Impaired sleep quality and cognition in patients of Parkinson's disease with REM sleep behavior disorder: a comparative study.

OBJECTIVES: The present study was undertaken to evaluate the cognitive profile of Parkinson's disease (PD) patients with REM sleep behavior disorder (RBD) and to correlate with the clinical stage and polysomnographic variables. METHODS: The study included 25 PD patients who had RBD and 25 PD patients who based on two questionnaires were determined as not having RBD. These patients underwent overnight polysomnography (PSG) and neuropsychological assessment using a defined battery of tests. RESULTS: The mean age of the patients with clinically probable RBD (RBD+) was 60.4 ± 8.2 years and PD patients without RBD (RBD-) was 57.3 ± 6.6 years (p = 0.14). The mean age at onset of the disease was 53.7 ± 9.4 years for RBD+ and 49.8 ± 7.8 years for RBD-patients (p = 0.12). The mean Unified Parkinson Disease Rating Scale (UPDRS) part III OFF score was 27.4 ± 11.1 for RBD+ and 32.7 ± 8.2 for RBD- (p = 0.06). The total sleep time of the patients was 4.3 ± 1.7 h with sleep efficiency of 53.8 ± 21.0%. Patients with RBD+ were found to have significant impairment in many neuropsychological tests compared to RBD-. CONCLUSIONS: RBD + patients had significant impairment in MMSE, category fluency test (FAS test), frontal assessment battery, attention (digit span backwards, Corsi span), verbal memory (story recall) and Rey's auditory verbal learning test. These patients also had poor sleep quality.

Evaluation of Cognition and Cortical Excitability in Huntington's Disease.

BACKGROUND: Recent advances in neurophysiological techniques have contributed to our understanding of the pathophysiology of Huntington's disease (HD). Studies of the motor cortical excitability and central motor pathways have shown variable results. OBJECTIVES: Our aims were to evaluate the cortical excitability changes in HD using transcranial magnetic stimulation (TMS) and correlate the changes with cognitive impairment. METHODS: The study included 32 HD patients and 30 age- and gender-matched controls. The demographic and clinical profiles of the patients were recorded. All subjects were evaluated by TMS and resting motor threshold (RMT), central motor conduction time (CMCT), silent period (SP), short-interval intracortical inhibition (SICI), and intracortical facilitation were determined. A battery of neuropsychological tests was administered to all subjects. RESULTS: The mean age of the patients was 42.1±14.1 years, and that of controls 39.4±12.4 years (p=0.61). There was no significant difference in RMT and CMCT between the two groups. There was a mild prolongation of the contralateral SP in HD, but it was not significant. SICI was significantly reduced in HD (p<0.0001). A significant impairment in attention, verbal fluency, executive function, visuospatial function, learning, and memory was observed in HD patients. However, there was no correlation between cortical excitability changes and cognitive impairment. CONCLUSIONS: TMS is a valuable method of evaluating cortical excitability changes in HD. These patients have reduced SICI and significant impairment of cognition in multiple domains.

Long Loop Reflex 2 in Patients with Cortical Dementias: A Pilot Study.

INTRODUCTION: Dementia is a major public health problem and it appears to be a global epidemic. The prevalence is doubling every 5 years and it is expected that 70% of persons above 60 years will live in developing countries by 2020 and 15% of them are likely to suffer from dementia. Disease modifying treatments work only if initiated very early; however, diagnostic tools are not always able to clearly differentiate the different types in very early stage. Therefore, inexpensive and easily available biomarkers are needed to know if collectively they will improve the sensitivity of specific diagnosis. Therefore, in this pilot study, we have tried to analyze if long loop reflex (LLR2) is differentially affected in these two conditions early in the course of Alzheimer's dementia (AD) and frontotemporal dementia (FTD) based on hypothesis taking into account the anatomical substrates involved. PATIENTS AND METHODS: Mild cases of clinically probable AD and FTD after appropriate inclusion criteria were subjected for LLR testing in the upper limb at median nerve. The presence or absence of LLR was assessed and also the latency, amplitude, and duration assessed. RESULTS AND CONCLUSION: LLR 2 is differentially affected in both these conditions. Absence of LLR2 was consistently seen in FTD which can be explained by early break down of frontal subcortical circuits in this condition as against AD. This is likely to serve as a very cheap and very early biomarker to differentiate the two common types of cortical dementias.

