Heterogeneity of obstructive sleep apnea phenotypes after ischemic stroke: Outcome variation by cluster analysis.

INTRODUCTION: Obstructive sleep apnea (OSA) is common but under-recognized after stroke. The aim of this study was to determine whether post-stroke phenotypic OSA subtypes are associated with stroke outcome in a population-based observational cohort. METHODS: Ischemic stroke patients (n = 804) diagnosed with OSA (respiratory event index ≥10) soon after ischemic stroke were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) project. Functional, cognitive, and quality of life outcomes were assessed at 90 days post-stroke and long-term stroke recurrence was ascertained. Latent profile analysis was performed based on demographic and clinical features, pre-stroke sleep characteristics, OSA severity, and vascular risk factors. Regression models were used to assess the association between phenotypic clusters and outcomes. RESULTS: Four distinct phenotypic clusters provided the best fit. Cluster 1 was characterized by more severe stroke; cluster 2 by severe OSA and higher prevalence of medical comorbidities; cluster 3 by mild stroke and mild OSA; and cluster 4 by moderate OSA and mild stroke. Compared to cluster 3 and after adjustment for baseline stroke severity, cluster 1 and cluster 2 had worse 90-day functional outcome and cluster 1 also had worse quality of life. No difference in cognitive outcome or stroke recurrence rate was noted by cluster. CONCLUSION: Post-stroke OSA is a heterogeneous disorder with different clinical phenotypes associated with stroke outcomes, including both daily function and quality of life. The unique presentations of OSA after stroke may have important implications for stroke prognosis and personalized treatment strategies.

Nose-to-brain delivery of paliperidone palmitate poloxamer-guar gum nanogel: Formulation, optimization and pharmacological studies in rats.

Oral delivery of paliperidone palmitate (PPD), a potent antipsychotic agent, has been reported with a potential risk of very serious drug-induced adverse events such as tachycardia, hyperprolactinemia, sexual dysfunction, and neutropenia. Alternatively, the potential of nasal delivery has also been explored to treat CNS complications by delivering the medicines directly to the brain bypassing the blood-brain barrier. Hence, the objectives of current work were to formulate, design, optimize, and investigate the therapeutic potency of PPD-loaded intranasal in-situ gel (PPGISG) in the treatment of schizophrenia. PPD-nanoemulsion (PNE) was fabricated using water titration technique, was further optimized via Box-Behnken design. Furthermore, the optimized PNE was evaluated for parameters such as globule size, polydispersity index, zeta potential, and % entrapment efficiency were found to be 21.44±1.58nm, 0.268±0.02, -25.56±1.6mV, and 99.89±0.25%, respectively. PNE was further converted to PPGISG utilizing two polymers, poloxamer, and guar gum. Simultaneously, ex-vivo permeation for PNE, PPGISG, and PPD-suspension was found to be 211.40±4.8, 297.89±3.9 and 98.66±1.6µg/cm2, respectively. While PPGISG nanoparticles showed 1.58 and 5.65-folds more Jss than PNE and PPD-suspension. Behavioral studies confirmed that no extrapyramidal symptoms were observed in experimental animals post intranasal administration. Finally, the outcomes of the in-vivo hemato-compatibility study proved that intranasal formulation did not cause any alteration in leukocytes, RBCs, and neutrophils count. Therefore, intranasal delivery of PPGISG can be considered a novel tool for the safe delivery of PPD in schizophrenic patients.

A forward modelling approach for the estimation of oxygen extraction fraction by calibrated fMRI.

The measurement of the absolute rate of cerebral metabolic oxygen consumption (CMRO2) is likely to offer a valuable biomarker in many brain diseases and could prove to be important in our understanding of neural function. As such there is significant interest in developing robust MRI techniques that can quantify CMRO2 non-invasively. One potential MRI method for the measurement of CMRO2 is via the combination of fMRI and cerebral blood flow (CBF) data acquired during periods of hypercapnic and hyperoxic challenges. This method is based on the combination of two, previously independent, signal calibration techniques. As such analysis of the data has been approached in a stepwise manner, feeding the results of one calibration experiment into the next. Analysing the data in this manner can result in unstable estimates of the output parameter (CMRO2), due to the propagation of errors along the analysis pipeline. Here we present a forward modelling approach that estimates all the model parameters in a one-step solution. The method is implemented using a regularized non-linear least squares approach to provide a robust and computationally efficient solution. The proposed framework is compared with previous analytical approaches using modelling studies and in vivo acquisitions in healthy volunteers (n=10). The stability of parameter estimates is demonstrated to be superior to previous methods (both in vivo and in simulation). In vivo estimates made with the proposed framework also show better agreement with expected physiological variation, demonstrating a strong negative correlation between baseline CBF and oxygen extraction fraction. It is anticipated that the proposed analysis framework will increase the reliability of absolute CMRO2 measurements made with calibrated BOLD.

