Transplantation of bone marrow-derived mesenchymal stem cells ameliorated dopamine system impairment in a D-galactose-induced brain ageing in rats.

BACKGROUND: Ageing is the primary risk factor for Parkinson's disease. Progressive motor and coordination decline that occurs with ageing has been linked to nigrostriatal dysfunction. Few studies have investigated the efficacy of mesenchymal stem cells in ameliorating the structural and functional alterations in the ageing nigrostriatal system. This study is the first to evaluate the effects of intravenous injection of bone marrow-derived mesenchymal stem cells (BMMSCs) in a D-galactose- induced rat model of nigrostriatal ageing. MATERIALS AND METHODS: BMMSCs were intravenously injected once every 2 weeks for 8 weeks. The transplanted cells survived, migrated to the brain, and differentiated into dopaminergic neurones and astrocytes. RESULTS: BMMSC transplantation improved locomotor activity, restored dopaminergic system function, preserved atrophic dopaminergic neurones in the substantia nigra, exerted antioxidative effects, and restored neurotrophic factors. CONCLUSIONS: Our findings demonstrate the efficacy of BMMSC injection in a nigrostriatal ageing rat model, and suggest that these cells may provide an effective therapeutic approach for the ageing nigrostriatal system.

Low-dose rituximab is efficacious in refractory idiopathic inflammatory myopathies.

OBJECTIVES: Rituximab (RTX) use early in the course of refractory idiopathic inflammatory myopathy (IIM) is not well studied. This study sought to determine the short-term efficacy of RTX in a registry-based cohort of refractory IIM. METHODS: Registry-based observational data about IIM patients receiving RTX between 2018 and 2021 were included. Total improvement score was calculated from the core set measures as per International Myositis Assessment and Clinical Studies group (IMACS) at baseline, 6 months and 12 months of follow-up. RESULTS: Forty-two patients (F:M, 29:13), with a mean (s.d.) age of 39.5 (11.5) years were studied. Majority of patients received RTX for refractory myositis, after a median (interquartile range) duration of 8 (4,18) months. Twenty-eight received RTX at a dosage of 1 g × two doses, while 14 received 500 mg × two doses with an interval of 15 days. At 6 months and 12 months post-RTX, the improvement was recorded in manual muscle testing (MMT-8) scores, physician global assessment (PGA), patient global assessment (PtGA) and median steroid dosage as compared with the baseline (P < 0.01 for all). A mean (s.d.) improvement of 44.5 (16) and 48.7 (19.2) in total improvement score was recorded at 6 and 12 months, respectively. The change in MMT-8, PGA and PtGA scores from baseline between the two dosage regimens of RTX were comparable at 6 and 12 months. Severe lower respiratory tract infections requiring hospitalization occurred in three patients of the cohort. CONCLUSION: RTX improved IMACS core set measures and had steroid sparing efficacy at 6 and 12 months in patients with IIM in this registry-based study. Rituximab as an induction regimen of two doses of 500 mg can be as efficacious as 1 g at 6 months and 12 months of follow-up.

Preventive effects of bone marrow-derived mesenchymal stem cell transplantation in a D-galactose-induced brain aging in rats.

BACKGROUND: Aging is a complex process accompanied by numerous morphological, functional, and metabolic impairments in the brain, and a critical risk factor involved in the increasing incidence of neurodegenerative diseases. Few studies have evaluated the efficacy of different sources of mesenchymal stem cells (MSCs) in ameliorating the early morphological and functional alterations in the aging brain. This study, for the first time, evaluated the potential efficacy of intravenous injection of bone marrow-derived mesenchymal stem cells (BMMSCs) in a D-galactose-induced rat model of brain aging. MATERIALS AND METHODS: BMMSCs (1 × 106) were intravenously injected into brain aging model rats once every 2 weeks for 8 weeks. RESULTS: The transplanted cells survived and migrated to the brain, and differentiated into astrocytes and neurons, including choline acetyltransferase neurons. BMMSC transplantation improved locomotor activity and cognitive functions, restored cholinergic system function, protected atrophic cholinergic neurons in the basal forebrain, induced antioxidative effects and restored neurotrophic factors, and modulated hippocampal synaptic plasticity by upregulating PSD95 and Egr1 expression. CONCLUSIONS: Our findings demonstrated the efficacy of BMMSC injection in an aging rat model and suggest that these cells may be developed into an effective cell therapy for the aging brain.

Prevalence and Clinical Correlates of Myositis Specific Autoantibodies in Idiopathic Immune-Mediated Inflammatory Myositis - Results from a Multicentric Cohort (MyoIN) from India.

