Major complications of airway management: a prospective multicentre observational study.

We conducted an observational study of serious airway complications, using similar methods to the fourth UK National Audit Project (NAP4) over a period of 1 year across four hospitals in one region in the UK. We also conducted an activity survey over a week, using NAP4 methods to yield an estimate for relevant denominators to help interpret the primary data. There were 17 serious airway complications, defined as: failed airway management leading to cancellation of surgery (eight); airway management in recovery (five); unplanned intensive care admission (three); and unplanned emergency front of neck access (one). There were no reports of death or brain damage. This was an estimate of 0.028% (1 in 3600) complications using the denominator of 61,000 general anaesthetics per year in the region. Complications in patients with 'predicted easy' airways were rare (approximately 1 in 14,200), but 45 times more common in those with 'predicted difficult' airways (approximately 1 in 315). Airway management in both groups was similar (induction of anaesthesia followed by supraglottic airway or tracheal tube). Use of awake/sedation intubation, videolaryngoscopy and high-flow nasal oxygenation were uncommon even in the predicted difficult airway patients (in 2.7%, 32.4% and 9.5% of patients, respectively). We conclude that the incidence of serious airway complications is at least as high as it was during NAP4. Despite airway prediction being used, this is not informing subsequent management.

A comparison of gastric gas volumes measured by computed tomography after high-flow nasal oxygen therapy or conventional facemask ventilation.

High-flow nasal oxygen therapy is increasingly used to improve peri-intubation oxygenation. However, it is unknown whether it may cause or exacerbate insufflation of gas into the stomach. High-flow nasal oxygen therapy is now standard practice in our hospital for adult patients undergoing percutaneous thermal ablation of liver cancer under general anaesthesia with tracheal intubation. We compared gastric gas volumes measured from computed tomography images that had been acquired immediately after intubation in two series of patients: 50 received peri-intubation high-flow nasal oxygen therapy and another 50 received conventional facemask pre-oxygenation and ventilation before intubation and before high-flow nasal oxygen therapy became standard practice in our unit. Median (IQR [range]) gastric gas volume was 24.0 (14.2-59.9 [3-167]) cm3 in the high-flow nasal oxygen therapy group and 23.8 (12.6-38.8 [0-185]) cm3 in the facemask group. There was no difference between the two groups in the volume of gastric gas measured by computed tomography imaging (Mann-Whitney U-test, U = 1136, p = 0.432, n1  = n2  = 50). Our results demonstrate that a small volume of gastric gas is commonly present after induction of anaesthesia, but that the use of peri-intubation high-flow nasal oxygen therapy for pre-oxygenation and during apnoea does not increase this volume compared with conventional facemask pre-oxygenation and ventilation. This is clinically relevant, as high-flow nasal oxygen therapy is increasingly being used in a peri-intubation context and in patients at higher risk of aspiration.

Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic.

BACKGROUND: Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' long-term survival. PATIENTS AND METHODS: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations. RESULTS: Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Per-patient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs. CONCLUSIONS: Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued.

Follicular porokeratosis: four new cases.

Porokeratosis, a disorder of keratinisation, is clinically characterized by the presence of annular plaques with a surrounding keratotic ridge. Clinical variants include linear, disseminated superficial actinic, verrucous/hypertrophic, disseminated eruptive, palmoplantar and porokeratosis of Mibelli (one or two typical plaques with atrophic centre and guttered keratotic rim). All of these subtypes share the histological feature of a cornoid lamella, characterized by a column of 'stacked' parakeratosis with focal absence of the granular layer, and dysmaturation (prematurely keratinised cells in the upper spinous layer). In recent years, a proposed new subtype, follicular porokeratosis (FP_, has been described, in which the cornoid lamella are exclusively located in the follicular ostia. We present four new cases that showed typical histological features of FP.

Patient involvement in blood transfusion safety: patients' and healthcare professionals' perspective.