Re-emergent tremor in Parkinson's disease: A clinical and electromyographic study.

BACKGROUND: Re-emergent tremor (ReT) in Parkinson's disease (PD) is the tremor that re-emerges after a variable period of latency while maintaining posture. The phenomenology and electrophysiological aspects of ReT have not been well characterized. The aims of this study were to characterize ReT clinically and electrophysiologically. METHODS: Sixty three patients with tremor dominant PD were recruited and subjected to clinical and electrophysiological evaluations. Group 1 consisted of 26 patients with rest tremor (RT) and ReT and group 2 consisted of 37 patients with RT and postural tremor (PT). The presence of silent period of ReT was determined clinically and confirmed electrophysiologically. RESULTS: The duration of illness was significantly shorter in patients with ReT as compared to patients without ReT (5.2±4.4years vs 7.4±4.5years, p=0.03). ReT was similar to RT in terms of both frequency (4.8±0.7Hz vs 4.7±0.6Hz, p=0.1) and pattern of contraction. The frequency of RT was not significantly different in the 2 groups (p=0.5). The mean duration of silent period was 8.1±8.7s. CONCLUSIONS: A significantly shorter duration of illness was found in patients with ReT as compared to patients without ReT. ReT is similar to RT in terms of frequency and pattern of contraction. However, the presence of silent period may imply additional pathophysiological mechanisms.

A Study of Cortical Excitability, Central Motor Conduction, and Cortical Inhibition Using Single Pulse Transcranial Magnetic Stimulation in Patients with Early Frontotemporal and Alzheimer's Dementia.

INTRODUCTION: Degenerative cortical dementias affect several million people worldwide. Early diagnosis and categorization are essential for initiating appropriate pharmacological and nonpharmacological treatment so that deterioration can be postponed, and disability adjusted life years can be saved both for the patient and for the caregiver. Therefore, an early, simple, noninvasive biomarker will serve as a boon. PATIENTS AND METHODS: Patients who satisfied probable Alzheimer's disease (AD) or frontotemporal dementia (FTD) using international consensus criteria for FTD and National Institute of Neurological Disorders and Stroke-AD and Related Disorders Association criteria for AD were evaluated using single pulse transcranial magnetic stimulation with figure of eight coil and motor evoked potential from right first dorsal interossei. Resting threshold (MT), central motor conduction time (CMCT), and silent period (SP) were evaluated. RESULTS: Resting MT and SP are reduced in patients with Alzheimer's disease whereas CMCT is prolonged in patients with FTD and SP is in the lower limit of normal in both conditions. CONCLUSION: The patterns of central motor conduction and MT are distinctly different in patients with early Alzheimer's disease (AD) and FTD.

Transcranial Magnetic Stimulation (TMS) as a Tool for Early Diagnosis and Prognostication in Cortico-Basal Ganglia Degeneration (CBD) Syndromes: Review of Literature and Case Report.

