Mechanism, spectrum, consequences and management of hyponatremia in tuberculous meningitis

Hyponatremia is the commonest electrolyte abnormality in hospitalized patients and is associated with poor outcome. Hyponatremia is categorized on the basis of serum sodium into severe (< 120 mEq/L), moderate (120-129 mEq/L) and mild (130-134mEq/L) groups. Serum sodium has an important role in maintaining serum osmolality, which is maintained by the action of antidiuretic hormone (ADH) secreted from the posterior pituitary, and natriuretic peptides such as atrial natriuretic peptide and brain natriuretic peptide. These peptides act on kidney tubules via the renin angiotensin aldosterone system. Hyponatremia <120mEq/L or a rapid decline in serum sodium can result in neurological manifestations, ranging from confusion to coma and seizure. Cerebral salt wasting (CSW) and syndrome of inappropriate secretion of ADH (SIADH) are important causes of hyponatremia in tuberculosis meningitis (TBM). CSW is more common than SIADH. The differentiation between CSW and SIADH is important because treatment of one may be detrimental for the other; evidence of hypovolemia in CSW and euvolemia or hypervolemia in SIADH is used for differentiation. In addition, evidence of dehydration, polyuria, negative fluid balance as assessed by intake output chart, weight loss, laboratory evidence and sometimes central venous pressure are helpful in the diagnosis of these disorders. Volume contraction in CSW may be more protracted than hyponatremia and may contribute to border zone infarctions in TBM. Hyponatremia should be promptly and carefully treated by saline and oral salt, while 3% saline should be used in severe hyponatremia with coma and seizure. In refractory patients with hyponatremia, fludrocortisone helps in early normalization of serum sodium without affecting polyuria or functional outcome. In SIADH, V2 receptor antagonist conivaptan or tolvaptan may be used if the patient is not responding to fluid restriction. Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided

Substance P induces localization of MIF/α1-inhibitor-3 complexes to umbrella cells via paracellular transit through the urothelium in the rat bladder

BACKGROUND: Macrophage migration inhibitory factor (MIF) is released into the intraluminal fluid during bladder inflammation in the rat complexed to α1-inhibitor-3 (A1-I3; a rodent proteinase inhibitor in the α-macroglobulin family). The location of A1-I3 in the bladder had not been investigated. Therefore, we examined the location of A1-I3 and MIF/A1-I3 complexes in the bladder and changes due to experimental inflammation. METHODS: Anesthetized male rats had bladders removed with no treatment (intact) or were injected with Substance P (SP; s.c.; saline vehicle). After one hour intraluminal fluid was removed, bladder was excised and MIF and A1-I3 levels were determined using ELISA and/or western-blotting. MIF co-immunoprecipitation determined MIF/A1-I3 complexes in the bladder. Bladder sections were immunostained for A1-I3 and MIF/A1-I3. RESULTS: A1-I3 immunostaining was observed in interstitial spaces throughout the bladder (including submucosa) but not urothelium in intact and saline-treated rats. RT-PCR showed that the bladder does not synthesize A1-I3, therefore, A1-I3 in the interstitial space of the bladder must be plasma derived. In SP-treated rats, A1-I3 in the bladder increased and A1-I3 was observed traversing through the urothelium. Umbrella cells that do not show MIF and/or A1-I3 immunostaining in intact or saline-treated rats, showed co-localization of MIF and A1-I3 after SP-treatment. Western blotting demonstrated that in the bladder MIF formed non-covalent interactions and also binds covalently to A1-I3 to form high molecular weight MIF/A1-I3 complexes (170, 130 and 75-kDa, respectively, verified by co-immunoprecipitation). SP-induced inflammation selectively reduced 170-kDa MIF/A1-I3 in the bladder while increasing 170 and 130-kDa MIF/A1-I3 in the intraluminal fluid. CONCLUSION: A1-I3 and MIF/A1-I3 complexes are resident in bladder interstitium. During SP-induced inflammation, MIF/A1-I3 complexes are released from the bladder into the lumen. Binding of MIF/A1-I3 complexes to urothelial cells during inflammation suggests these complexes participate in the inflammatory reaction through activation of receptors for MIF and/or for A1-I3