Use of 5% lidocaine medicated plasters for the treatment of pain in routine hospital practice: patient reported pain, functioning and satisfaction.

OBJECTIVE: 5% lidocaine medicated plasters are a topical option in the treatment of peripheral neuropathic pain, as monotherapy or as an adjunct to systemic medication. This study sought to determine the impact of lidocaine plaster use on self-reported pain, functioning and patient satisfaction within a large teaching hospital. RESEARCH DESIGN AND METHODS: Patients were selected from the pain and rheumatology outpatient departments in Cardiff, Wales (2008-9). Postal surveys were sent to patients prescribed lidocaine plaster asking whether patients currently used the plaster and, if not, reason for discontinuation. Patients were asked to record pain score before and after therapy initiation, percentage pain relief, duration of effectiveness and impact on functioning. MAIN OUTCOME MEASURES: Pain scores, pain relief and levels of functioning before and after treatment. RESULTS: A total of 850 surveys were dispatched; 408 (48.0%) responses received; 197 (48.3%) patients were current users at survey completion. Median pain score prior to plaster use was 8 (IQR 7-9). One month after initiation, median pain score was 6 (4-8, p < 0.001) overall and 5 (4-7, p < 0.001) for current users. Median pain relief, after initial month of plaster use, was 30% (10-60%) for all patients and 50% (30-70%) for current users, whilst pain relief at time of survey was 30% (0-60%) and 50% (30-70%), respectively. A total of 181 (93.3%) current users claimed the plasters were effective. All three measures of functioning were significantly improved in current users: sleep (63.3% versus 20.1%, p < 0.001), mood (59.2% versus 18.6%, p < 0.001) and activity level (50.0% versus 19.5%, p < 0.001). Median satisfaction was 5 (IQR 1-8) for all patients and 7 (5-9) for current plaster users. CONCLUSIONS: The results of this study need to be considered within the context of a self-reported survey. However, pain, functioning and patient satisfaction were significantly improved in current users of 5% lidocaine medicated plasters.

Response of Dry Bean Genotypes to Fusarium Root Rot, Caused by Fusarium solani f. sp. phaseoli, Under Field and Controlled Conditions.

Fusarium root rot of dry bean (Phaseolus vulgaris), caused by Fusarium solani f. sp. phaseoli, is a major yield-limiting disease in North Dakota and Minnesota. Although a few sources of partial resistance are available, most commercial cultivars grown in this region are susceptible, especially in the red kidney bean market class. This study evaluated three methods of screening for resistance to Fusarium root rot. A sand-cornmeal inoculum layer method, spore suspension method, and paper towel method were used to evaluate 11 dry bean genotypes for resistance to Fusarium root rot under growth-chamber conditions. These same genotypes were also evaluated in field trials at Fargo, ND, and Park Rapids and Perham, MN, in 2005. In all trials, the small red genotype VAX 3 was found to have a consistently high level of resistance to Fusarium root rot and could be used as a source of resistance by dry bean breeders. Correlation analyses between field and growth-chamber root rot ratings indicated that all three growth-chamber methods had significantly (P ≤ 0.05) positive correlations with field results from Perham and Fargo, which suggests that all three methods could be used to screen germplasm efficiently for resistance to Fusarium root rot.

Response of Canola Cultivars to Sclerotinia sclerotiorum in Controlled and Field Environments.

Sclerotinia stem rot (SSR), caused by Sclerotinia sclerotiorum, can be a devastating disease of canola (Brassica napus) in the northern United States. No canola cultivars are marketed as having resistance to SSR. Field trials were established in Red Lake Falls, MN (2001, 2003, and 2004) and Carrington, ND (2001, 2002, 2003, and 2004) to evaluate canola cultivars for resistance to SSR. These cultivars also were evaluated for resistance to SSR under controlled conditions using the following methods: petiole inoculation technique (PIT), detached leaf assay (DLA), and oxalic acid assay (OAA). Significant (P ≤ 0.05) differences were detected among cultivars for SSR and yield in the field trials, with SSR levels varying from low to high among years and locations. Cultivars with consistent high levels and low levels of SSR in the field trials were identified. Significant (P ≤ 0.05) differences were detected among cultivars for SSR using the PIT and OAA methods, but not the DLA method. No significant (P ≤ 0.05) correlations between SSR levels in the controlled studies with SSR levels in the field trials were detected; however, significant negative correlations were detected between SSR area under the disease process curve values from the PIT method and yield from Carrington, ND in 2001 and 2002. Although the PIT and OAA methods differentiated cultivars, neither method was able to predict the reaction of cultivars to SSR in the field, indicating that field screening for SSR resistance is still critical for the development of resistant cultivars.

