Neuroprotective strategies in parkinson’s disease: protection against progressive nigral damage induced by free radicals

Brain undergoes neurodegeneration when excess free radicals overwhelm antioxidative defense systems during senescence, head trauma and/or neurotoxic insults. A site-specific accumulation of ferrous citrate-iron complexes in the substantia nigra dopaminergic neurons could lead to exaggerated dopamine turnover, dopamine auto-oxidation, free radical generation, and oxidant stress. Eventually, this iron-catalyzed dopamine auto-oxidation results in the accumulation of neuromelanin, a progressive loss of nigral neurons, and the development of Parkinson's disease when brain dopamine depletion is greater than 80%. Emerging evidence indicates that free radicals such as hydroxyl radicals ((.-)OH) and nitric oxide ((.-)NO) may play opposite role in cell and animal models of parkinsonism. (.-)OH is a cytotoxic oxidant whereas oNO is an atypical neuroprotective antioxidant. (.-)NO and S-nitrosoglutathione (GSNO) protect nigral neurons against oxidative stress caused by 1-methyl-4-phenylpyridinium (MPP(+)), dopamine, ferrous citrate, hemoglobin, sodium nitroprusside and peroxynitrite. MPP(+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), increases the nigral uptake of iron complexes and dopamine overflow leading to the generation of (.-)OH, protein oxidation, lipid peroxidation, and associated retrograde degeneration. In addition to GSNO, MPP(+)-induced oxidative neurotoxicity can be prevented by antioxidants including selegiline, 7-nitroindazole, 17beta-estradiol, melatonin, alpha-phenyl-tert-butylnitrone and U78517F. Similar to selegiline, 7-nitroindazole is a MAO-B inhibitor, which blocks the bio-activation of MPTP and oxidative stress. Freshly prepared but not light exposed, (.-)NO-exhausted GSNO is about 100 times more potent than the classic antioxidant glutathione. Via S-nitrosylation, GSNO also inhibits proteolysis and cytotoxicity caused by caspases and HIV-1 protease. Furthermore, in addition to protection against serum deprivation stress, the induction of neuronal NOS1 in human cells increases tolerance to MPP(+)-induced neuro-toxicity since newly synthesized (.-)NO prevents apoptosis possibly through up-regulation of bcl-2 and down regulation of p66(shc). In conclusion, reactive oxygen species are unavoidable by-products of iron-catalyzed dopamine auto-oxidation, which can initiate lipid peroxidation, protein oxidation, DNA damage, and nigral loss, all of which can be prevented by endogenous and exogenous (.-)NO. Natural and man-made antioxidants can be employed as part of preventative or neuroprotective treatments in Parkinson's disease and perhaps dementia complexes as well. For achieving neuroprotection and neuro-rescue in early clinical parkinsonian stages, a cocktail therapy of multiple neuroprotective agents may be more effective than the current treatment with extremely high doses of a single antioxidative agent.     

Pharmacokinetics of tacrolimus and mycophenolic acid are altered, but recover at different times during hepatic regeneration in rats.

Hepatic regeneration is very critical to the success of living donor liver transplantation, which allows a reduced size liver to grow in size to accommodate the requirements of both the donor and the recipient. The objectives of this study were to evaluate 1) the hepatic metabolism of the two immunosuppressive drugs, tacrolimus and mycophenolic acid (MPA), and 2) the pharmacokinetics of tacrolimus and mycophenolic acid at various time points after initiation of hepatic regeneration by partial hepatectomy in rats. The hepatic intrinsic clearance of tacrolimus was decreased to 70% and 51% of the control level at the 24th h and the 6th day, respectively, but returned to normal level by day 14. The total body clearance of tacrolimus was reduced transiently but recovered completely by day 18. The hepatic intrinsic clearance of MPA was decreased to 52% and 51% of that in control rats at the 24th h and the 6th day, respectively, but recovered to normal level by day 14. The total body clearance of MPA was reduced at the 24th h but recovered by day 6. The magnitude of reduction in the clearance of tacrolimus and MPA was much smaller than what was predicted from in vitro data. The elimination clearance of MPA glucuronide was also impaired during hepatic regeneration but recovered to normal level with time. In conclusion, the pharmacokinetics of tacrolimus and mycophenolic acid were altered during hepatic regeneration but recovered completely at different rates over time. Caution must be exercised in extrapolating in vitro data to in vivo conditions during hepatic regeneration.     

Maffucci syndrome: Case report and review of diagnostic signs of the rare disease

Maffucci syndrome is a non-hereditary congenital condition that affects the skin and skeleton. Enchondromas (benign cartilage enlargements), bone abnormalities, and venous anomalies (hemangiomas) are all symptoms. Enchondromas occur as a result of mesodermal dysplasia and have the potential to become cancerous. They are most commonly found on the phalanges and long bones. Venous abnormalities commonly manifest themselves as soft lumps or tumors on the distal extremities. A 19-year-old boy presented with swellings on his fingers and left foot since the age of 5, along with a few bluish soft tissue swellings on his left heel. Multiple expansile lytic lesions and soft tissue swellings with phleboliths were seen on X-ray. Histology confirmed the diagnosis of hemangiomas and enchondromas. Soft tissue swellings were found to have hyper echoic areas, as well as modest marginal blood flow on Doppler, which could indicate hemangiomas. Maffucci syndrome was identified, and treatment with a multidisciplinary approach was initiated. Maffucci syndrome is a rare genetic illness reported in the literature less than 200 times. The enchondromas and hemangiomas have a strong link to malignant changes, with chondrosarcomas accounting for 30% of the associated malignancies. On X-ray, enchondromas are easily identified as osteolytic lesions with cortex thinning and endosteal scalloping while color Doppler ultrasound detects the presence of hemangiomas. Phleboliths are easily identified as small calcifications on X-rays. Radiographic examinations should be considered in patients presenting with bone or soft tissue swellings for an early diagnosis of Maffucci syndrome.     

