Maternal characteristics associated with place of delivery and neonatal mortality rates among very-low-birthweight infants,Georgia

To determine whether the Healthy People 2000 objective to deliver very-low-birthweight (VLBW) infants at subspecialty perinatal care centres was met, and if improvements in the regional perinatal care system could reduce neonatal mortality further for 2010, we examined place of delivery for VLBW infants, associated maternal characteristics and the potential impact on neonatal mortality. We used linked birth and death records for the 1994-96 Georgia VLBW (i.e. 500-1499 g) birth cohorts. Among 4770 VLBW infants, 77% were delivered at hospitals providing subspecialty perinatal care. The strongest predictor of birth hospital level was the mother's county of residence, defined using three levels: residence in a county with a subspecialty hospital, residence in a county adjacent to one with such a hospital or residence in a non-adjacent county. Eighty-nine per cent of infants born to women who resided in counties with subspecialty care hospitals delivered at such hospitals, compared with 53% of infants born to women who resided in a non-adjacent county. Women were also more likely to deliver outside subspecialty care if they had less than adequate prenatal care [adjusted odds ratio (AOR) 1.5, P-value = 0.0001]. The neonatal mortality rate varied by level of perinatal care at the birth hospital from 132.1/1000 to 283/1000 live births, with the highest death rate for infants born at hospitals offering the lowest level of care. Assuming that the differences in mortality were due to care level of the birth hospital, potentially 16-23% of neonatal deaths among VLBW infants could have been prevented if 90% of infants born outside subspecialty care were delivered at the recommended level. These findings suggest that a state's support of strong, collaborative, regional perinatal care networks is required to ensure that high-risk women and infants receive optimal health care. Improved access to recommended care levels should further reduce neonatal mortality until interventions are identified to prevent VLBW births.     

Plasmodium vivax MSP-1 peptides have high specific binding activity to human reticulocytes

Plasmodium vivax merozoites have high preferential ability to interact with and invade reticulocytes, although these cells correspond to only 2% of the red blood cells (RBC) population. P. vivax merozoite surface protein-1 (Pv-MSP-1) is believed to have an important role in attachment and invasion process. Using 88 non-overlapping 20-mer peptides, covering the entire Pv-MSP-1 Belem strain sequence, RBC and reticulocyte binding assays were performed. Fourteen sequences were identified with high specific binding activity to reticulocytes, but only three had high specific binding activity to mature erythrocytes. These peptides showed affinity constant values between 20 and 150nM, indicating a strong interaction between these sequences and reticulocyte receptors. Critical residues in binding to reticulocytes for these peptides were determined by competition binding assays with glycine scanning analogues. All high binding peptides bind to reticulocyte surface proteins having a molecular mass of around 18-20kDa which are not present in mature RBC. Interestingly, some high activity binding peptides (HABPs) are located close to the hypothesised 42 and 19kDa fragment cleavage sites for this protein, suggesting that these sequences have an important role in target cell attachment and invasion process by Pv-MSP-1.HABPs may be clustered in two regions, with region I being located between amino acids 280-719, and region II between amino acids 1060-1599 with higher than 25% identity level. A P. falciparum MSP-1 antigenic domain binds to RBCs and inhibits parasite invasion. Peptides 1721 and 1724 bind with high activity to reticulocytes in homologous Pv-MSP-1, suggesting similar functions for these two sequences.     

Biodistribution and internal dosimetry of the 188Re-labelled humanized monoclonal antibody anti-epidemal growth factor receptor, nimotuzumab, in the locoregional treatment of malignant gliomas

OBJECTIVE: To evaluate the biodistribution, internal radiation dosimetry and safety of the 188Re-labelled humanized monoclonal antibody nimotuzumab in the locoregional treatment of malignant gliomas. METHODS: Single doses of 370 or 555 MBq of 188Re-labelled nimotuzumab were locoregionally administered to nine patients with recurrent high-grade gliomas, according to an approved dose-escalation study. SPECT, planar scintigraphy and magnetic resonance images were combined for dosimetric and pharmacokinetic studies. Blood and urine samples were collected to evaluate clinical laboratory parameters and for absorbed doses calculations. Biodistribution, internal dosimetry, human anti-mouse antibody response and toxicity were evaluated and reported. RESULTS: The 188Re-nimotuzumab showed a high retention in the surgically created resection cavity with a mean value of 85.5+/-10.3%ID 1 h post-injection. It produced mean absorbed doses in the tumour region of approximately 24.1+/-2.9 Gy in group I (patients receiving 370 MBq) and 31.1+/-6.4 Gy in group II (patients receiving 555 MBq); the normal organs receiving the highest absorbed doses were the kidneys, liver and urinary bladder. About 6.2+/-0.8%ID was excreted by the urinary pathway. The maximum tolerated dose was 370 MBq because two patients showed severe adverse effects after they received 555 MBq of 188Re-nimotuzumab. No patient developed human anti-mouse antibody response. CONCLUSIONS: A locoregional single dose of 188Re-labelled nimotuzumab of approximately 370 MBq could be used safely in the routine treatment of patients suffering with high-grade gliomas. The efficacy of this therapy needs to be evaluated in a phase II clinical trial.     