There is a need to understand the clinical and antibody associations in patients with IIM in various ethnicities and geographical areas. Patients who fulfilled Bohan's and Peter criteria of IIM and seen between October 2017 through Jan 2020 were enrolled in this study at 3 centres. Clinical and relevant laboratory parameters were recorded in a pre designed case record form. MSA and MAA to 16 antigens were performed by line blot assay using Euroimmun (Luebec, Germany) as per manufacturer's instruction. Of the 150 patients, 13 were juvenile onset. Ninety sera had either one MSA or MAA. Sixty sera had neither MSA/MAA. anti-Ro 52 were the commonest antibody and anti-Mi-2α and b the commonest MSA. Novel associations identified were severe myositis with anti-Ro 52, cutaneous ulcerations with anti-MDA5 and anti-PM-Scl and calcinosis with anti-PM-Scl. One-third sera had no MSA or MAA. Larger sample size and use of antibody assays together with muscle biopsy will improve subtyping and phenotype associations in IIM.

Citicoline improved cardiovascular function in animal model of dysautonomia.

The autonomic nervous system controls cardiovascular function. Autonomic dysfunction or dysautonomia is commonly encountered in several diseases like Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a chemical that changes into the neurotoxin MPP+, which causes catecholamine depletion. We aimed to study the effects of citicoline on cardiovascular function in MPTP-treated albino rats. Twenty-four male albino rats were divided into four groups (6 rats/group): negative control received intraperitoneal (i.p.) saline injection for five consecutive days, a positive control (Citicoline group) received citicoline (250 mg/kg) by oral gavage for consecutive 20 days, MPTP treated with MPTP-HCL (30 mg/kg, i.p.) for five consecutive days, MPTP + citicoline treated with MPTP-HCL (30 mg/kg, i.p.) for five consecutive days followed by treatment with oral doses of citicoline (250 mg/kg) for 20 days. Cardiovascular functions evaluated through recording electrocardiogram (ECG), echocardiography, measuring arterial blood pressure and assessment of aortic rings vascular reactivity. Biochemical measurements on cardiac tissue for tyrosine hydroxylase, norepinephrine, glucose transporter 1 (GLUT1), insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ co-activator-1 (PPAR-γ co-activator-1) (PGC-1), phosphatase and tensin homolog-induced kinase 1 (PINK1), carnitine palmitoyltransferase I (CPT1), uncoupling protein 2 (UCP2) and adenosine monophosphate-activated protein kinase alpha 2 (AMPKα2). Citicoline increased cardiac norepinephrine and tyrosine hydroxylase and improved markers related to ROS scavenger, mitochondrial permeability, calcium homeostasis on the cellular level, metabolic homeostasis, and mitochondrial biogenesis. We conclude that citicoline improved cardiovascular dysautonomia and that was reflected on cardiac contractility, electrical activity, blood pressure, and vascular reactivity.

Surgical management of primary appendiceal malignancy.

AIM: Primary appendiceal neoplasms are rare, with carcinoid being more common than carcinoma. Preoperative diagnosis is infrequent. We report a series of 24 primary appendiceal neoplasms treated over a 5-year period. METHOD: All primary appendiceal neoplasms diagnosed in a university teaching hospital between April 2003 and June 2008 were identified from the prospective histopathology database. Patient records were reviewed for clinical, operative and pathological data. RESULTS: Fourteen carcinomas and 10 carcinoids were identified in the 5-year period. The former presented at median age 55.8 years with median symptom duration of 35 days, compared with 48 years and 3 days, respectively, for carcinoids. An abdominal mass was commoner in carcinomas (8/14 vs 1/10). Six patients with carcinoma underwent appendicectomy followed by completion right-hemicolectomy, two of whom had residual disease; seven underwent primary right-hemicolectomy and one had abscess drainage. Five patients with appendiceal carcinoma died of the disease during a median follow-up of 633 (256-1158) days. Six patients underwent appendicectomy for acute appendicitis, one had a primary right-hemicolectomy for a caecal mass. Three had a subsequent right-hemicolectomy for a high-risk carcinoid. An appendiceal carcinoid was an incidental finding in three right-hemicolectomy specimens removed for other indications. No metastases or deaths were recorded at median follow-up 451 (51-975) days. CONCLUSION: Appendiceal carcinomas follow a more protracted clinical course than carcinoids, which usually present as acute appendicitis. Caution is needed when diagnosing simple appendicitis in older patients with longer symptom duration, particularly if a mass is present. Patients with appendiceal carcinoma should be offered completion right-hemicolectomy. Carcinoma has a poor prognosis.