BACKGROUND: Cortico basal degeneration (CBD) of the brain is a rare progressive neurodegenerative disease which encompasses unique neuropsychiatric manifestations. Early diagnosis is essential for initiating proper treatment and favorable outcome. Transcranial Magnetic Stimulation (TMS), a well-known technique for assessment of cortical excitatory and inhibitory properties. It was suggested that in a degenerative disease like CBD which involves the cortex as well as the subcortical structures, comparing both hemispheres, a differential pattern in TMS can be obtained which would help in early identification, prognostication and early therapeutic intervention. CASE REPORT: We describe a case of CBD with corroborative clinical and imaging picture wherein single pulse TMS was used over both the hemispheres measuring the following parameters of interest which included: Motor Threshold (MT), Central Motor Conduction Time (CMCT) and Silent Period (SP). RESULTS AND CONCLUSION: Differential patterns of MT, CMCT and SP was obtained by stimulating over both the hemispheres with the affected hemisphere showing significantly reduced MT and prolonged CMCT implying early impairment of cortical and subcortical structures thereby revealing the potential application of TMS being utilized in a novel way for early detection and prognostication in CBD syndromes.

Evaluation of the Erosive Potential of Various Pediatric Liquid Medicaments: An in-vitro Study.

BACKGROUND: The present in-vitro study was a scanning electron microscope (SEM) study conducted in primary teeth in order to evaluate the erosive potential of ten commonly used pediatric liquid medications (PLMs). MATERIALS & METHODS: 10 commonly used PLMs and 33 exfoliated or extracted primary teeth were collected. The 33 teeth were divided into two groups, the control group (n=3) and the study group (n=30). The endogenous pH of all the teeth was measured using a pH electrode meter. The control group teeth were immersed in artificial saliva for three different time intervals- 1 minute, 10 minutes and 8 hours. The study group teeth were also maintained for 1 minute, 10 minutes and 8 hours in various selected PLMs. The primary enamel surface (PES) changes were then observed under the SEM for all the teeth of both groups. RESULTS: All the PLMs used in the study showed an erosive effect on the PES when viewed under SEM. Majority of the medications caused etched prism pattern followed by crater formation and sporadic rod ends in that order on PES. CONCLUSION: There is a need to educate parents and professionals about the association between dental erosion and PLMs which predisposes to dental caries. How to cite the article: Tupalli AR, Satish B, Shetty BR, Battu S, Kumar JP, Nagaraju B. Evaluation of the Erosive Potential of Various Pediatric Liquid Medicaments: An In-vitro Study. J Int Oral Health 2014;6(1):59-65.

Transcranial magnetic stimulation in patients with early cortical dementia: A pilot study.

CONTEXT: The diagnostic accuracy of the currently available tools carries poor sensitivity resulting in significant delay in specific diagnosis of cortical dementias. Considering the properties of default mode networking of the brain it is highly probable that specific changes may be seen in frontotemporal dementias (FTDs) and Alzheimer's disease sufficiently early. AIM: The aim of this study is to look for changes in Transcranial Magnetic Stimulation (TMS) in cortical dementia. MATERIALS AND METHODS: Evaluated with a single pulse TMS with the figure of eight coil and recorded from right first dorsal interossei (FDI). Resting Motor Threshold (RMT) was estimated on the opposite motor cortex (T1). Second site of stimulation was cervical spine at C7-T2. Central motor conduction time (CMCT) is equal toT1-T2. Silent Period (SP) identified by applying TMS pulse to contracting FDI. CONCLUSIONS: RMT was reduced in seven out of eight Alzheimer's dementias. CMCT was in the upper limit of normal in both patients with FTD. The most consistent observation was that SP was reduced and there were escape discharges noticed during the SP suggesting increased cortical excitability and decreased cortical inhibition. This suggests probable early asymptomatic changes in the gamma-aminobutyric acid (GABA) nergic and cholinergic system is taking place. This if confirmed may give some insight into early diagnosis and therapeutic role of GABA agonists in these disorders.

Alterations of cortical excitability and central motor conduction time in Wilson's disease.