Preliminary results of coloanal anastomosis

Coloanal anastomosis after resection of the rectum is the ultimate procedure to preserve the patient's sphincter and avoid a permanent colostomy. Carcinoma of the midrectum, and sometimes of the lower third of the rectum, may not require excision of the pelvic floor and anus for cure. A colonal anastomosis was achieved in 38 patients in whom the indications for surgery were carcinoma in 29, recurrent or extensive adenomas in four, radiation proctitis in two, rectal fistula following radical cystectomy in one, secondary low Hartmann reconstruction after a failed attempt in one, and stenosis of a very low colorectal anastomosis in one. Twenty-six patients were men and 12 women, with a mean age of 62. Dukes' staging for carcinoma were A: 9, B: 7, C: 11, and two had a palliative resection. The mean distance from the anus was 6.0 cm. All had a temporary defunctioning colostomy. There were no postoperative deaths and 17 (45 percent) had postoperative complications, major in 7 (18 percent), minor in 10 (26 percent). Mean follow-up is now 40 months (range, 12 to 64 months). Among patients who underwent curative resection, three have had pelvic recurrences. Two of these patients died of widespread distant disease and one underwent abdominoperineal resection and is now free of disease. All others are alive with no evidence of disease. The colostomy was closed in all but six (16 percent). Two (palliative) died within the colostomy and the other four are awaiting closure. Anastomotic stricture was the most common long-term problem, occurring in 16 and requiring more than one dilatation in eight. Six months after closing the colostomy, the mean daily number of bowel movements is 3.8. Twenty-six (87 percent) are continent to solid stools, two are incontinent to solid stools, and 16 have to wear a pad to prevent soiling. All but one prefer their present status to having their colostomy. In selected cases of rectal carcinoma with little or no extramural spread, the authors estimate that resection and colonal anastomosis is a good alternative with acceptable function and a low rate of recurrent disease, which is comparable to complete rectal excision but avoids a permanent colostomy. However, it should not be a substitute for standard abdominoperineal resection for extensive lower rectal carcinoma or for a colorectal anastomosis when the latter is technically feasible.     

A high prevalence of biallelic RPE65 mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy

Background: Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD), are primary causes of inherited childhood blindness. Both are autosomal recessive diseases, with mutations in more than 25 genes explaining approximately ~70% of cases. However, the genetic cause for many cases remains unclear. Sequencing studies from genetically isolated populations with increased prevalence of a disorder has proven useful for rare variant studies, making Costa Rica an ideal place to study LCA/EORD genetics.

Materials and Methods: Twenty-eight affected children (25 LCA, three EORD) and their immediate family members, totaling 52 individuals (30 affected) from 22 families, were sequenced. Whole exome sequencing was performed on all affected individuals. Available parents were analyzed either by whole exome sequencing (WES) or Sanger sequencing to determine transmission.

Results: All affected individuals demonstrated compound heterozygous or homozygous mutations in known Inherited Retinal Disease (IRD) associated genes. Twelve variants were identified in at least one individual in three genes, RDH12, RPE65, and USH2A. Four recurrent RPE65 mutations were observed in 97% of individuals and 95% of families. All patients with LCA and two of the three individuals with EORD had biallelic mutations in RPE65; one child with EORD had a homozygous RDH12 mutation.

Conclusions: These data suggest that the majority of LCA/EORD in Costa Rica is due to four founder mutations in RPE65 which have been maintained in this genetically isolated population. This finding is of great clinical significance due to the availability of gene therapy recently approved in the US and European Union for patients with biallelic RPE65 defects.     

