An ultra-low noise optical head for liquid environment atomic force microscopy.

The design considerations and eventual performance of a new, ultra-low noise optical head for dynamic atomic force microscopy (AFM) are presented. The head, designed specifically for the study of hydration layers and ion organization next to solid surfaces and biomolecules, displays an integrated tip-sample distance noise below 3 pm. The sensitivity of the optical beam deflection sensor, operating at frequencies up to 8.6 MHz (3 dB roll-off), is typically below 10 fm/√Hz, enabling utilization of high frequency cantilevers of low thermal noise for fundamental and higher mode imaging. Exceptional signal stability and low optical noise are achieved by replacing the commonly used laser diode with a helium-neon laser. An integral photothermal excitation of the cantilever produces pure harmonic oscillations, minimizing the generation of higher cantilever modes and deleterious sound waves characterizing the commonly used excitation by a piezoelectric crystal. The optical head is designed to fit on top of the widespread Multimode(®) (Bruker) piezo-tube and accommodate its commercial liquid cell. The performance of the new AFM head is demonstrated by atomic resolution imaging of a muscovite mica surface in aqueous solution.

The contribution of Niemann-Pick SMPD1 mutations to Parkinson disease in Ashkenazi Jews.

INTRODUCTION: Parkinson disease is noted for its association with mutations in GBA and the p.G2019S mutation in LRRK2. This study aimed to evaluate the frequency of Ashkenazi founder mutations in sphingomyelin phosphodiesterase 1 (SMPD1) in Ashkenazi patients diagnosed with Parkinson's disease (PD); and their impact on PD phenotypic expression. SMPD1 underlies the lysosomal storage disease - Niemann-Pick. METHODS: A case (n = 287) control (n = 400) study was undertaken. All patients underwent a physical, neurobehavioral and neurologic examination that incorporated the Unified Parkinson's Disease Rating Scale. Three founder SMPD1 Ashkenazi mutations (c.996delC (fsP330), p.L302P and p.R496L) were investigated in patients and controls, previously evaluated for carriage of founder mutations in GBA and the p.G2019S mutation in LRRK2. RESULTS: Nine (3.1%) PD patients compared to two (0.5%) individuals from the control group were found to carry one of the three Ashkenazi SMPD1 founder mutations (p = 0.007). The overall clinical characteristics of PD patients carrying SMPD1 mutations were similar to those of PD patients with no mutations in SMPD1, GBA and LRRK2 (n = 189). CONCLUSION: We maintain that disruptive mutations in SMPD1 constitute a risk factor for PD.

Restless legs syndrome in stroke patients.

BACKGROUND: Restless legs syndrome (RLS) is associated with cerebrovascular risk factors, but its possible association with cerebrovascular disease has yielded conflicting results. OBJECTIVE: This was a case-control, in-hospital study to evaluate the association between RLS and acute stroke or transient ischemic attack (TIA). METHODS: We evaluated patients hospitalized with acute stroke/TIA and an age and gender 2:1 frequency-matched control group, for the presence of RLS. RESULTS: Twenty-two of 149 patients (15%) and 10 of 298 controls (3%) suffered from RLS (p <0.0001). A multivariate logistic regression model employing cerebrovascular risk factors as predictors, that is, hypertension, hyperlipidemia, diabetes, and body mass index (BMI), determined that stroke/TIA was significantly associated with RLS with odds ratio for RLS among patients with stroke/TIA versus controls of 7.60 (95% confidence interval (CI): 2.07-27.87; p = 0.002). Another multivariate logistic regression model adjusting for possible RLS risk factors, that is, hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function, determined that stroke/TIA was significantly associated with RLS with odds ratio of 6.85 (95% CI: 6.85-1.79; p = 0.005). Stepwise logistic regression with hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function as potential predictors revealed that only stroke/TIA predicted RLS with similar odds ratio to the RLS-based multivariate model of 6.54 (95% CI: 2.63-16.27; p <0.0001). CONCLUSIONS: Examining stroke patients while in hospital allowed us to conclude that RLS and acute stroke/TIA are significantly associated. However, the cross-sectional design did not allow for the determination of a causative relationship between the two.