Wilson's disease (WD) leads to widespread structural alterations of central nervous system and our objectives were to determine the cortical excitability changes in WD by using transcranial magnetic stimulation (TMS). Thirteen patients with WD, diagnosed by the presence of Kayser-Fleischer ring and biochemical tests, were studied. TMS was performed using a figure-of-eight coil attached to Magstim 200 stimulator. Motor evoked potentials (MEP) were recorded from right first dorsal interosseous at rest. Resting motor threshold (RMT) was determined using standard techniques and central motor conduction time (CMCT) by 'F' wave method. Comparison was made with control data of our laboratory. Dysarthria was the presenting symptom in 5 patients (38.5%) and chorea, tremors, dystonia and abnormal gait in 2 patients each (15.4%). RMT was recordable in 10 patients and not recordable in 3. Compared to controls, patients in whom RMT was recordable, had significantly higher mean RMT (80.9 ± 14.8 vs. 41.1 ± 7, p<0.0001) and CMCT (6.7 ± 0.5 ms vs. 4.8 ± 0.6 ms; p<0.0001). In 2 of the 3 patients with non-recordable RMT, MEP could be obtained with active contraction. CMCT in these 2 patients was also prolonged. Patients with WD have reduced cortical excitability and prolonged CMCT which may be due to the intracortical presynaptic motor dysfunction.

Large cystic renal cell carcinoma leading to diagnostic dilemma: a case report.

Large cystic renal tumours can be confused with hepatic lesions even on crosssectional imaging. Careful clinical, sonographic and imaging analysis is needed for establishing correct diagnosis. We report a case of papillary cystic renal carcinoma in a 60 year old man, which was confused with amoebic liver abcess and was initially drained. Subsequent recurrence of symptoms prompted us to re-evaluate the case and repeat sonography confirmed the extrahepatic origin of mass based on simple observation that the liver and mass were moving separately on inspiration. Later guided aspiration from solid component of the mass confirmed the diagnosis as renal cell carcinoma. He was successfully treated with radical nephrectomy with uneventful post-operative recovery.

Production of alkaline protease by Bacillus altitudinis GVC11 using castor husk in solid-state fermentation.

Castor (Ricinus communis L.) is an important oil seed crop having its main cultivated area in India, China, and Brazil in dry land farming. Castor husk is generated as waste in castor oil production. Use of castor husk waste as substrate is studied for alkaline protease production by Bacillus altitudinis GVC11 in solid-state fermentation. Various parameters like moisture content, incubation period, particle size, effect of carbon and nitrogen sources are studied and optimized for enzyme production. Highest enzyme production of 419,293 units per gram husk is obtained. Cost of enzyme production can be reduced by using castor husk as substrate.

Efficacy of single-dose chemotherapy (rifampicin, ofloxacin and minocycline-ROM) in PB leprosy patients with 2 to 5 skin lesions, India: randomised double-blind trial.

UNLABELLED: We conducted randomized double-blind trial for single-dose of Rifampicin, Ofloxacin and Minocycline (ROM) compared to WHO-PB-MDT among paucibacillary (PB) leprosy patients with 2-5 skin lesions. We enrolled 1526 patients from five centres (ROM=762; WHO-PB-MDT=764) and followed them for 36 months posttreatment during 1998-2003. We generated information on clearance of skin lesions and relapse rates per 100 person-years (PY) for all the five centres. At base-line, the patients in the two arms were comparable. Complete clearance of skin lesions was similar (72% vs. 72.1%; p=0.95) in both the arms. Clinical scores declined steadily and equally. Difference in relapse rates was statistically highly significant (ROM=1.13 and WHO-PB-MDT=0.35 per 100 PY; mid-p exact=0.001016). Twenty eight of 38 of these relapses occurred within 18 months. In all, 10 suspected adverse drug reactions were.observed (ROM=2; WHO-PB-MDT=8). We extended the follow-up to 48 months for 1082 of 1526 patients from two programme-based centres. No further relapses occurred. Decline in clinical score was not dependent on age, gender, number of lesions or affected body parts. Single dose ROM, though less effective than the standard WHO-PB-MDT regimen conceptually offers an alternative treatment regimen for PB leprosy patients with 2-5 lesions only when careful follow-up for relapse is possible. Registered at the Clinical Trials Registry of India; REGISTRATION NUMBER: CTRI/2012/05/002645

LC and LC-MS/MS study of forced decomposition behavior of anastrozole and establishment of validated stability-indicating analytical method for impurities estimation in low dose anastrozole tablets.