BACKGROUND: Blood transfusion is one of the major areas where serious clinical consequences, even death, related to patient misidentification can occur. In the UK, healthcare professional compliance with pre-transfusion checking procedures which help to prevent misidentification errors is poor. Involving patients at a number of stages in the transfusion pathway could help prevent the occurrence of these incidents. OBJECTIVES: To investigate patients' willingness to be involved and healthcare professionals' willingness to support patient involvement in pre-transfusion checking behaviours. MEASURES: A cross-sectional design was employed assessing willingness to participate in pre-transfusion checking behaviours (patient survey) and willingness to support patient involvement (healthcare professional survey) on a scale of 1-7. PARTICIPANTS: One hundred and ten patients who had received a transfusion aged between 18 and 93 (60 male) and 123 healthcare professionals (doctors, nurses and midwives) involved in giving blood transfusions to patients. RESULTS: Mean scores for patients' willingness to participate in safety-relevant transfusion behaviours and healthcare professionals' willingness to support patient involvement ranged from 4.96-6.27 to 4.53-6.66, respectively. Both groups perceived it most acceptable for patients to help prevent errors or omissions relating to their hospital identification wristband. Neither prior experience of receiving a blood transfusion nor professional role of healthcare staff had an effect on attitudes towards patient participation. CONCLUSION: Overall, both patients and healthcare professionals view patient involvement in transfusion-related behaviours quite favourably and appear in agreement regarding the behaviours patients should adopt an active role in. Further work is needed to determine the effectiveness of this approach to improve transfusion safety.

Consent to transfusion: patients' and healthcare professionals' attitudes towards the provision of blood transfusion information.

BACKGROUND: Patients should be informed about the risks and benefits of blood transfusion and their consent should be documented. However, this is not routinely practised in the UK, and there have been few studies to investigate patients' and healthcare professionals' attitudes towards this process. OBJECTIVES: To investigate patients' and healthcare professionals' attitudes towards the information patients are provided with about transfusion and obtaining consent for transfusion. MEASURES: A cross-sectional qualitative survey design was employed. Attitudes towards transfusion-related information and consenting to transfusion were assessed using a patient survey and healthcare professional survey. PARTICIPANTS: One hundred and ten patients who had received a transfusion aged between 18 and 93 (60 males and 50 females) and 123 healthcare professionals (doctors, nurses and midwives) involved in administering transfusions. RESULTS: Sixty-one patients recalled consenting transfusion. The majority said they were just told they needed a transfusion (N = 67) and only 1 patient said a full discussion about the risks and the benefits of the transfusion took place. However, although 82 patients said they were satisfied with the information, 22 patients reported they would have liked to have been given more details. The majority of healthcare professionals (N = 83) felt that patients were often not given sufficient information about transfusion. CONCLUSION: Greater efforts should be made to provide information to patients about the risks and benefits of blood transfusions. Future research should explore the most effective ways of delivering this information to patients in an appropriate and timely manner.

Tailoring interfacial effect in multilayers with Dzyaloshinskii-Moriya interaction by helium ion irradiation.

We show a method to control magnetic interfacial effects in multilayers with Dzyaloshinskii-Moriya interaction (DMI) using helium (He[Formula: see text]) ion irradiation. We report results from SQUID magnetometry, ferromagnetic resonance as well as Brillouin light scattering results on multilayers with DMI as a function of irradiation fluence to study the effect of irradiation on the magnetic properties of the multilayers. Our results show clear evidence of the He[Formula: see text] irradiation effects on the magnetic properties which is consistent with interface modification due to the effects of the He[Formula: see text] irradiation. This external degree of freedom offers promising perspectives to further improve the control of magnetic skyrmions in multilayers, that could push them towards integration in future technologies.

Anteromedial Surface Plating for Midshaft Fracture Humerus Through an Anterolateral Approach - A Better Option than Anterolateral Plating.