Montelukast Inhibits Leukotriene Stimulation of Human Dendritic Cells in vitro

Background: Leukotrienes are potent inflammatory mediators which modulate immune responses and induce bronchoconstriction in susceptible individuals. Montelukast (MK) is a leukotriene receptor (CysLT1) antagonist that has been shown to prevent exacerbation of asthma. Considering the plethora of potential cellular targets for MK, specific mechanisms for its therapeutic action are still not fully understood. In vitro, we determined whether human dendritic cell function could be affected by leukotriene C(4) (LTC(4)) treatment and whether MK had potential in modulating this response. We also studied the effect of LTC(4) in the context of response to an airway virus (respiratory syncytial virus, RSV). Methods: Human monocyte-derived dendritic cells (moDCs) exposed to LTC(4), MK, or both, were cocultured with autologous T cells, with or without RSV. The effects of LTC(4) and MK on cell function were determined by ELISA and proliferation assays. Results: Both moDCs and their precursors - monocytes - express LTC(4) receptor CysLT1, making them potential targets for MK. moDCs cultured with LTC(4) release the eosinophil chemoattractant RANTES (CCL5) and induce greater T cell proliferation. Both were blocked by the presence of MK. MK treatment, albeit anti-inflammatory, did not interfere with the moDC-dependent T cell-proliferative responses induced by RSV. Conclusions: LTC(4), chronically present in the airways of asthma patients, could induce an exaggerated inflammatory response to airway infection via dendritic cell activation, which would be prevented by MK. Our study provides additional insight into the mechanisms of action of this leukotriene receptor antagonist.     

CD34 and SMA expression of superficial zone cells in the normal and pathological human meniscus

The aim of this study was to evaluate histological changes in torn (0.5-27 weeks after injury) and osteoarthritic (OA) knee menisci versus normal menisci after PAS-AB, SAF-O-FG, and immunostaining for CD34, CD31, and smooth muscle actin (SMA). Cell layers in the superficial zone and the cell density in the deep zone of the menisci were counted. In the superficial zone of normal menisci, cells expressing CD34 were demonstrated. CD34(+) CD31(-) cells were absent in OA menisci and disappeared in torn menisci as a function of time. In contrast, an increase of SMA(+) cells combined with an increase of cell layers was observed in the superficial zone of torn menisci. SMA(+) cells were absent in normal and OA menisci. The predominant tissue type in torn menisci evolved from fibrocartilage-like to fibrous-like tissue as a function of time, whereas in OA menisci it became cartilage-like. The response of the superficial zone was reflected by the decrease of CD34(+) and the increase of SMA(+) cells in torn menisci and the transformation of a fibrous-like into a cartilage-like surface layer in OA menisci. These results potentially illustrate the contribution of CD34(+) cells to the homeostasis of meniscus tissue.     

Small intestinal transplantation

The purpose of this study was to determine whether small intestinal transplantation could be considered as an alternative in the treatment of patients suffering from the short-bowel syndrome. The site of absorption of oral cyclosporine A was determined as were the changes that follow small intestinal transplantation. The interactions between the lipophilic cyclosporine A molecule and fat emulsion solutions used for total parenteral nutrition were investigated. Finally, a technique for harvesting the entire small bowel in man was developed. The absorption of oral cyclosporine A in normal dogs, and in bowel-resected, autotransplanted, and allotransplanted dogs was determined. Cyclosporine A levels were monitored in all animals. This demonstrated that cyclosporine A is absorbed through the small bowel and carried through the lymphatics; that absorption is decreased to 40 percent of normal after autotransplantation or allotransplantation without rejection. Rejection further hampers cyclosporine A absorption. Administration of olive oil alone enhances absorption of cyclosporine A. We also administered cyclosporine A IV to five dogs, with and without a concomitant infusion of fat emulsion solution (Intralipid). No changes in plasma cyclosporine A levels, in the clearance of cyclosporine A, or in the in vivo distribution of cyclosporine A were noted. Finally, dissections in six cadavers and in four brain-dead organ donors were performed, and a reproducible technique for harvesting the small bowel in man was established. In selected patients with the short-bowel syndrome, small intestinal transplant may be considered as an alternative therapy to home total parenteral nutrition.     

Right Atrial Thrombus Mimicking a Myxoma: Synergism of Hormonal Contraceptives and Antiphospholipid Antibodies

Cardiac thrombus, the most common intracardiac mass, is typically seen in the left side of the heart in the presence of atrial fibrillation, mitral stenosis, or impaired global wall motion. Right atrial thrombus, which is rarer, is usually associated with central venous catheter placement or pulmonary embolism. We present the case of a 24-year-old woman with a history of mitral valve prolapse who presented with fatigue and palpitations. Echocardiograms and cardiac magnetic resonance images revealed a right atrial mass compatible with a myxoma. However, after surgical excision of this and a second mass discovered intraoperatively, pathologic evaluation confirmed organized thrombus rather than myxoma.The patient''s only risk factor was her use of oral contraceptive pills. Test results for hypercoagulable disorders revealed the presence of antiphosphatidylserine, an uncommon antiphospholipid antibody. The patient stopped taking the contraceptive. This case suggests the need to examine further the role of antiphosphatidylserine antibodies in the diagnosis of antiphospholipid syndrome.