Anastrozole tablets were subjected to different ICH prescribed stress conditions of thermal, hydrolysis, humidity, photolysis and oxidation stress. The drug was found to be stable for all the stressed conditions except for oxidation. Separation of anastrozole from its potential impurities, degradation products and five anastrozole related compounds as main impurities were achieved on Inertsil ODS-3V, 250 mm x 4.6 mm i.d, 5 microm analytical column using reversed phase high performance liquid chromatography (RP-HPLC). The elution of impurities employed time dependent gradient programmed mobile phase consisting of water as mobile phase-A and acetonitrile as mobile phase-B at column flow rates of 1 ml/min and at 215 nm UV detection. The same method was also extended to LC-MS/MS studies which were carried out to identify the degradation product. The method developed was established to have sufficient intermediate precision as similar separation was achieved on another instrument handled by a different operator. The LOQ for anastrozole related compound-A (RC-A), related compound-B (RC-B), related compound-C (RC-C), related compound-D (RC-D), related compound-E (RC-E) and anastrozole were 0.05, 0.03, 0.03, 0.06, 0.06 and 0.06 microg ml(-1) respectively. The linearity of the proposed method for all the above related compounds was investigated in the range of LOQ to 0.600 microg ml(-1) respectively. The specificity was established through peak purity testing using a photo-diode array detector. Method was validated according to ICH guidelines and statistical analysis of the data proved to be suitable for stability testing at quality control.

Design and realization of an all-fiber broadband tunable gain equalization filter for DWDM signals.

Design and fabrication of a tunable gain equalization filter for dense wavelength division multiplexed (DWDM) signals through erbium doped fiber amplifiers (EDFA) is reported. It is based on a side-polished fiber (SPF) half-coupler block loaded with a displaceable tapered multimode overlay waveguide (MMOW). A simple and accurate normal mode analysis is employed to design this filtering device for its subsequent realization. Equalization of a typical EDFA gain spectrum in the C-band within +/-0.35 dB or even less in the presence of various ITU standard C-band DWDM signal channels is demonstrated under varied operating conditions like add/drop of signals. Tunability of the filter notch is achieved through displacement of the SPF relative to the MMOW.

Utility of serodiagnostic tests for leprosy: a study in an endemic population in South India.

In order to evaluate the usefulness of natural disaccharide (PGL1) and 35 kDa antigens based serology in diagnosis of leprosy and in detecting high risk groups for leprosy, this study was conducted in an endemic population in South India. Out of 3346 cases and their households and neighbouring household contacts, serum samples from 2994 and 2875 individuals were screened for antibodies against PGL1 and 35kDa antigens respectively. While the overall positivity for contacts and leprosy cases was 3.3% for PGL1 antibody, the positivity for 35 kDa antibody was 6.3%. The positivity for contact population was 2.7% and 5.4% for PGL1 and 35 kDa antibodies, respectively. Lepromatous and borderline lepromatous patients showed positivity of 35.1% for PGL1 antibody and 45.7% for 35 kDa antibody. Follow-up of contacts showed that the majority (>90%) remained seronegative for both the antibodies and most of the new cases emerged from the seronegative group. The study clearly indicates that specific serological assays are not sensitive enough for application, both for diagnosis and for identifying any individual at risk for leprosy in the south Indian endemic population.

Application of lot quality assurance sampling for leprosy elimination monitoring--examination of some critical factors.