INTRODUCTION: Osteosynthesis by plate fixation of humeral shaft fractures as a gold standard for fracture fixation has been proven beyond doubt. However, during conventional anterolateral plating Radial nerve injury may occur which can be avoided by applying plate on the medial flat surface. The aim of this study was to evaluate the results of application of plate on the flat medial surface of humerus rather than the conventional anterolateral surface. MATERIALS AND METHODS: This study was conducted between Oct 2010 to Dec 2015. One-hundred-fifty fracture shafts of the humerus were treated with the anteromedial plating through the anterolateral approach. RESULTS: One-hundred-fifty patients with a fracture shaft of the humerus were treated with anteromedial plating. Twenty were female (mean ±SD,28 years±4.5) and 130 were male (mean ± SD, 38 years±5.6). One hundred and forty-eight out of 150 (98.6%) patients achieved union at 12 months. Two of three patients developed a superficial infection, both of which were treated successfully by antibiotics and one developed a deep infection, which was treated by wound debridement, prolonged antibiotics with the removal of the plate and subsequently by delayed plating and bone grafting. CONCLUSION: In the present study, we applied plate on the anteromedial flat surface of humerus using the anterolateral approach. It is an easier and quicker fixation as compared to anterolateral plating because later involved much more dissection than a medial application of the plate and this application of plate on a medial flat surface, does not required Radial nerve exposure and palsy post-operatively. The significant improvement in elbow flexion without brachialis dissection is also a potential benefit of this approach. Based on our results, we recommend the application of an anteromedial plate for treatment of midshaft fractures humerus.

Runs of homozygosity and testicular cancer risk.

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

Fine mapping of the GLC1K juvenile primary open-angle glaucoma locus and exclusion of candidate genes.

PURPOSE: Primary open-angle glaucoma is a leading cause of blindness worldwide. We previously identified a region on chromosome 20p12 associated with juvenile-onset primary open-angle glaucoma (JOAG) that was designated GLC1K. The aim of this study is to refine the boundaries of the GLC1K region and to screen selected candidate genes located within the refined region for biologically significant mutations. METHODS: Four JOAG families (44 individuals) with linkage to GLC1K were used for this study. Informative single nucleotide polymorphism (SNP) markers located throughout the previously defined region were used for haplotype analysis. Four candidate genes within the refined region were screened for biologically significant mutations using direct genomic sequencing: bone morphogenetic protein 2 (BMP2); phospholipase C beta 1 (PLCB1); phospholipase C beta 4 (PLCB4); and BTB POZ domain containing 3 (BTBD3). RESULTS: Haplotype analysis identified a new critical interval of 12.7 Mb using a combination of SNPs and microsatellite markers. This analysis extended the region of GLC1K from D20S846 to rs6081603 in affected individuals, and the region was further reduced to 9 Mb if unaffected recombinant individuals were included in the analysis. Biologically significant DNA sequence variants were not identified in the BMP2, PLCB1, PLCB4, or BTBD3 genes in these families. CONCLUSIONS: Using recombinant breakpoint mapping and haplotypes based on a combination of SNP and microsatellite markers, the GLC1K region has been reduced to a maximum of 12.7 Mb and a minimum of 9 Mb. Four genes that are located within the refined region with attractive ocular expression and function have been excluded as causative genes for JOAG.

Relapse following use of Ponseti method in idiopathic clubfoot.

