Granulocyte macrophage colony stimulating factor (GM-CSF), the critical intermediate of inflammation-induced fetal membrane weakening, primarily exerts its weakening effect on the choriodecidua rather than the amnion.

INTRODUCTION: We have previously demonstrated two associations of PPROM, (1) inflammation/infection (modeled by tumor necrosis factor (TNF)) and (2) decidual bleeding (modeled by thrombin), both decrease fetal membrane (FM) rupture strength in-vitro. Furthermore, Granulocyte-Macrophage-Colony-Stimulating-Factor (GM-CSF) induced by both TNF and thrombin is a critical intermediate, necessary and sufficient for weakening by either agent. The amnion is the strength component of FM and must weaken for FM to rupture. It is unclear whether GM-CSF weakens amnion (AM) directly, or initially targets choriodecidua (CD) which secondarily releases agents to act on amnion. METHODS: Full thickness FM fragments were treated with/without GM-CSF. Some were preincubated with alpha-lipoic acid (LA), a known inhibitor of FM weakening. The FM fragments were then strength-tested. Separately, FM fragments were initially separated to AM and CD. AM fragments were cultured with Medium ± GM-CSF and then strength-tested. In other experiments, CD fragments were cultured with Medium, GM-CSF, LA, or LA + GM-CSF. Conditioned medium from each group was then incubated with AM. AM was then strength-tested. Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) were analyzed by Mutiplex Elisa. RESULTS: GM-CSF weakened intact FM which was blocked by LA. GM-CSF did not weaken isolated AM. However, GM-CSF conditioned CD media weakened AM and this weakening was inhibited by LA. GM-CSF treatment of CD increased MMPs 2, 9, and 10, and decreased TIMPs 1-3. LA reversed these effects. CONCLUSIONS: GM-CSF does not weaken amnion directly; GM-CSF acts on CD to increase proteases and decrease anti-proteases which secondarily weaken the amnion.

In an in-vitro model using human fetal membranes, α-lipoic acid inhibits inflammation induced fetal membrane weakening.

INTRODUCTION: We established an in-vitro model for the study of human fetal membrane (FM) weakening leading to pPROM. In this model, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical intermediate for both tumor necrosis factor-α (TNF; modeling infection/inflammation) and thrombin (modeling decidual bleeding/abruption)-induced weakening. Thus, inhibitors of FM weakening can be categorized as targeting GM-CSF production, GM-CSF downstream action, or both. Most progestogens inhibit both, except 17-α hydroxyprogesterone caproate which inhibits FM weakening at only one point, GM-CSF production. α-lipoic acid (LA), an over-the-counter dietary supplement, has also been previously shown to inhibit TNF and thrombin induced FM weakening. OBJECTIVE: To determine the point of action of LA inhibition of FM weakening. METHODS: FM fragments were mounted in Transwell inserts and preincubated with/without LA/24 h, then with/without addition of TNF, thrombin or GM-CSF. After 48 h, medium was assayed for GM-CSF, and FM fragments were rupture-strength tested. RESULTS: TNF and thrombin both weakened FM and increased GM-CSF levels. GM-CSF also weakened FM. LA inhibited both TNF and thrombin induced FM weakening and concomitantly inhibited the increase in GM-CSF in a concentration-dependent manner. In addition, LA inhibited GM-CSF induced FM weakening in a concentration dependent manner. CONCLUSIONS: LA blocks TNF and thrombin induced FM weakening at two points, inhibiting both GM-CSF production and downstream action. Thus, we speculate that LA may be a potential standalone therapeutic agent, or supplement to current therapy for prevention of pPROM related spontaneous preterm birth, if preclinical studies to examine feasibility and safety during pregnancy are successfully accomplished.

Hypoglycemia in the preterm neonate: etiopathogenesis, diagnosis, management and long-term outcomes.

Glucose, like oxygen, is of fundamental importance for any living being and it is the major energy source for the fetus and the neonate during gestation. The placenta ensures a steady supply of glucose to the fetus, while birth marks a sudden change in substrate delivery and a major change in metabolism. Hypoglycemia is one of the most common pathologies encountered in the neonatal intensive care unit and affects a wide range of neonates. Preterm, small for gestational age (GA) and intra-uterine growth restricted neonates are especially vulnerable due to their lack of metabolic reserves and associated co-morbidities. Nearly 30-60% of these high-risk infants are hypoglycemic and require immediate intervention. Preterm neonates are uniquely predisposed to developing hypoglycemia and its associated complications due to their limited glycogen and fat stores, inability to generate new glucose using gluconeogenesis pathways, have higher metabolic demands due to a relatively larger brain size, and are unable to mount a counter-regulatory response to hypoglycemia. In this review we will discuss the epidemiology; pathophysiology; clinical presentation; management and neurodevelopmental outcomes in affected infants and summarize evidence to develop a rational and scientific approach to this common problem.