Incidental focal colonic lesions found on (18)Fluorodeoxyglucose positron emission tomography/computed tomography scan: further support for a national guideline on definitive management.

AIM: (18)Fluorodeoxyglucose ((18)FDG) positron emission tomography/computed tomography (PET/CT) is an established part of staging in a wide variety of malignancies. Incidental abnormal uptake of (18)FDG of unknown significance is frequently encountered. Therefore, we investigated patients with abnormal colonic uptake of (18)FDG, determined by PET/CT images, using colonoscopy. METHOD: The radiology reports of all patients referred to a tertiary referral centre for a PET/CT scan were reviewed retrospectively. Patients with abnormal colonic uptake of (18)FDG were identified and the PET/CT findings were correlated with colonoscopic findings. RESULTS: Of 555 consecutive patients identified over a 26-month period, 53 had abnormal colonic uptake of (18)FDG, as determined by PET/CT images. Twenty-nine were not investigated following discussion in a specialist multidisciplinary (MDT) meeting, according to local protocol. Twenty out of 24 patients investigated by endoscopy had a colonic lesion correlating to the site identified on the PET/CT image: 16 patients had tubulovillous adenomas (nine of which were > 10 mm), two had invasive adenocarcinomas, two had diverticular disease and one had collagenous colitis; no colonic lesion was detected in three. These findings were incidental and not related to the primary diagnosis for which the scan was being performed. Accordingly, a positive predictive value of 83% is associated with the finding of abnormal uptake of (18)FDG on PET/CT images. CONCLUSION: Incidental abnormal colonic uptake of (18)FDG, determined by a PET/CT scan requires definitive colonic investigation in patients suitable for further treatment because significant colonic pathology is frequently identified. The benefit of this approach should be discussed in specialist MDT meetings and tailored to each patient; however, national guidelines for management are required.

V-Y advancement flap for treatment of fistula-in-ano.

PURPOSE: The management of high fistula-in-ano presents a difficult surgical challenge. Laying open of high transsphincteric, intersphincteric, and suprasphincteric fistulas is associated with incontinence. Mucosal advancement flap can be technically difficult and is associated with ectropion and incontinence. We report a new technique for the treatment of fistulas, which may eliminate these problems. PATIENTS AND METHODS: Between 1997 and 2002, 18 patients (13 males), median age 46 (range, 25-64) years with high fistula-in-ano were treated. There were ten transsphincteric, four intersphincteric, and four suprasphincteric fistulas. In all patients, perianal sepsis was allowed to resolve completely with a drainage seton before definitive surgery. The surgical technique used involved core fistulectomy, curettage of any cavity, closure of the defect in the internal anal sphincter, and a V-Y advancement buttock flap to cover the internal opening, leaving the site of the external opening for drainage while preserving both internal and external sphincters. Outcome was assessed in terms of healing and continence. RESULTS: Most patients were discharged from the hospital within 48 hours. Median follow-up was 19 (range, 3-60) months. There were three patients who failed to heal. Of these, two underwent repeat surgery and healed. Two further patients had recurrent fistulas, both of whom continued with conservative treatment. Overall, 15 of 18 (83 percent) patients experienced healing of their fistula. Continence was preserved in all patients. CONCLUSION: This procedure is easy to perform, healing is rapid, and it appears to be effective in curing fistula-in-ano while preserving both external and internal anal sphincters.

Nanofiltration of single plasma donations: feasibility study.

BACKGROUND AND OBJECTIVES: Major technical developments have been made in recent years to improve the quality and safety of human plasma for transfusion and fractionation. The present study was performed to assess, for the first time, the feasibility of applying a nanofiltration process, using 75-nm and 35-nm mean pore size membranes (Planova) 75N and Planova 35N), to human plasma. MATERIALS AND METHODS: Ten apheresis plasma units were obtained from 10 plasma donors. Within 4 h of collection, plasma was subjected to leucoreduction and filtration (using 75-nm and 35-nm mean pore size membranes) at 35 degrees C, at less than 1 bar pressure. Aliquots of plasma were taken at all steps of the filtration procedure and numerous plasma quality parameters were measured. In addition, six hepatitis C virus (HCV)-positive plasma donations were experimentally subjected to the same filtration sequence and subsequently assessed by RNA polymerase chain reaction (PCR) and branched-chain DNA-quantification assays. RESULTS: Leucoreduced plasma can be reproducibly nanofiltered onto a sequence of 75-nm and 35-nm membranes, at a flow rate of 450 ml/h and a temperature of 35 +/- 0.5 degrees C. Some protein dilution, or loss, was found during filtration, but the plasma filtered through membranes with a mean pore size of 75 nm and 35 nm met in vitro specifications for use in transfusion or fractionation. There were no signs of activation of the coagulation system. HCV-positive plasma donations became negative, as judged by PCR and branched-chain DNA assay results, after filtration through the 35-nm membrane. CONCLUSIONS: It is possible to apply a 75 + 35-nm filtration process to leucoreduced human plasma. This technology may have important future benefits in improving the quality and safety of plasma, by removing blood cell debris and infectious agents.