Preimplantation genetic diagnosis of chromosomal abnormalities by multicolour fluorescence in situ hybridisation.

Preimplantation genetic diagnosis (PGD) is an early diagnosis of genetic disorders, prior to the onset of pregnancy. PGD incorporates the latest techniques in assisted reproduction and molecular genetics. Embryos or oocytes are biopsied during culture in vitro and genetic analysis is carried out on the blastomeres or polar bodies. Embryos shown to be free of the genetic disease under investigation are transferred to the uterus. Multicolour fluorescence in situ hybridisation (FISH) is used to diagnose numerical and certain structural abnormalities of chromosomes in the embryo. The common probes used are for chromosomes 13, 18, 21, X and Y. FISH can also be used for PGD of translocations, when one of the parents is a carrier. PGD was carried out recently in 4 cases using multicolour FISH. In one of the embryos, trisomy 18 was detected. Tetraploidy was seen in another embryo. Only chromosomally normal embryos were transferred back to the uterus. Care has to be taken while interpreting FISH signals as the signal may be split, diffused, superimposed or in a different focus.

FGF signaling is essential for the early events in the development of the chick nervous system and mesoderm.

Fibroblast growth factor (FGF) belongs to a family of polypeptides with diverse biological functions. In the present study we have assessed the role of FGF signaling in the development of nervous system and mesodermal tissues in chick embryo. Treatment of in vitro cultured embryos with exogenous, human recombinant FGF led to abnormalities in neural induction and development, notochord formation and somitogenesis as studied by gross morphology and histology. Overall growth and development was also adversely affected as seen from the measurement of body axis length. Further, treatment of embryos with FGF resulted in differential modulation of expression of two genes important in normal development as studied by whole mount in situ hybridization using DIG-labeled riboprobes. The expression of Brachyury, which is necessary for mesoderm formation, was down-regulated in FGF-treated embryos. The expression of noggin, the product which participates in the patterning of the chick neural tube was, on the other hand, up-regulated within 2 h. We also studied development of neural and mesodermal tissues in conditions where FGF signaling was defective. This was achieved by culturing the embryos in the presence of suramin. In the presence of low doses of suramin (100-150 nmole/culture), abnormalities were detected mainly in the mesodermal structures while at higher doses (200-400 nmole/culture), the nervous system too was found to be abnormal in a large proportion of embryos. Treatment of chick embryos with suramin (200 nmole/culture) also modulated the expression of Brachyuryand noggin within a 2 h period. The results showthat FGF signaling plays an important role in the molecular events leading to the development of nervous system and mesodermal tissues in the chick embryo.

Comparative performance of pearl millet- and sorghum- based diets vs. wheat- and rice-based diets for trace metal bioavailability.

Pearl millet and sorghum offer a cheap source of energy compared to wheat and rice and are widely consumed by rural communities in many parts of the world. Due to the low consumption of vegetables and animal foods, millets also are the major suppliers of micronutrients especially for low-income groups. It is of prime importance to study how millets perform in terms of bioavailable contents of trace metals. Investigations were carried out using weanling mice which offer a model for the initial testing of bioavailability of trace metals before human trials. Four isocaloric diets differing only in the type of cereal, i.e. pearl millet, sorghum, wheat and rice, were prepared representing habitual dietary patterns observed by National Nutrition Monitoring Bureau (NNMB) of India. Mice were allocated randomly to 4 groups of 8 mice each, and housed individually in metal free metabolic cages. A fifth group of 8 mice fed a balanced synthetic diet served as control. All the groups were fed ad libitum. The absorption of zinc and iron averaged for 3 periods of 5 days each was significantly higher for the wheat and pearl millet group than for the other 2 experimental groups (p < 0.05), as were also the levels of liver zinc and iron. The weight gain was also highest (6.9 +/- 1.2 g) in the pearl millet group as compared to sorghum (1.58 +/- 0.59 g), wheat (1.66 +/- 1.27 g) and rice (-0.72 +/- 0.62 g) groups. The levels of liver copper were comparable in all the 5 groups. These results further confirm our earlier in vitro results indicating the superiority of pearl millet but not sorghum in bioavailability of zinc and iron.