To evaluate stereoacuity in patients with acquired esotropia and to determine factors associated with favourable outcomes.

AIM: To evaluate stereoacuity in patients with acquired esotropia and determine the factors associated with favorable outcomes. MATERIALS AND METHODS: A total of 68 subjects aged 6 years and above were included in the study. Thorough clinical evaluation including binocular status examination using the Bagolini-striated glass test, The Netherland Organization (TNO), and Randot stereo test were done. The subjects were divided into two groups 1 and 2, based on the amount of deviation. Statistical analysis of the result was performed. RESULT: The duration of misalignment in the group with deviation less than or equal to 8 prism diopters (PD) was 1.49 ± 0.86 years, whereas in the group with deviation more than or equal to 10 PD was 4.64 ± 2.99 years (P = 0.000). Among the subjects in group 1, 89.5% achieved fusion and 52.6% had stereoacuity on both TNO and Randot, whereas in group 2 40% achieved fusion and 3.3% stereopsis on both TNO and Randot (one case with only coarse stereopsis). A subanalysis within group 1 revealed a statistically significant difference for the duration of misalignment (P = 0.02), but a marginal difference for the amount of deviation (P = 0.3). CONCLUSION: A horizontal deviation up to 8 PD was compatible with stereopsis. Also, the duration of constant misalignment affects the attainment of stereopsis despite successful realignment.

Evaluation of periosteal fixation of lateral rectus and partial VRT for cases of exotropic Duane retraction syndrome.

PURPOSE: The purpose of this study is to evaluate the lateral rectus periosteal fixation and partial vertical rectus transpositioning (VRT) as treatment modalities to correct exotropic Duane retraction syndrome (Exo-DRS). MATERIALS AND METHODS: Prospective interventional case study of cases of Exo-DRS with limitation of adduction. A total of 13 patients were subdivided into two groups. Six patients underwent only lateral rectus periosteal fixation (group A) and seven patients also underwent partial VRT (group B). Assessment involved prism bar cover test, abduction and adduction range, extent of binocular single visual field and exophthalmometry. These tests were repeated at 1 week, 1 month and 3 months post-operatively and data analyzed. RESULTS: The pre-operative mean values and ranges were 26.2 Δ (22-35) exotropia for group A and -21.3 Δ (14-30) exotropia for group B. The post-operative mean and range was +0.6 Δ esotropia (+20 to -8) for group A and 8 Δ (-2 to -20) exotropia for group B. Mean grade of limitation of abduction changed from -3.8 to -3.6 versus -3.6 to -2.8 and mean grade of limitation of adduction changed from -1.9 to -0.7 versus -1.5 to -0.5 in the groups A and B respectively. Mean binocular single visual field changed from 14.7° to 23.3° in group A and 11.8° to 26.4° in the group B respectively. CONCLUSION: Lateral rectus periosteal fixation is an effective surgery to correct the exodeviation, anomalous head posture and improving adduction in Exo-DRS and partial VRT in addition is effective in improving abduction and binocular single visual fields.

Evaluation of FD2 (Frisby Davis distance) stereotest in surgical management of intermittent exotropia.

AIM: To evaluate Frisby Davis distance (FD2) stereotest for determining the timing of surgical intervention in intermittent exotropia (X(T)). METHODS: A prospective case-control study was conducted including 30 patients with X(T) and 30 age-matched controls. Stereoacuity was measured preoperatively and 3 months postoperatively using FD2 for distance and TNO and Randot for near. RESULTS: Preoperative distance stereoacuity was 43.83 ± 35.51 arcsec (median 30 arcsec; range 10-120) which improved postoperatively to 27 ± 33.74 arcsec (median 15 arcsec; range 5-120) (p=0.001). Cases with FD2 stereoacuity worse than 70 arcsec did not show significant improvement. Mean preoperative near stereoacuity by TNO was 94.00 ± 79.48 arcsec (median 60 arcsec) and Randot was 50.33 ± 39.23 arcsec (median 30 arcsec) which improved to 80.00 ± 80.08 arcsec (median 60 arcsec) and 34.17 ± 57.00 arcsec (median 20 arcsec), respectively, after surgery (both p=0.001). The controls had a mean distance stereoacuity of 14.66 ± 4.13 arcsec (median 15 arcsec; range 5-20) and near stereoacuity of 63.00 ± 21.35 arcsec (median 60 arcsec (TNO)) and 23.66 ± 5.07 arcsec (median 20 arcsec (Randot)). There was a significant correlation between FD2 and Randot in the cases but not in controls (p=0.005), however no correlation was found between TNO and FD2. CONCLUSIONS: Distance stereoacuity is reduced in X(T) to a greater extent than the near stereoacuity and both improve after surgery. FD2 is useful for deciding timing of surgery and a stereoacuity worse than 20 arcsec is an indication for surgical intervention. A preoperative distance stereoacuity which is worse than 70 arcsec implies a poor prognosis for stereoacuity improvement after surgery.