Defunctioning loop ileostomy and stapled side-to-side closure has low morbidity.

INTRODUCTION: Low pelvic anastomoses are associated with a high leak rate. Therefore, defunctioning loop ileostomies are being increasingly fashioned to protect against the consequences of a leak. However, the reported complication rates of such stoma creation and closure is between 5.7-69%. AIMS: To determine the outcome associated with construction and side-to-side closure of loop ileostomies in one specialist unit. PATIENTS AND METHODS: Data were obtained from a computer audit and case note analysis. RESULTS: Between 1994 and 1998, 71 patients (41 M, 30 F) with a median age of 51 years (range 19-88 years) had a loop ileostomy constructed for: (i) 26 ileoanal pouches; (ii) 36 left colonic and rectal resections; and (iii) 9 for other reasons. Side-to-side stoma closure was achieved using a GIA linear stapler through a parastomal incision. The median hospital stay following stoma creation was 12 days (range 7-63 days) and stoma closure was 7 days (range 6-16 days). The median time to closure was 140 days (range 10-790 days). There were no ileostomy-related deaths. There were 10 (13.8%) ileostomy-related complications, 4 following creation and 6 following closure. CONCLUSIONS: Loop ileostomy is easy to create and close and is associated with a low morbidity. Therefore, we recommend a defunctioning ileostomy as a procedure of choice for temporary faecal diversion for complex colorectal surgery.

[Further experiences with transplantation of the head of the fibula]. / Weitere Erfahrungen mit der Transplantation des Fibulakopfes.

We are presenting our experience with vascularized epiphyseal transplantation of the upper end of the fibula, based distally on the anterior tibial artery in two patients, one suffering from septic epiphysitis of the hip with complete loss of the head and neck of the femur, the other suffering from radial club hand following septic loss of the radius, excluding its proximal and distal articular segments. In the first patient, the fibular epiphysis bridged the bone defect and provided growth at the neck of the femur. This restored hip stability, reduced limb-length discrepancy, initiated some degree of acetabular development, and maintained a functional range of hip motion. In the second patient, transplantation of the upper end of the fibula was used to bridge a gap resulting from complete resorption of the right radius and provide for growth of the radius. At follow-up, complete union of the graft was noted. The club-hand appearance improved markedly. Pronation and supination were regained. However, donor-site morbidity was a problem. It included sloughing of part of the peroneal muscles and the skin edge of the incision. This was due to loss of the anterior tibial artery as well as injury to the peroneal vessel collaterals supplying the skin and peroneal muscles. The latter occurred due to opening of the posterior compartment of the leg in an attempt to locate the anterior tibial artery at its origin from the popliteal artery. It is therefore concluded, that transplantation of the upper end of the fibula is a valuable reconstructive alternative for septic epiphysitis with complete loss of the head and neck of the femur as well as for septic loss of the radius. However, whenever an extended part of the upper end of the fibula needs being harvested, this should be performed through an anterior approach, in order to avoid sloughing of the skin and muscles of the anterior and lateral compartments of the leg.

Lateral repair of parastomal hernia.

INTRODUCTION: Parastomal hernia is a common complication of stoma construction. Although the majority of patients are asymptomatic, about 10% require surgical correction. AIMS: We describe a new surgical approach for the repair of parastomal hernias, which avoids both the need for laparotomy and stoma mobilization. PATIENTS AND METHODS: Nine patients (4 female) with parastomal hernia underwent surgical repair. Median age was 55 years (range 38-73 years). There were 8 para-ileostomy herniae and one paracolostomy hernia. A lateral incision was made approximately 10 cm from the stoma, and carried down to the rectus sheath. The dissection was carried medially towards the stoma, and around the defect in the abdominal musculature. The hernia sac was excised when possible and the fascial defect closed with non-absorbable, monofilament suture. A polyprolene mesh was placed round the stoma by making a slit in the mesh. The skin was closed with subcuticular monofilament absorbable suture. RESULTS: All patients returned to normal diet on the first postoperative day, and were discharged from hospital within 72 h. There were no wound infections, and no recurrences after a median follow up of 6 months (range 3-12 months). DISCUSSION: The technique we describe is simple and avoids the need of laparotomy. The mucocutaneous junction of the stoma is not disturbed, reducing the risk of contamination of the mesh, stenosis or retraction of the stoma. Grooving of the stoma and difficulty in fitting appliances is avoided because the wound is not placed near the mucocutaneous junction. This approach may be superior to other mesh repairs for parastomal hernia.