Asymmetric pain processing in Parkinson's disease.

BACKGROUND AND PURPOSE: Reduced endogenous pain inhibition, as part of the degenerative process, is presumed to be the mechanism underlying the common presence of pain in patients with Parkinson's disease (PD). The present study aimed to assess an endogenous pain inhibitory system in PD using the conditioned pain modulation paradigm. METHODS: Twenty-six predominantly unilateral PD patients and 19 controls underwent psychophysical pain assessment before and after patients' morning dopaminergic medication. RESULTS: An unexpected increase in several parameters of pain perception for PD patients was found after dopaminergic medication (e.g. for 49°C noxious heat stimulation an increase from 70.6 ± 4.0 to 77.6 ± 4.0 on the numerical pain scale, P < 0.001). This increase was seen in patients with predominantly left-sided PD, regardless of the stimulated side (for 49°C noxious heat stimulation, predominantly left-sided PD patients, pain perception increased from 73.5 ± 6.8 to 85.0 ± 6.8, P < 0.001, whereas predominantly right-sided PD patients did not show a significant increase, 68.3 ± 6.8 to 70.4 ± 6.5, P = 0.777). Baseline efficiency of conditioned pain modulation inversely correlated with age at disease onset (r = -0.522; P = 0.009) and disease severity (Unified PD Rating Scale, r = 0.447; P = 0.032) but did not differ between patients and controls. CONCLUSIONS: Increased sensory response causing hyperalgesia occurs after dopaminergic medication in patients with predominantly left-sided PD.

The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers.

OBJECTIVE: In view of the fact that cancer patterns in patients with Parkinson disease (PD) differ from the general population, we aimed to verify whether patients with PD with LRRK2 mutations have an increased risk for particular cancer types. METHODS: In this cross-sectional study, eligible consenting Jewish patients with PD were genotyped for the predominant LRRK2 G2019S mutation. Oncologic data were obtained by personal interview and reviewing patients' files. Stepwise logistic regression was applied to model the probability of cancer occurrence in carriers vs noncarriers. RESULTS: Overall, 79/490 (16.1%) genotyped patients carried the G2019S mutation. Seventy-seven (16%) were diagnosed with cancer; of those, 67 (14%) with a non-skin cancer. Eighteen (23%) carriers vs 49 (12%) noncarriers had a non-skin cancer (p = 0.01, odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.19-3.99). A significant ethnicity effect was noted (p = 0.045, OR = 1.84, 95% CI 1.02-3.34). Among Ashkenazi patients, age and LRRK2 emerged as significant using stepwise logistic regression including age, gender, and LRRK2 status as explanatory variables. The OR for LRRK2 mutation carriers adjusted for age was 3.38 (95% CI 1.64-6.97, p = 0.0009). CONCLUSIONS: Ashkenazi Jewish patients with PD who harbor the G2019S LRRK2 mutation are more likely to have a concomitant non-skin cancer than noncarriers.

Sleep disturbances after whiplash injury: objective and subjective findings.