Feasibility study for measuring patients’ visual acuity at home by their caregivers

Purpose:To assess the feasibility of measuring patients’ visual acuity (VA) in their homes by their caregivers.Methods:Patients consulting in a tertiary eye care institute were prospectively enrolled with informed consent. All underwent standard COMPlog distance VA testing. Patients and caregivers were oriented to test distance VA using the Peek Acuity app. The app was installed on the caregiver’s or patient’s smartphone. The patient’s VA was measured by the caregiver in the clinic (baseline value) under supervision. After 1 week, the caregivers recorded the patient’s VA with the Peek Acuity app at their home and reported the value in a telephone consultation. A questionnaire to assess the ease of using the app was administered at both the baseline visit and 1 week later.Results:A total of 100 patients (age group: 13 to 76 years) and 100 caregivers (age group: 17 to 65 years) participated. VA measurements with the Peek Acuity app were comparable with COMPlog (P > 0.1) both during the baseline and after 1-week measurement, regardless of the underlying ocular condition or educational level of the caregivers/patients. Most caregivers (95%) felt the app was easy to use.Conclusion:Though the Peek Acuity app was originally developed for health care workers to be used in field visits, we found that with proper orientation, the layperson can also use it. Such orientation can enable caregivers to effectively measure VA at home. Such a tool would enhance teleophthalmology consultations and can minimize the need for short follow-up visits.     

Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease

JUSTIFICATION: Acute rheumatic fever and rheumatic chronic valvular heart disease is an important preventable cause of morbidity and mortality in suburban and rural India. Its diagnosis is based on clinical criteria. These criteria need verification and revision in the Indian context. Furthermore, there are glaring differences in management protocols available in literature. These facts prompted Indian Academy of Pediatrics to review the management of rheumatic fever. PROCESS: Management of Rheumatic fever was reviewed and recommendation was formulated at national consultative meeting on 20th May 2007 at New Delhi. OBJECTIVES: To formulate uniform guidelines on management of acute rheumatic fever and rheumatic heart disease in the Indian context. Guidelines were formulated for the management of streptococcal pharyngitis, acute rheumatic fever and its cardiac complication as well as secondary prophylaxis for recurrent episodes. RECOMMENDATIONS: (1) Streptococcal eradication with appropriate antibiotics (Benzathine penicillin single dose or penicillin V oral or azithromycin). (2) Diagnosis of rheumatic fever based on Jones criteria. (3) Control inflammatory process with aspirin with or without steroids (total duration of treatment of 12 weeks). (4) Treatment of chorea according to severity (therapy to continue for 2-3 weeks after clinical improvement). (5) Protocol for managing cardiac complication like valvular heart disease, congestive heart failure and atrial fibrillation. (6) Secondary prophylaxis with benzathine penicillin and management of anaphylaxis.     

Efficacy of erenumab and factors predicting response after 3 months in treatment resistant chronic migraine: a clinical service evaluation

BackgroundCalcitonin gene-related peptide (CGRP) inhibitors have been developed as options for treatment of chronic and episodic migraine. We present our experience of the use of erenumab in a tertiary headache centre.MethodsThis was a prospective clinical audit of all patients commenced on erenumab following a locally agreed pathway and criteria over a consecutive period. Patients received monthly erenumab 140 mg for 3 months. Data were collected prospectively at baseline and 3 months follow up.ResultsOne hundred three patients were commenced on erenumab during the study period. Patients had tried a median of 7 previous prophylactics, including onabotulinum toxin A in 94%. At 3 months there was a reduction in median total (28 to 20, 29% reduction, p < 0.0001) and severe (15 to 5, 67% reduction, p < 0.0001) headache days. 39.8% of patients achieved at least a 30% reduction in total headache days; 61.8% of patients achieved at least a 50% reduction in severe headache days. Meeting either of these thresholds was considered a positive response, 68% of patients achieved this. Presence of daily headache pattern was negatively associated with response, (56% response vs. 90% without daily headache, p = 0.0003). There was no association between age, gender, presence of medication overuse or number of previously tried prophylactic treatments and response to erenumab. 43% of patients reported at least one adverse effect, most commonly constipation (26%); treatment was discontinued in 3 patients due to adverse effects.ConclusionsErenumab was an effective treatment for chronic migraine in this treatment resistant population over 3 months of follow up. Presence of daily headache predicted poorer response but there was still a significant positive response rate in this group.     

Multiple bladder calculi: a rare cause of irreducible uterine prolapse

Background A vesical calculus in a prolapsed cystocele is rare. Objective To highlight bladder calculi as a cause of irreducible uterine prolapse. Case Report A case of irreducible total uterine prolapse caused by multiple vesical calculi is presented. Bladder stones were removed through vaginal cystolithotomy followed by vaginal hysterectomy. Conclusion In cases of acute irreducible pelvic organ prolapse, the possibility of bladder stones should be kept in mind and X-ray pelvis including the prolapsed mass should be done to confirm the diagnosis.