Gender differentials in the social impact of leprosy.

Prevalence rates of leprosy have reduced considerably in many states where multidrug therapy is in operation. However, reduction in prevalence alone is not sufficient as the social consequences of the diseases on the life of the patient are often severe and persist even after its cure. The present paper, therefore, investigates social impact with special reference to gender differentials. Data obtained from structured questionnaires (n = 606) is analysed for this purpose. It was observed that the initial delay in identifying the skin changes as the symptoms of the disease were higher for females (29 months) than males (24 months). Even after identifying the symptoms, women were observed to depend exclusively on nonmedical treatment for a longer period (10 months) than males (6 months). Upon starting the medical treatment females were observed to be more compliant than males, but the benefits of regularity appeared to be outweighed by the initial delay in starting medical treatment. The social impact on daily life was more severe for females than males as revealed by the isolation from daily activities, such as, restrictions on participation in familial functions, restrictions on touching children. The paper highlights implications of gender bias on detection and treatment, and suggests modifications for control programmes.

Double jeopardy: women and leprosy in India.

This article presents evidence from two states of India, Bihar and Maharashtra, on the process of "dehabilitation" among male and female leprosy patients, and suggests gender-sensitive interventions to address existing problems in leprosy control. While the study investigated a wide range of gender differences in the impact of leprosy, this article focuses on only two-marriage and family reactions. Important gender differences were apparent in the impact of the disease. While both men and women were negatively affected in terms of their family and marital lives, women suffered more isolation and rejection. Psychologically, women appeared more vulnerable because they were deprived of personal contact with others in the domestic environment where they were accustomed to receiving their greatest emotional rewards. Women reported that indifference to them by other family members, or seeming negation of their presence, caused them the greatest suffering. This underscores the importance of providing information to both leprosy patients and their families about the disease and its treatment, including the possibility of cure with MDT (multi-drug therapy) and of counselling family members about their crucial role in helping patients cope and recover. This support is even more critical for women, who often lack access to the variety of outside advice and assistance available to men. The evidence presented in the article demonstrates the importance of analysing leprosy from a gender perspective, not only because this approach helps to inform our understanding of the determinants and consequences of the disease, but also because it provides new insights for improved disease control.

PIP: As part of a larger study of gender differences in the stigmatization connected with leprosy in India as well as in its detection and treatment, this article presents data on the impact of leprosy on marriage and the family. A review of previous studies shows that women's immune responses to leprosy may be weakened by pregnancy, that congenital transmission is possible but rare, and that affected women may not receive counseling about risks of pregnancy or the side effects of the drugs they are given. The present study gathered data from 2495 inhabitants of Bihar and Maharashtra including 934 who were receiving treatment and living relatively normal lives (59% male), 300 members of their families, 1071 who had to leave home or a job (63% male), 100 who were rehabilitated (55% male), and 90 health workers treating the patients. Additional data were gathered from in-depth interviews and 25 case studies (13 males). The findings of this study, including the fact that the impact of leprosy was greater for women because they suffered more isolation and rejection than men, led to the following conclusions: 1) in order to improve early detection and treatment of women, they should be encouraged to seek treatment for any skin ailments; 2) leprosy workers should alleviate concerns about the efficacy of smaller pills and should counsel families about the importance of the medical regimen; 3) women should be counseled about the risks of pregnancy associated with leprosy and about the side effects of the drugs; 4) calendars and family members should be used to help patients follow their drug regimen; 5) leprosy workers should undergo gender sensitization, and more women should be recruited to examine women; and 6) the needs of children of leprosy patients should receive attention so they can have equal access to education, employment, and health care.

The value of neonatal autopsies.

Autopsy was performed on 221 of the 223 neonatal deaths that occurred over a period of 3 years (1989-1991). Clinically active problems at the time of death were identified in a combined clinicopathological approach. Prematurity associated conditions accounted for 51 per cent of deaths. Autopsy alone gave the diagnosis in 22 per cent of cases, confirmed the clinically suspected diagnosis in 68 per cent of cases and in 9 per cent of cases it was non-contributory; 69 per cent of deaths were considered non-preventable in our centre.