OBJECTIVE: A controlled objective and subjective evaluation of sleep in a consecutive series of persons who had had a whiplash injury, shortly following the injury and 3 to 5 months later. METHODS: In whiplash-injured subjects and healthy controls, sleep characteristics were monitored objectively throughout the night by means of an actigraph. The following morning, participants in both groups filled out a prestructured "sleep log" that conveyed their subjective impressions as to how they had slept. The correlation between objectively measured sleep characteristics and the symptoms and physical findings, respectively, resulting from whiplash injury were also examined. RESULTS: Actigraphic monitoring did not reveal a significant group difference between whiplash-injured subjects and controls with respect to any of the sleep characteristics recorded. In self-maintained "sleep logs," however, the whiplash-injured subjects reported a significantly prolonged sleep latency and significantly impaired sleep quality compared with controls (P<.001 and P<.04, respectively). In whiplash-injured subjects, the number of arousals was positively correlated with the number of symptoms and with the number of physical signs of whiplash injury (P<.01 and P<.001, respectively). Sleep efficiency was inversely correlated with the number of injury-related findings on physical examination (P<.009). CONCLUSION: Sleep, as monitored by actigraph in whiplash-injured subjects, was not adversely affected by whiplash injury. The subjective impressions of the subjects, as recorded in "sleep logs," suggest the opposite conclusion. A significant correlation exists between certain symptoms and signs of whiplash injury and abnormalities in given sleep characteristics as detected by actigraph.

Evidence for activation of the coagulation system in migraine with aura.

Migraine with aura has been shown to be an independent risk factor for stroke. Although the precise mechanism of migraine-related stroke is not known, risk factors for hypercoagulability have been found in migraineurs. Prothrombin factor 1.2 (F1.2) is a cleavage product of prothrombin. Elevated plasma F1.2 has been shown to be a sensitive and a specific marker of ongoing thrombin generation, and thus may serve as an indicator of hypercoagulability. In this study we determined plasma F1.2 levels in 35 patients with migraine (22 with aura and 13 without aura) and in 24 healthy age- and sex-matched volunteers. Elevated F1.2 levels were found in 11 of 22 (50%) patients with migraine with aura (1.25-3.5 nmol/l). None of the patients with migraine without aura nor any of the healthy volunteers had elevated plasma F1.2 levels (normal < 1.1 nmol/l). We conclude that prothrombin F1.2 levels are elevated in a significant number of patients with migraine with aura but not in patients with migraine without aura. This finding suggests that there is activation of the clotting system in certain patients with migraine with aura.

Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene.

Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by glycogen branching enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.

Adult-onset Niemann-Pick type C disease. Clinical, biochemical, and genetic study.

BACKGROUND: Niemann-Pick type C disease is an autosomal recessive neurometabolic disorder of unknown origin mapped to chromosome 18q11-12 in most of the studied families. In contrast to the sphingomyelin lipidoses, in Niemann-Pick type C disease, fibroblasts are impaired in intracellular homeostatic responses to exogenous low-density lipoprotein (LDL) cholesterol. Biochemical heterogeneity of the disorder in relation to abnormal LDL processing is associated with various clinical presentations, but adult-onset Niemann-Pick type C disease is rare and has not been comprehensively characterized. OBJECTIVE: To describe clinical, biochemical, and genetic features of adult-onset Niemann-Pick type C disease in 3 siblings. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS: The 3 siblings manifested a variable combination of vertical supranuclear ophthalmoplegia, ataxia, and splenomegaly. Brain magnetic resonance imaging showed cerebellar atrophy; brainstem auditory evoked responses were unobtainable, and bone marrow examination disclosed typical foam cells. The patients were 20, 26, and 28 years old and belonged to a sibship of 13 born of consanguineous healthy parents. METHODS: Esterification of exogenous LDL cholesterol in cultured skin fibroblasts and filipin staining for free intracellular cholesterol. Polymerase chain reaction-based DNA linkage study using AC microsatellite markers D18S40, D18S44, D18S480, and D18S66. RESULTS: Fibroblasts of the 3 patients showed a 23% to 58% block in the induced cholesterol esterification after 4 1/2 hours and a mild to moderate accumulation of free cholesterol. DNA study demonstrated linkage to the major 18q11-12 Niemann-Pick type C locus and identified unaffected carriers. CONCLUSIONS: These results confirm the diagnosis of the least biochemically affected Niemann-Pick type C phenotype in this family with adult-onset disease and support a correlation between the mild laboratory and clinical findings in this age group.