PURPOSE: We assessed the pattern of relapse as well as the correlation between the number of casts required for correction and Pirani and Dimeglio scores at presentation, and age at presentation. We hypothesized that the Ponseti method would be effective in treatment of relapsed clubfoot as well. METHODS: We evaluated 115 idiopathic clubfeet in 79 children presenting with relapse following treatment by the Ponseti method. The mean age was 33.8 months with mean follow-up of 24 months. All patients were assessed for various patterns of relapsed deformities. Quantification of deformities was done using the Pirani and Dimeglio scores. All relapsed feet were treated by a repeat Ponseti protocol. RESULTS: Non-compliance to a foot abduction brace was observed to be the main contributing factor in relapse, in 99 clubfeet (86%). Combination of three static deformities (equinus, varus and adduction) together was observed most commonly (38.3% feet). Overall, relapse of equinus deformity was noted most commonly followed by adduction. A painless plantigrade foot was obtained in all 115 feet with a mean of five casts. In all, 71 feet (61.7%) underwent percutaneous tenotomy. A total of 15 feet (13%) required tibialis anterior tendon transfer. Re-relapse rate in group 1 was 21% compared with 12.6% in group 2 and overall 16.5%. CONCLUSION: We conclude that the Ponseti method is effective and the preferred initial treatment modality for relapsed clubfeet. Surgical intervention should be reserved for residual deformity only after a fair trial of Ponseti cast treatment. Regular follow-up and strict adherence to brace protocol may reduce future relapse rates. Further research is required to identify high-risk feet and develop individualized bracing protocol. LEVEL OF EVIDENCE: IV.

Open reduction for late-presenting posterior dislocation of the elbow.

PURPOSE: To evaluate results of open reduction for late-presenting (more than 3 weeks) posterior dislocation of the elbow in 10 patients. METHOD: Elbow stiffness was the main indication for surgery. The mean age of the patients was 34 (range, 13-65) years; the mean time since injury was 4 (range, 2-6) months. All patients had non-functional elbow movement for any activity of daily living. Three patients had associated fractures around the elbow joint. RESULTS: At a mean follow-up of 19 (range, 11-28) months, 8 patients regained a functional range of movement for activities of daily living and maintained a median arc of flexion of 100 degrees and a supination-pronation arc of 140 degrees. According to the Mayo Elbow Performance Index, the results of 5 patients were excellent, 3 were good, and 2 were poor. Complications included pin site infection (n=2), ulnar neuritis (n=1), and delayed wound healing (n=1). CONCLUSION: In patients with late-presenting, unreduced elbow dislocation occurring up to 6 months earlier, open reduction is effective in restoring the joint to a painless, stable and functional state.

Mendelian randomisation analysis provides no evidence for a relationship between adult height and testicular cancer risk.

Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41-1.55, p = 2.7 × 10-57 ; rs12228415: OR = 1.17, 95% CI: 1.11-1.22, p = 3.1 × 10-10 ; rs7568069: OR = 1.13, 95% CI: 1.07-1.18, p = 1.1 × 10-6 ). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors occurring in utero.

Radiographic and functional outcome of posterolateral lumbosacral fusion for low grade isthmic spondylolisthesis in children and adolescents.

AIMS: We reviewed 34 consecutive patients (18 female-16 male) with isthmic spondylolysis and grade I to II lumbosacral spondylolisthesis who underwent in situ posterolateral arthodesis between the L5 transverse processes and the sacral ala with the use of iliac crest autograft. Ten patients had an associated scoliosis which required surgical correction at a later stage only in two patients with idiopathic curves unrelated to the spondylolisthesis. METHODS: No patient underwent spinal decompression or instrumentation placement. Mean surgical time was 1.5 hours (1 to 1.8) and intra-operative blood loss 200 ml (150 to 340). There was one wound infection treated with antibiotics but no other complication. Radiological assessment included standing posteroanterior and lateral, Ferguson and lateral flexion/extension views, as well as CT scans. RESULTS: A solid posterolateral fusion was confirmed in all patients at mean latest follow-up of 4.7 years (3.4 to 9.8) beyond skeletal maturity into early adult life. Fusion of the isthmic lesion was documented in nine patients bilaterally and eight patients unilaterally. The poor fusion rate across the spondylolysis has not affected the excellent functional results of the procedure, which in our series depended on achieving a stable lumbosacral junction. CONCLUSION: Quality of life assessment demonstrated significant improvement in all functional scores and high patient satisfaction with 28 patients returning to previous sports activities at an elite competitive level. TAKE HOME MESSAGE: Posterolateral arthrodesis in situ with autologous iliac crest bone without instrumentation has achieved a solid fusion between the L5 transverse processes and the sacral ala in patients with grade I to II isthmic lumbosacral spondylolisthesis and this has produced excellent clinical outcomes and high patient satisfaction.

Antibody response to Toxoplasma gondii in saliva samples from human immunodeficiency virus-infected patients.

Toxoplasma gondii is an important opportunistic infection among human immunodeficiency virus (HIV)-infected patients as it causes fatal encephalitis. In the present study, antibody response to T. gondii is assessed in saliva samples from 100 HIV-seropositive patients and 25 HIV-negative healthy controls by indirect enzyme-linked immunosorbent assay (ELISA). Sensitivity and specificity for detection of IgG and IgM in saliva is calculated using a positive antibody response in serum samples (from an earlier study) as the gold standard. IgG and IgM antibodies were found in 20% and 25% patients, respectively. One control subject showed the presence of IgM antibody. Sensitivity for IgG and IgM antibodies was 64% and 81.25%, respectively, while specificity was 94.67% and 85.71%, respectively. This study indicates that saliva samples can be used as an alternative to serum samples to detect anti-toxoplasma antibodies, particularly IgM, for the diagnosis of toxoplasma encephalitis in HIV/acquired immune deficiency syndrome patients.

Antigenaemia and antibody response to Toxoplasma gondii in human immunodeficiency virus-infected patients.

Toxoplasma encephalitis in immunocompromised patients results from reactivation of previously acquired (latent) infection. The aim of the study is to assess the antigenaemia and antibody response to Toxoplasma gondii in human immunodeficiency virus (HIV)-infected patients to determine the best marker for early diagnosis of toxoplasmosis in such patients. Indirect enzyme-linked immunosorbent assay (ELISA) for detection of IgG, IgM and IgA anti-toxoplasma antibodies and double-sandwich ELISA for toxoplasma antigen is carried out in serum samples collected from 100 HIV seropositive patients and 75 controls. Toxoplasma-specific IgG, IgM and IgA antibody response and antigenaemia were detected in 12%, 6%, 7% and 14% of HIV-infected patients, respectively. On retrospective analysis of 14 patients with antigenaemia only one had central nervous system (CNS) symptoms attributable to toxoplasma infection. In this patient, the CD4+ cell count was below 50/microL and none of the specific immunoglobulin isotype responses could be detected. The patient showed clinical improvement following specific chemotherapy for toxoplasmosis. In 25 HIV-negative and anti-toxoplasma IgG antibody-positive controls, IgM was detected in two (8%), IgA in five (20%) and antigenaemia in 10 (40%), while 50 HIV seronegative healthy controls were negative for both antigen and antibody responses. The study indicates that detection of toxoplasma antigen in addition to IgG antibody response may prove to be a useful indicator in the early diagnosis of reactivated toxoplasmosis in HIV/AIDS patients.

Screening of patients with acute febrile illness for leptospirosis using clinical criteria and serology.

BACKGROUND: Leptospirosis is one of the common zoonoses but, in most instances, the infection goes unnoticed. Rapid diagnostic modalities are needed to diagnose the disease in the early stages. We assessed the usefulness of clinical criteria and compared these with enzyme-linked immunosorbentassay (ELISA) for the early detection of leptospirosis. METHODS: One hundred patients with a febrile illness for > 7 days were screened by Faine criteria and their sera were subjected to both IgM and IgG ELISA using a commercially available kit (Institut Virion Serion GmbH, Warburg, Germany). RESULTS: Twenty-six patients satisfied the clinical criteria for leptospirosis and 8 of them tested positive for IgM antibodies while 1 patient who was clinically negative tested positive by serology. Thus, Faine criteria had a sensitivity of 88.9%, specificity of 80.2%, positive predictive value of 30.8% and a negative predictive value of 98.6%. Paired serum samples were obtained from 70 patients but the IgG levels of only 2 showed a 4-fold rise. CONCLUSION: Faine criteria has moderate sensitivity and specificity but a high negative predictive value in comparison with IgM ELISA. The high negative predictive value may help to screen patients with acute febrile illness for leptospirosis during the early phase of the disease.

