement of both wrist-brachial index (WBI) and finger pressure was carried out for all patients pre-operatively and on the first post-operative day. Of the patients with AVF created at the elbow, there was a decrease of WBI in seven patients (70%) and a decrease of finger pressure in three (30%); one patient (14%) had steal syndrome. Creation of AVF at the wrist resulted in a decrease of WBI in one patient (6.25%) and a decrease of finger pressure in another patient (6.25%). WBI changes as a result of creation of AVF at the elbow were significantly greater than the changes of those fistulas performed at the wrist (P < 0.001). On the other hand, the difference between the effect of both procedures on finger pressure was statistically not significant. These results may help to explain the higher incidence of steal syndrome in patients with elbow fistulas compared to patients with wrist fistulas. Further studies on a larger scale are required to determine the value of non-invasive indices at which AVF creation would have future risk of compromised distal limb circulation.

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.

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.

Central vein stenosis in patients with prior subclavian vein catheterization for maintenance dialysis.

We evaluated the prevalence of central vein stenosis in patients with prior central vein catheterization for vascular access for hemodialysis. A total of 36 patients with end-stage renal disease (ESRD) who were referred to the division of vascular surgery at King Khalid University Hospital in Riyadh were evaluated. Bilateral ascending venogram was performed in all cases. The patients were divided into three groups: Group I included 38 extremities in 32 patients who were referred for construction of an arteriovenous fistula. All these patients had previous history of subclavian vein catheterization. This included six patients who had bilateral catheter insertion. Venography demonstrated greater than 50% central vein lesions in 13 of the 38 extremities yielding a prevalence of 34%. Group II included four extremities in four patients who were on hemodialysis for many years all of whom presented with features suggestive of venous obstruction in their already existing arteriovenous fistulae. All four patients gave history of prior subclavian vein catheterization for dialysis. Three of these patients had > 50% subclavian vein stenosis while one showed complete occlusion of the vein. Group III included 30 extremities without history of prior central vein cannulation and none of them showed any lesions on venography. Our study further confirms previous reports that show a high prevalence of central vein stenosis following use of subclavian catheter as vascular access. We suggest that the subclavian route should be abandoned in patients with ESRD and temporary venous cannulation, if needed, should be performed in the femoral or internal jugular veins. Also, in individuals with history of prior central vein cannulation, venography is strongly recommended before an arteriovenous fistula is made.

Vascular injuries associated with limb fractures.

The records of 46 patients with vascular injuries of the lower and upper limbs associated with bone fractures and managed in the authors' vascular and orthopaedics divisions were reviewed. All were young men, 26 with blunt and 20 with penetrating vascular injuries; 20 were treated by end to end anastomosis, 12 by vein interposition grafting, six by prosthetic graft, six by vein patches and lateral sutures and two by ligations. The limb salvage rate was 93 per cent. Three patients died (6.5 per cent) of severe associated injuries. Amputations were needed in three patients (6.5 per cent) with popliteal, tibial arteries and vein injuries. An aggressive approach to limb salvage is needed in these extensive injuries.

Klippel-Trénaunay syndrome: clinical features, complications, and management.

Klippel-Trénaunay Syndrome (KTS) is rare and not well recognized among most physicians, which has lead to inappropriate management and delayed referral in many cases. Presented herein is the largest series ever reported from a single center in Saudi Arabia, comprised of 18 patients seen between 1990 and 1996, whose clinical features, complications, and management are discussed. All 18 patients had large angiomatous navei, hypertrophy of the soft tissue with bone overgrowth in the lower limbs, and extensive lower limb varicosities, which extended to the buttocks and lower abdomen in 2 patients. There were 4 patients who had undergone at least one operation for lower limb varicose veins prior to referral. The diagnostic workup and treatment for KTS is discussed in detail. It is essential that physicians understand how this complex syndrome presents, and the most appropriate means of investigating and managing it, to avoid unnecessary surgery being performed prior to referral to a specialist center.

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.