Reconstruction after resection of tumors around the knee: role of the free vascularized fibular graft.

We present our experience with reconstruction after resection of tumors around the knee, using free vascularized fibular grafting. The study included 23 patients. The lower femur was involved in 17 cases, the upper tibia in 6. The cases included giant cell tumor of the lower femur (2 patients), giant cell tumor of the upper tibia (1 patient), malignant fibrous histiocytoma of the lower femur (1 patient), parosteal osteosarcoma (1 patient), and periosteal osteosarcoma (1 patient). The remaining patients suffered from conventional osteogenic sarcomas. The size of the defect ranged from 12 to 16 cm in length. Skin flap necrosis after tumor resection was the most common complication encountered. Other complications included peroneal nerve involvement in one case and rupture of the arterial anastomosis in another. All transferred fibulas progressed to union within 7-9 months. Union time of both upper and lower ends of the fibula and time of appearance of periosteal reaction were identical. In evaluating periosteal hypertrophy of the fibula, the hypertrophy (de Boer) index (de Boer HD, Wood MB, J Bone Joint Surg 1989;71B:374-378) proved unreliable. False positive results are obtained, when callus formation around the lower end of the femur is far more abundant than at the upper end of the fibula. For this reason, we introduced the graft index. The latter is the ratio between the diameter of the graft at its thinnest portion at latest follow-up to its diameter on the day of operation, as calculated on plain radiographs. Two of the viable fibulas developed stress fractures after plate removal. Functional and quality-of -life results were satisfactory. It is concluded that the free vascularized fibular graft remains a valuable reconstruction option after the resection of tumors around the knee, provided certain precautions are followed. First, before closure of the wound, the skin flaps should be assessed for their viability. Necrotic parts should be excised. Stable fixation is a necessary prerequisite at the time of operation. Removal of the fixation device should not be guided by union or periosteal hypertrophy, but by true widening of the medullary canal.

HLA-DO-related restriction fragment length polymorphisms in rheumatoid arthritis: evidence for a link with disease expression.

Eighty-three patients with rheumatoid arthritis (RA) were investigated for HLA-DQ and DR locus restriction fragment length polymorphisms (RFLP). Of the 83 patients, 61 (73%) possessed the DR4 allele and within this group we have investigated the relative frequencies of two DQ beta gene variants of DQw3, DQw7 and DQw8, one of which we had previously found to be raised in Felty's syndrome. This analysis revealed a significantly higher frequency of DQw7 containing haplotypes in DR4 positive rheumatoid patients (64%) than in DR-matched healthy controls (42%). Furthermore, the distribution of DQw7 was biased towards those patients with greater disability indicated by the HAQ score, more systemic disease and higher titres of rheumatoid factor, suggesting that DQw7 may contribute to disease expression.

Virological markers and antibody responses in fulminant viral hepatitis.

Clinical profiles, serological markers, and antibody responses to antigens of hepatitis B virus (HBV) were studied in patients with fulminant viral hepatitis. Whereas hepatitis A and B were found to be uncommon causes (6.9% and 12.2%, respectively), non-A, non-B (NANB) hepatitis was found to be the most common cause of fulminant hepatitis (80.9%). As against this, the incidence of hepatitis B and NANB hepatitis was very similar in nonfulminant acute viral hepatitis in adults (41.2% and 51.9%, respectively). Pregnancy with labour was an important precipitating factor for development of fulminant hepatitis of the NANB type only; 32% of fulminant NANB hepatitis patients were pregnant women and 22.6% had a history of labour preceding hepatic coma. Only 0.8% of nonfulminant NANB hepatitis cases were pregnant women. Another major precipitating factor for the development of the fulminant form of NANB hepatitis was concomitant chronic HBV carrier state. A total of 38.6% of fulminant NANB hepatitis patients were HBV carriers, whereas only 19.2% of nonfulminant acute NANB hepatitis cases were HBV carriers. Sera of 32 chronic HBV carriers with fulminant NANB hepatitis and 10 cases of fulminant hepatitis B were tested for delta antibody, and all were nonreactive. The antibody responses of the fulminant hepatitis B patients to the antigens of HBV were found to be greater compared to those of patients with nonfulminant acute hepatitis B. Antibody responses of chronic HBV carriers with fulminant NANB hepatitis to antigens of HBV were found to be depressed in comparison with those of chronic asymptomatic carriers.