Standardized methods for enhanced quality and comparability of tuberculous meningitis studies

Tuberculous meningitis remains a major cause of death and disability in tuberculosis endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of tuberculous meningitis clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrolment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention tuberculous meningitis studies should improve the quality of future research outputs, facilitate multi-centre studies and meta-analyses of pooled data, and could provide the foundation for a global tuberculous meningitis data repository

Screening intervals for diabetic retinopathy and incidence of visual loss: a systematic review

Screening for diabetic retinopathy can help to prevent this complication, but evidence regarding frequency of screening is uncertain. This paper systematically reviews the published literature on the relationship between screening intervals for diabetic retinopathy and the incidence of visual loss. The PubMed and EMBASE databases were searched until December 2012. Twenty five studies fulfilled the inclusion criteria, as these assessed the incidence/prevalence of sight‐threatening diabetic retinopathy in relation to screening frequency. The included studies comprised 15 evaluations of real‐world screening programmes, three studies modelling the natural history of diabetic retinopathy and seven cost‐effectiveness studies. In evaluations of diabetic retinopathy screening programmes, the appropriate screening interval ranged from one to four years, in people with no retinopathy at baseline. Despite study heterogeneity, the overall tendency observed in these programmes was that 2‐year screening intervals among people with no diabetic retinopathy at diagnosis were not associated with high incidence of sight‐threatening diabetic retinopathy. The modelling studies (non‐economic and economic) assessed a range of screening intervals (1–5 years). The aggregated evidence from both the natural history and cost‐effectiveness models favors a screening interval >1 year, but ≤2 years. Such an interval would be appropriate, safe and cost‐effective for people with no diabetic retinopathy at diagnosis, while screening intervals ≤1 year would be preferable for people with pre‐existing diabetic retinopathy. A 2‐year screening interval for people with no sight threatening diabetic retinopathy at diagnosis may be safely adopted. For patients with pre‐existing diabetic retinopathy, a shorter interval ≤1 year is warranted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100323/1/dme12274.pd

Mechanism, spectrum, consequences and management of hyponatremia in tuberculous meningitis

Hyponatremia is the commonest electrolyte abnormality in hospitalized patients and is associated with poor outcome. Hyponatremia is categorized on the basis of serum sodium into severe (< 120 mEq/L), moderate (120-129 mEq/L) and mild (130-134mEq/L) groups. Serum sodium has an important role in maintaining serum osmolality, which is maintained by the action of antidiuretic hormone (ADH) secreted from the posterior pituitary, and natriuretic peptides such as atrial natriuretic peptide and brain natriuretic peptide. These peptides act on kidney tubules via the renin angiotensin aldosterone system. Hyponatremia <120mEq/L or a rapid decline in serum sodium can result in neurological manifestations, ranging from confusion to coma and seizure. Cerebral salt wasting (CSW) and syndrome of inappropriate secretion of ADH (SIADH) are important causes of hyponatremia in tuberculosis meningitis (TBM). CSW is more common than SIADH. The differentiation between CSW and SIADH is important because treatment of one may be detrimental for the other; evidence of hypovolemia in CSW and euvolemia or hypervolemia in SIADH is used for differentiation. In addition, evidence of dehydration, polyuria, negative fluid balance as assessed by intake output chart, weight loss, laboratory evidence and sometimes central venous pressure are helpful in the diagnosis of these disorders. Volume contraction in CSW may be more protracted than hyponatremia and may contribute to border zone infarctions in TBM. Hyponatremia should be promptly and carefully treated by saline and oral salt, while 3% saline should be used in severe hyponatremia with coma and seizure. In refractory patients with hyponatremia, fludrocortisone helps in early normalization of serum sodium without affecting polyuria or functional outcome. In SIADH, V2 receptor antagonist conivaptan or tolvaptan may be used if the patient is not responding to fluid restriction. Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided