The role of nanoparticles in bleed air in the etiology of Aerotoxic Syndrome: A review of cabin air-quality studies of 2003-2023.

Aerotoxic Syndrome may develop as a result of chronic, low-level exposure to organophosphates (OPs) and volatile organic compounds in the airplane cabin air, caused by engine oil leaking past wet seals. Additionally, acute high-level exposures, so-called "fume events," may occur. However, air quality monitoring studies concluded that levels of inhaled chemicals might be too low to cause adverse effects. The presence of aerosols of nanoparticles (NPs) in bleed air has often been described. The specific hypothesis is a relation between NPs acting as a vector for toxic compounds in the etiology of the Aerotoxic Syndrome. These NPs function as carriers for toxic engine oil compounds leaking into the cabin air. Inhaled by aircrew NPs carrying soluble and insoluble components deposit in the alveolar region, where they are absorbed into the bloodstream. Subsequently, they may cross the blood-brain barrier and release their toxic compounds in the central nervous system. Olfactory absorption is another route for NPs with access to the brain. To study the hypothesis, all published in-flight measurement studies (2003-2023) of airborne volatile (and low-volatile) organic pollutants in cabin air were reviewed, including NPs (10-100 nm). Twelve studies providing data for a total of 387 flights in 16 different large-passenger jet aircraft types were selected. Maximum particle number concentrations (PNC) varied from 104 to 2.8 × 106 #/cm3 and maximum mass concentrations from 9 to 29 µg/m3. NP-peaks occurred after full-power take-off, in tailwind condition, after auxiliary power unit (APU) bleed air introduction, and after air conditioning pack failure. Chemical characterization of the NPs showed aliphatic hydrocarbons, black carbon, and metallic core particles. An aerosol mass-spectrometry pattern was consistent with aircraft engine oil. It is concluded that chronic exposure of aircrew to NP-aerosols, carrying oil derivatives, maybe a significant feature in the etiology of Aerotoxic Syndrome. Mobile NP measuring equipment should be made available in the cockpit for long-term monitoring of bleed air. Consequently, risk assessment of bleed air should include monitoring and analysis of NPs, studied in a prospective cohort design.

Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression.

Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch's membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.

The role of carbon monoxide in aerotoxic syndrome.

Chronic low-level exposure to toxic compounds in airplane cabin air may result in Aerotoxic Syndrome (AS). Aetiologic agents are organophosphates and numerous volatile organic hydrocarbons originating from leaks of engine oil and hydraulic fluids. Despite a documented history spanning decades, the role of carbon monoxide remains controversial. What evidence exists that carbon monoxide (CO), present in the cocktail of toxic compounds in bleed air, contributes to the AS? We selected 22 publications encompassing 888 flights with 18 different aircraft types. In one study of 100 flights, fume events were confirmed in 38. Four studies were initialized after air quality incidents. The cabin CO concentrations could be categorized in three levels, 1) low (<5 ppm), without health implications, 2) moderate (5-10 ppm) with probably health implications in case of chronic exposure, and 3) high > 10 ppm, with health effects in case of acute and chronic exposure. These levels were recorded in 12, 6 and 4 studies respectively. In the six studies in category 2, max CO concentrations ranged from 5.8-9.4 ppm. The four studies with CO > 10 ppm comprised 376 of the 888 flights (42%) with six aircraft types. Toxic CO levels ranging between 13-60 ppm were identified in at least 129 of 888 (14.5%) flights. In one study with high CO levels four flight attendants were diagnosed with CO poisoning with elevated HbCO levels. Max CO levels in aviation are either the same or higher than current occupational exposure limits (OEL) for ground-based workplace exposures or levels for urban street transport environments. Specific aspects of aviation should be taken into consideration: the effect of low(er) air pressure at high altitudes increasing the toxicity of CO, and the binding of CO to CYP enzymes, leading to impaired organophosphate detoxification. We conclude that CO must be considered an important factor in the lubrication derived cocktail of airborne toxic compounds causing AS. In line with the WHO advice, a reduction of the OEL to 5 ppm over 8 hr time weighted average (TWA) for aircrew is strongly recommended. And we advocate continuous monitoring during all phases of flight and installation of CO detectors in the air supply ducts to the aircraft cabin.

Fetuses and infants with Amyoplasia congenita in congenital Zika syndrome: The evidence of a viral cause. A narrative review of 144 cases.

OBJECTIVES: Amyoplasia congenita is the most frequent type of arthrogryposis causing fetal hypokinesia, leading to congenital contractures at birth. The pathogenesis is thought to be impaired blood circulation to the fetus early in pregnancy, with hypotension and hypoxia damaging the anterior horn cells. In animal studies however a prenatal infection with a poliomyelitis-like viral agent was demonstrated. Congenital Zika virus syndrome (CZVS) has recently been described in infants with severe microcephaly, and in 10-25% of cases arthrogryposis. METHODS: A search in PubMed for CZVS yielded 124 studies. After a selection for arthrogryposis, 35 papers were included, describing 144 cases. The studies were divided into two categories. 1) Those (87 cases) focussing on imaging or histological data of congenital brain defects, contained insufficient information to link arthrogryposis specifically to lesions of the brain or spinal motor neuron. 2) In the other 57 cases detailed clinical data could be linked to neurophysiological, imaging or histological data. RESULTS: In category 1 the most frequent brain abnormalities in imaging studies were ventriculomegaly, calcifications (subcortical, basal ganglia, cerebellum), hypoplasia of the brainstem and cerebellum, atrophy of the cerebral cortex, migration disorders and corpus callosum anomalies. In category 2, in 38 of 57 cases clinical data were indicative of Amyoplasia congenita. This diagnosis was confirmed by electromyographic findings (13 cases), by MRI (37 cases) or histology (12 cases) of the spinal cord. The latter showed small or absent lateral corticospinal tracts, and cell loss and degeneration of motor neuron cells. Zika virus-proteins and flavivirus-like particles were detected in cytoplasm of spinal neurons. CONCLUSION: The phenotype of arthrogryposis in CZVS is consistent with Amyoplasia congenita. These findings warrant search for an intrauterine infection with any neurotropic viral agent with affinity to spinal motor neurons in neonates with Amyoplasia.

Three patients with probable aerotoxic syndrome.

Introduction: "Aerotoxic syndrome" is a debated entity. Regulatory authorities consider long-term health effects to be an unlikely consequence of exposure to contaminated air because several air quality monitoring studies report low concentrations of toxic chemicals in cabin air. We describe two pilots and one flight attendant, who developed ill health during their flying career which improved after cessation of flying.Case details: The most frequently reported symptoms were headache, balance problems, fatigue, gastro-intestinal complaints and cognitive impairment. One of these patients had reduced levels of butyrylcholinesterase after a flight suggesting exposure to organophosphate compounds had occurred. All three were found to have elevated neuronal and glial auto-antibodies, biomarkers of central nervous system injury, and all three had genetic polymorphisms of paraoxonase (PON-1) and two of cytochrome P450, leading to a reduced ability to metabolize organophosphate compound (OPs).Discussion: A similar constellation of symptoms has been described in other studies of aircrew, although objective evidence of exposure is lacking in most of these studies. Reduced levels of butyrylcholinesterases in one of our cases is suggestive of causation and elevated neuronal and glial autoantibodies provide objective evidence of damage to the central nervous system. We consider further research is warranted.

[Addendum to the Dutch guideline for minor head/brain injury]. / Addendum richtlijn licht traumatisch hoofd-hersenletsel.

- After introduction of the Dutch guideline for 'Care for patients with minor head/brain injury' (LTH guideline) in 2010, the number of CT scans has increased. Some of these scans were for patients with only trivial trauma and may not have been necessary.- In addition, since this guideline was implemented, there have been changes in the use of anticoagulants and platelet aggregation inhibitors. Non-vitamin-K-dependent oral anticoagulants (NOACs) and platelet aggregation inhibitors, or combinations of these, are prescribed more often.- These two factors have led the Netherlands Society of Neurology to initiate a request for modification of the LTH guideline for adults in two ways: (a) identification of minimal or trivial trauma for which no CT scan is required and (b) inclusion of NOACs and platelet aggregation inhibitors, or combinations of these, in the guideline.

Outpatient follow-up after mild traumatic brain injury: Results of the UPFRONT-study.

OBJECTIVE: To investigate outpatient follow-up after mild traumatic brain injury (mTBI) by various medical specialists, for both hospitalized and non-hospitalized patients, and to study guideline adherence regarding hospital admission. METHODS: Patients (n = 1151) with mTBI recruited from the emergency department received questionnaires 2 weeks (n = 879), 3 months (n = 780) and 6 months (n = 668) after injury comprising outpatient follow-up by various health care providers, and outcome defined by the Glasgow Outcome Scale Extended (GOS-E) after 6 months. RESULTS: Hospitalized patients (60%) were older (46.6 ± 19.9 vs. 40.6 ± 18.5 years), more severely injured (GCS <15, 50% vs. 13%) with more Computed Tomography (CT) abnormalities on admission (21% vs. 2%) compared to non-hospitalized patients (p < 0.01) . Almost half of the patients visited a neurologist at the outpatient clinic within six months (60% of the hospitalized and 25% of the non-hospitalized patients (χ2 = 67.10, p < 0.01)), and approximately ten per cent consulted a psychiatrist/psychologist. Outcome was unfavourable (GOS-E <7) in 34% of hospitalized and 21% of non-hospitalized patients (χ2 = 11.89, p < 0.01). CONCLUSION: Two-thirds of all mTBI patients consult one or more specialists within six months after injury, with 30% having an unfavourable outcome. A quarter of non-hospitalized patients was seen at the outpatient neurology clinic, underling the importance of regular follow-up of mTBI patients irrespective of hospital admittance.

Headache in epilepsy patients: the (un)awareness of this phenomenon among Dutch neurologists.

PURPOSE: Headache is a frequently heard complaint that can strongly influence quality of life. This is probably even more so in people with a chronic illness. Knowing that headache, and especially migraine, is more frequent among epilepsy patients, the knowledge concerning this problem has been studied among Dutch neurologists. METHODS: Seven hundred and seventy two neurologists, working in 89 hospitals and two tertiary epilepsy clinics were asked to participate. Using a questionnaire, neurologists were surveyed on different subjects, e.g. whether they thought current headaches are more frequent in people with epilepsy than in the general population, their interest for epilepsy and how many patients with epilepsy visited their polyclinic per month. RESULTS: In total, 334 questionnaires were returned (response rate of 43%) of which 18 were excluded. One third of neurologists responded affirmatively that current headaches are more prevalent among people with epilepsy and eight percent knows that this is, more specified, migraine. The number of years of experience does not influence knowledge on headaches in epilepsy patients. The interest in epilepsy and the number of epilepsy patients per month on the polyclinic does. CONCLUSIONS: These results show that the occurrence of headache in people with epilepsy is underestimated by Dutch neurologists. This leaves an often bothersome and potentially treatable condition underexposed.

Periictal and interictal headache including migraine in Dutch patients with epilepsy: a cross-sectional study.

As early as in 1898, it was noted that there was a need to find "a plausible explanation of the long recognized affinities of migraine and epilepsy". However, results of recent studies are clearly conflicting on this matter. In this cross-sectional study, we aimed to define the prevalence and characteristics of both seizure-related and interictal headaches in patients with epilepsy (5-75years) seeking help in the tertiary epilepsy clinic SEIN in Zwolle. Using a questionnaire, subjects were surveyed on the existence of headaches including characteristics, duration, severity, and accompanying symptoms. Furthermore, details on epilepsy were retrieved from medical records (e.g., syndrome, seizure frequency, and use of drugs). Diagnoses of migraine, tension-type headache, or unclassifiable headache were made based on criteria of the International Classification of Headache Disorders. Between March and December 2013, 29 children and 226 adults were evaluated, 73% of whom indicated having current headaches, which is significantly more often when compared with the general population (p<0.001). Forty-nine percent indicated having solely interictal headache, while 29% had solely seizure-related headaches and 22% had both. Migraine occurs significantly more often in people with epilepsy in comparison with the general population (p<0.001), and the occurrence of tension-type headaches conforms to results in the general population. These results show that current headaches are a significantly more frequent problem amongst people with epilepsy than in people without epilepsy. When comparing migraine prevalence, this is significantly higher in the population of patients with epilepsy.

[CT scans in children with head/brain injury: five years after the revision of the guideline on "mild traumatic head/brain injury"]. / CT-scans bij kinderen met hoofd-hersenletsel: 5 jaar na herziening richtlijn 'Licht traumatisch hoofd/hersenletsel'.

In 2010 the guideline on mild traumatic head/ brain injury for both adults and children was revised under the supervision of the Dutch Neurology Society. The revised guideline endorsed rules for decisions on whether to carry out diagnostic imaging investigations (brain CT scanning) and formulates indications for admission. Unfortunately, 5 years after its introduction, it is clear that the guideline rules result in excessive brain CT scanning, in which no more serious head injury is diagnosed. Brain injury may be present in (small) children even if symptoms are absent at first presentation. Also, clinical signs do not predict intracranial complications. This was nicely demonstrated in a study by Tilma, Bekhof and Brand of 410 children with mTBI: no clinical symptom or sign reliably predicted the risk of intracranial bleeding. They advise hospitalisation for observation instead of brain CT scanning. It may be necessary to review part of the Dutch guideline on mTBI.

Placental telomere length decreases with gestational age and is influenced by parity: a study of third trimester live-born twins.

BACKGROUND: In contrast to the postnatal period, little is known about telomere length (TL) during prenatal life. The decrease in placental TL remains unknown, although intra uterine growth retardation and preeclampsia are associated with shorter placental TL. The aim of this study is to assess the decrease of placental TL during the third trimester of gestation and to explore the role of potential "growth influencing factors". METHODS: The study sample consisted of 329 live-born twins from the East Flanders Prospective Twin Survey. TL was determined using a multiplex quantitative PCR method. Gestational age, sex, birth order, placental characteristics, parity, maternal and paternal age, diabetes, hypertension, smoking, alcohol use, and socio economic status (SES) were considered "growth influencing factors". Bivariable multilevel regression analysis with "growth influencing factors" was performed. RESULTS: Placental TL ranged from 4.3 kbp to 84.4 kbp with a median of 10.8 kbp. Ln(TL) decreased in a linear fashion with an estimated TL decreasing from 13.98 kbp at 28 weeks to 10.56 kbp at 42 weeks. The regression coefficient of gestational age became smaller if considered together with SES (b = -0.017; p = 0.08) or diabetes (b = -0.018; p = 0.07) and bigger if considered together with parity (b = -0.022; p = 0.02), indicating that part of the association between gestational age and telomere length is explained by these three confounding factors. CONCLUSION: Placental TL decreases during the third trimester of gestation of live-born twins with approximately 25% indicating that telomere shortening may play a role in aging of the placenta.

Sensitivity and specificity of the 'Awaji' electrodiagnostic criteria for amyotrophic lateral sclerosis: retrospective comparison of the Awaji and revised El Escorial criteria for ALS.

The Awaji Commission recently proposed a modification of the electrodiagnostic criteria for ALS. We assessed whether the Awaji recommendations improve the sensitivity of the early diagnosis of ALS. In a retrospective study we reviewed clinical and neurophysiological data for 213 patients who visited our motor neuron disease outpatient clinic between October 2006 and December 2008. Using the El Escorial criteria, 51 patients were diagnosed with definite or probable ALS, 14 with probable laboratory-supported ALS, and 28 with possible ALS. An alternative diagnosis was present in 120 patients. Applying the Awaji recommendations, 66 patients were diagnosed with either definite or probable ALS, and 27 with possible ALS. Of the 14 patients diagnosed with probable laboratory-supported ALS, eight switched to probable ALS and six to possible ALS using the Awaji recommendations; none of the patients with an ALS mimic was diagnosed with ALS according to the Awaji recommendations. In conclusion, the new criteria for ALS do not result in a loss of specificity and can potentially improve the sensitivity by 16%. However, this diagnostic improvement appears eliminated if patients with probable laboratory-supported ALS - due to UMN signs in one region - should be categorized as possible ALS.

Vagus nerve stimulation for epilepsy activates the vocal folds maximally at therapeutic levels.

PURPOSE: Vagus nerve stimulation (VNS) for medically refractory epilepsy can give hoarseness due to stimulation of the recurrent laryngeal nerve. For a group of VNS-therapy users this side-effect interferes severely with their daily activities. Our goal was to investigate the severity of intra-operative VNS-related vocal fold contraction at different pulse widths and current output parameters. We investigated electromyographic and morphometric alterations on the vocal folds during VNS. METHODS: Vocal fold EMG experiments were conducted intra-operatively during the implantation of a VNS system. During surgery the VNS pulse generator was programmed to stimulate at different pulse durations. At each pulse width the EMG-threshold current was determined by electrical stimulation of the vagus nerve with increasing stimulation currents. Laryngostroboscopic examination was performed after surgery to analyze the effects of spontaneous stimulation on the larynx. RESULTS: The vocal fold EMG and morphodynamic changes in the larynx have been analyzed in eight patients. In all patients left vocal fold EMG-threshold was between 0.25 and 0.50 mA. Pulse duration had little influence on the EMG-threshold level. Vocal fold EMG saturation levels were reached between 0.75 and 1.00 mA. Video stroboscopic monitoring showed that stimulation induced an adductory spasm of either the ipsilateral vocal fold or the vestibular fold, and was present remarkably irrespective of the presence of hoarseness. CONCLUSIONS: VNS causes pronounced effects on the vocal folds even at low stimulation amplitudes. At therapeutic levels even at the lowest stimulation pulse durations, the vocal fold contract, however, this does not necessarily give hoarseness.

Widespread thalamic and cerebellar degeneration in a patient with a complicated hereditary spastic paraplegia (HSP).

The hereditary spastic paraplegias (HSP) are a heterogeneous group of familial movement disorders sharing progressive spastic paraplegia as a common disease sign. In the present study, we performed the first pathoanatomical investigation of the central nervous degeneration of a female patient with a complicated HSP form who suffered from progressive spastic paraplegia, dysarthria, emotional symptoms, cognitive decline and a variety of additional neuropsychological deficits. This pathoanatomical investigation revealed in addition to loss of layer V Betz pyramidal cells in the primary motor cortex, widespread cerebellar neurodegeneration (i.e., loss of Purkinje cells and neuronal loss in the deep cerebellar nuclei), extensive and severe neuronal loss in a large number of thalamic nuclei, involvement of some brainstem nuclei, as well as damage to descending (i.e., lateral and ventral corticospinal tracts) and ascending (i.e., dorsal and ventral spinocerebellar tracts, gracile fascicle) fiber tracts. In view of their known functional role, damage to these central nervous gray and white matter components offers explanations for the patient's pyramidal signs, her cerebellar, psychiatric and neuropsychological disease symptoms.

Complement factor H gene polymorphisms and Chlamydia pneumoniae infection in age-related macular degeneration.

PURPOSE: To investigate the association of the complement factor H gene (CFH)Y402H polymorphism and age-related macular degeneration (AMD) in the Austrian population (Caucasoid descent), and to determine whether there is an association between exposure to Chlamydia pneumoniae-responsible for up to 20% of community-acquired pneumoniae-and the AMD-associated CFHrisk polymorphism. METHODS: Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis in 75 unrelated AMD patients and compared with 75 healthy, age-matched control subjects. C. pneumoniaeserum IgG was tested by ELISA (R&D) in both groups. The association between the CFHY402H genetic polymorphism and the disease was examined by chi (2)-test and logistic regression. RESULTS: CFH Y402H genotypefrequencies differed significantly between AMD patients and healthy controls (1277 TT, 22.7%; 1277 TC, 53.3%; and 1277 CC, 22.7% in the AMD group; 1277 TT, 48.0%; 1277 TC, 38.7%; and 1277 CC, 13.3% in the control group) showing a P-value <0.005 (OR:2.920/3.811).No association was found between a positive C. pneumoniae titre and AMD (P=0.192), nor was any association found between C. pneumoniae and the CFH Y402H polymorphism. CONCLUSIONS: Our data confirm that the CFHY402H polymorphism is a risk factor for AMD in the Austrian population with a higher frequency of the Y402 polymorphism in AMD patients. No association between preceding C. pneumoniaeinfection and diagnosed AMD was found.

Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation.

OBJECTIVES: Few adverse events on heart rate have been reported with vagus nerve stimulation (VNS) for refractory epilepsy. We describe three cases with intraoperative bradycardia during device testing. PATIENTS AND METHODS: At our hospital 111 patients have received a VNS system. Intraoperative device testing is performed under ECG-monitoring. We reviewed the patients and their VNS-therapy follow-up outcome who experienced a change in heart rate, during device testing (Lead Test). RESULTS: Three patients with medically refractory epilepsy showed a bradycardia during intraoperative Lead Test. Postoperative the VNS-therapy started under ECG-monitoring. No change in cardiac rhythm occurred. Subsequent chronic stimulation is uneventful. All three have reduced seizure frequency. Two already have had their second implant, without the occurrence of bradycardia. CONCLUSION: In case of intraoperative bradycardia VNS-therapy onset should be done under ECG-monitoring. Subsequent chronic stimulation is safe in respect to heart rate. Bradycardia during intraoperative device testing is no reason to abort the operation.

Vagus nerve stimulation for medically refractory epilepsy: a long-term follow-up study.

INTRODUCTION: Vagus nerve stimulation (VNS) is thought to have a cumulative effect in time on seizure frequency reduction. There also might be other variables than reduction of seizure frequency in order to determine VNS efficacy. In this study we describe the long-term outcome of the first group of vagus nerve stimulation patients with pharmacoresistant epilepsy at the Medisch Spectrum Twente, The Netherlands. METHODS: This long-term descriptive prospective study included 19 patients, 11 males and 8 females, aged 17-46 years with pharmacoresistant epilepsy. They had received 3-16 (mean 9) different anti-epileptic drugs and were not eligible for surgical resection of an epileptic focus. A vagus nerve stimulator was implanted in the period April 1999-October 2001. Follow-up ranges from 2 to 6 years (mean 4 years). Efficacy was measured as the percentage change in seizure rate during 1 year and then after each year follow-up of VNS compared to 5 months baseline before implantation. RESULTS: Mean seizure reduction at 1-6 years was, respectively, 14% (n = 19), 25% (n =1 9), 29% (n = 16), 29% (n = 15), 43% (n = 9) and 50% (n = 7). Because of VNS two patients were able to start living without supervision. One patient died after 2 years of follow-up possibly as a result of SUDEP. Four patients had no apparent reduction in seizure frequency. Two of them had their stimulator removed. The other two patients however had significantly reduced post-ictal periods and seizure time and received a new pulse generator when the battery was depleted. One stimulator was switched off due to adverse effects, even though there was a positive effect on his seizure reduction. In six patients the medication regimen was changed during VNS by adding one anti-epileptic drug, however without significant change in seizure reduction. Adverse effects were hoarseness and coughing during stimulation. One patient had a temporary paralysis of his left vocal cord. CONCLUSION: We think that VNS is an effective treatment for pharmacoresistant epilepsy and its positive effect persists during the years of follow-up. Our results suggest that seizure reduction should not be considered as the only variable of importance to describe the outcome of VNS on epilepsy and it is worthwhile to look at other outcome measures.

Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid.

Polymorphisms in the complement factor H gene (CFH) are associated with a significantly increased risk for, or protection against, the development of age-related macular degeneration (AMD). The most documented risk-conferring single-nucleotide polymorphism results in a tyrosine-to-histidine substitution at position 402 (Y402H) of the CFH protein. In this work, we examined the ocular distributions and relative abundance of CFH, several CFH-binding proteins, and abundant serum proteins in the retinal pigmented epithelium (RPE), Bruch's membrane, and choroid (RPE-choroid) in CFH homozygotes possessing either the "at-risk" 402HH or "normal" 402YY variants. Although CFH immunoreactivity is high in the choroid and in drusen, no differences in CFH-labeling patterns between genotypes are apparent. In contrast, at-risk individuals have significantly higher levels of the CFH-binding protein, C-reactive protein (CRP), in the choroidal stroma. Immunoblots confirm that at-risk individuals have approximately 2.5-fold higher levels of CRP in the RPE-choroid; no significant differences in the levels of CFH or other serum proteins are detected. Similarly, we find no differences in CFH transcription levels in the RPE-choroid nor evidence for local ocular CRP transcription. Increased levels of CRP in the choroid may reflect a state of chronic inflammation that is a by-product of attenuated CFH complement-inhibitory activity in those who possess the CFH at-risk allele. Because the CRP-binding site in CFH lies within the domain containing the Y402H polymorphism, it is also possible that the AMD risk-conferring allele alters the binding properties of CFH, thereby leading to choroidal CRP deposition, contributing to AMD pathogenesis.

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

INTRODUCTION: Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology. SUBJECTS: Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded. RESULTS: Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls. CONCLUSION: We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.

Refinement of the chromosome 16 locus for benign familial infantile convulsions.

Benign familial infantile convulsions (BFIC) is an autosomal dominantly inherited partial epilepsy syndrome of early childhood with remission before the age of 3 years. The syndrome has been linked to loci on chromosomes 1q23, 2q24, 16p12-q12, and 19q in various families. The aim of this study was to identify the responsible locus in four unrelated Dutch families with BFIC. Two of the tested families had pure BFIC; in one family, affected individuals had BFIC followed by paroxysmal kinesigenic dyskinesias at later age, and in one family, BFIC was accompanied by later-onset focal epilepsy in older generations. Linkage analysis was performed for the known loci on chromosomes 1q23, 2q24, 16p12-q12, and 19q. The two families with pure BFIC were linked to chromosome 16p12-q12. Using recombinants from these and other published families, the chromosome 16-candidate gene region was reduced from 21.4 Mb (4.3 cm) to 2.7 Mb (0.0 cm). For the other two families, linkage to any of the known loci was unlikely. In conclusion, we confirm the linkage of pure BFIC to chromosome 16p12-q12, with further refinement of the locus. Furthermore, the lack of involvement of the known loci in two of the families indicates further genetic heterogeneity for BFIC.