Inclusion body myositis: atypical clinical presentations.

Inclusion body myositis affects primarily the proximal muscles but distal limb muscles are involved too in this chronic myopathy. Characteristic histopathologic findings include "rimmed vacuoles', inflammation and typical cytoplasmic and nuclear filamentous inclusions. The patients are usually unresponsive to steroids. We present four inclusion body myositis patients with atypical clinical presentations: one with scapuloperoneal syndrome, one with post-polio-like syndrome and two with associated immune-mediated diseases (one with undefined autoimmune disorder and the second with scleroderma). Two patients responded to high-dose steroid therapy. We suggest that the clinical spectrum of inclusion body myositis is wider than previously appreciated.

Cutaneous ulceration resembling pyoderma gangrenosum in the primary antiphospholipid syndrome: a report of two additional cases and review of the literature.

The antiphospholipid antibody syndrome has been associated with various cutaneous manifestations, the most common of which may be leg ulceration. Cutaneous ulcers with clinical features suggestive of pyoderma gangrenosum have been reported in this setting only rarely. We report here two additional cases of the association between antiphospholipid antibody syndrome and pyoderma gangrenosum-like skin lesions. These patients suffered from the primary antiphospholipid syndrome. We suggest that clinicians assay for antiphospholipid antibodies when a clinical diagnosis of pyoderma gangrenosum is entertained.

Antibiotic induced meningitis.

Three patients with antibiotic induced meningitis, one following penicillin with seven episodes, are reported on--the first well documented description of penicillin induced meningitis. In this patient episodes of headache and nuchal rigidity appeared with and without CSF pleocytosis. Two patients had a total of five episodes of antibiotic induced meningitis after trimethoprim-sulphamethoxazole (co-trimoxazole) administration. The features common to all three patients were myalgia, confusion and low CSF glucose. CSF analysis was not a reliable method to differentiate antibiotic induced meningitis from partially treated bacterial meningitis.

Crusted (Norwegian) scabies in patients with AIDS: the range of clinical presentations.

Crusted (Norwegian) scabies in AIDS patients can be manifested in both typical and atypical forms. Although the classic, hyperkeratotic, nonpruritic lesions are most common, reported cases have ranged in spectrum from crusting with pruritus to a pruritic, papular dermatitis to those resembling Darier's disease or psoriasis. We report two additional cases of crusted scabies in AIDS patients, one with typical crusted, hyperkeratotic though pruritic lesions and one with severe pruritus and rare papules, initially misdiagnosed as "pruritus of AIDS." Because of the extremely contagious nature of crusted scabies, as well as its potential for complete cure with appropriate therapy, a high degree of suspicion for this disorder should be maintained in AIDS patients, even when the lesions do not have the classical appearance. The discovery of crusted scabies, whether in its common or its atypical form should prompt testing for the human immunodeficiency virus (HIV).

Multiple myeloma and AL amyloidosis mimicking Sjögren's syndrome.

A 49-year-old white man had xerostomia, orthostatic hypotension, salivary gland enlargement, and a monoclonal gammopathy. Salivary gland biopsy revealed AL amyloidosis without histopathologic evidence of Sjögren's syndrome; serologic evidence of Sjögren's syndrome was also absent. Bone marrow biopsy revealed more than 30% plasma cells, and a diagnosis of multiple myeloma was made. The association of myeloma amyloidosis with salivary gland infiltration and xerostomia is rare. Unusual causes of xerostomia, such as myeloma amyloidosis, should be considered when histopathologic and serologic evidence of Sjögren's syndrome are absent.

Percutaneous reduction and fixation of displaced juvenile Tillaux fractures: a new surgical technique.

Although it is not a very common injury, the juvenile Tillaux fracture is an intraarticular injury, so that accurate reduction is essential to restore the articular surface. Closed percutaneous reduction and internal fixation is a new method of treatment, used when manipulative reduction fails to restore the articular surface.