Incidence of lamivudine resistance associated mutations in pol-gene of HIV-1 in patients from north India: a preliminary report.

Screening of drug-resistant variants is very important for the effective clinical management of HIV-infected patients and development of new strategies. The present study was aimed to detect codon-184 mutations in the pol-gene of HIV leading to resistance to lamivudine (3-TC) by nested cum ARMS-PCR approach in 10 treated and 9 treatment naive patients. For correlation the whole blood CD4/CD8 cell counts and the soluble TNFRII levels in plasma were also determined. Of the 19 patients tested, mutant variants were observed in 2 patients (Met Val in one and Met Val & lle in second) both being treated with 3-TC. No mutations were detected in the treatment-naive patients. The results confirmed that, drug resistant variants of codon-184 emerge rapidly in patients receiving 3-TC containing regimens including our population, which is mainly infected with subtypeC of the virus that could be detected along with wild viral population using sensitive approaches such as ARMS-PCR.

Pentoxiphylline reduces nitric oxide production among patients with HIV infection.

Tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) levels are elevated among patients with human immunodeficiency virus (HIV) infection. TNF-alpha is known to lower NO production. In this study we used a TNF-alpha inhibitor, pentoxiphylline, to treat patients with HIV infection who were free of opportunistic infections and see if NO production was altered with this drug. NO production was determined by spectrophotometric analysis using nitrite and citrulline as surrogate markers and TNF-alpha levels were determined by ELISA before and after 4 weeks of the treatment. Nineteen patients (ten males, mean age 36.6+/-5.2 years) and 16 age and sex matched healthy controls were studied. Mean CD4 counts of patients were 206.5 mm(3). Nitrite level among patients at recruitment was 99.7+/-26.5 nmol/ml (range 50-167 nmol/ml) and was significantly higher than 46.4+/-16.2 nmol/ml; the value of healthy controls (P<0.05). Patient levels declined significantly to 44. 2+/-19.7 nmol/ml (range 10-106.6 nmol/ml) following 4 weeks of therapy (P<0.01). Citrulline level at recruitment was 810.8+/-425.8 nmol/ml (range 366.6-1888.7 nmol/ml), which was significantly higher than 488.6+/-224.5 nmol/ml, the level of controls (P<0.01). There was a statistically significant decrease in these levels among patients to 533.6+/-299.5 nmol/ml (range 250-163.4 nmol/ml) after 4 weeks of therapy (P<0.01). TNF-alpha levels showed a significant decline in the OD values from 0.34+/-0.22 at the start of therapy to 0.24+/-0.18 (P<0.05). We conclude that the use of pentoxiphylline is associated with decrease in TNF-alpha levels and NO production.

Maintaining mitochondrial membrane impermeability. an opportunity for new therapy in glaucoma?

Apoptosis may contribute to retinal ganglion cell loss in glaucoma and glaucoma models. Recent research has suggested that mitochondrially dependent apoptosis signaling may contribute to apoptosis in a rat model of glaucoma involving chronic increases in intraocular pressure. In some forms of apoptosis, mitochondrially dependent signaling involves increases in mitochondrial membrane permeability and the mitochondrial release of factors that signal for cell degradation. Opening of a multi-protein, mitochondrial megapore is one factor that contributes to the increased permeability and some anti-apoptotic proteins, particularly BCL-2 and BCL-X(L), bind at the megapore and facilitate megapore closure and reduce increases in mitochondrial membrane permeability. Phosphorylated protein kinase B (Akt) serves as an integrator for cellular survival signals and facilitates the megapore actions of BCL-2 and BCL-X(L), which could protect retinal ganglion cells against insults that induce apoptosis. Several anti-apoptotic agents are being evaluated for use in glaucoma, including brimonidine and propargylamines, which oppose mitochondrially dependent apoptosis through pathways involving phosphorylated Akt.