BACKGROUND: The concept of elimination of an infectious disease is different from eradication and in a way from control as well. In disease elimination programmes the desired reduced level of prevalence is set up as the target to be achieved in a practical time frame. Elimination can be considered in the context of national or regional levels. Prevalence levels depend on occurrence of new cases and thus could remain fluctuating. There are no ready pragmatic methods to monitor the progress of leprosy elimination programmes. We therefore tried to explore newer methods to answer these demands. With the lowering of prevalence of leprosy to the desired level of 1 case per 10000 population at the global level, the programme administrators' concern will be shifted to smaller areas e.g. national and sub-national levels. For monitoring this situation, we earlier observed that lot quality assurance sampling (LQAS), a quality control tool in industry was useful in the initially high endemic areas. However, critical factors such as geographical distribution of cases and adoption of cluster sampling design instead of simple random sampling design deserve attention before LQAS could generally be recommended. The present exercise was aimed at validating applicability of LQAS, and adopting these modifications for monitoring leprosy elimination in Tamil Nadu state, which was highly endemic for leprosy. METHODS: A representative sample of 64000 people drawn from eight districts of Tamil Nadu state, India, with maximum allowable number of 25 cases was considered, using LQAS methodology to test whether leprosy prevalence was at or below 7 per 10000 population. Expected number of cases for each district was obtained assuming Poisson distribution. Goodness of fit for the observed and expected cases (closeness of the expected number of cases to those observed) was tested through chi(2). Enhancing factor (design effect) for sample size was obtained by computing the intraclass correlation. RESULTS: The survey actually covered a population of 62157 individuals, of whom 56469 (90.8%) were examined. Ninety-six cases were detected and this number far exceeded the critical value of 25. The number of cases for each district and the number of cases in the entire surveyed area both followed Poisson distribution. The intraclass correlation coefficients were close to zero and the design effect was observed to be close to one. CONCLUSIONS: Based on the LQAS exercises leprosy prevalence in the state of Tamil Nadu in India was above 7 per 10000. LQAS method using clusters was validated for monitoring leprosy elimination in high endemic areas. Use of cluster sampling makes this method further useful as a rapid assessment procedure. This method needs to be tested for its applicability in moderate and low endemic areas, where the sample size may need increasing. It is further possible to consider LQAS as a monitoring tool for elimination programmes with respect to other disease conditions.

Studies on rapid assessment methods in leprosy.

A study was undertaken in Pudukottai district, Tamilnadu, India to test rapid assessment methods: viz (i) sample surveys with lower coverages for clinical examination in estimating the disease problem in the community, (ii) utility of registered case prevalence for estimating the actual prevalence in a given area, (iii) leprosy in school-going children and its utility in estimating leprosy prevalence in the community, and (iv) information on disability and smear positivity in estimating leprosy prevalence; and develop correction factors for estimating leprosy situation. A sample of 23 clusters from 582 clusters of contiguous villages and hamlets was further divided into two random sub-samples for two surveys with differing coverages. One team covered nine clusters comprising 34 villages with a population of 17,562 and examined 15,596 with a population of 26,927 and examined 16,622 (62%) persons for leprosy. The results showed that: (i) leprosy sample surveys with lowered coverages would tend to miss valuable information, in terms of quality and quantity; (ii) from 'known case' registers, to estimate the true burden of leprosy disease and to monitor its trend over time is inadequate; (iii) school surveys are of limited value for estimating the disease burden in the community or to monitor its trend over time; (iv) the number of smear-positive cases is to small to serve as an indicator for the total case load in the community; and (v) the prevalence of active disease and that of grade 2 disability in the community are poorly correlated. Reliable methods other than those used here need to be developed for evaluation and monitoring of the disease burden particularly in the post-MDT era.

Comparative leprosy vaccine trial in south India.

This report provides results from a controlled, double blind, randomized, prophylactic leprosy vaccine trial conducted in South India. Four vaccines, viz BCG, BCG+ killed M. leprae, M.w and ICRC were studied in this trial in comparison with normal saline placebo. From about 3,00,000 people, 2,16,000 were found eligible for vaccination and among them, 1,71,400 volunteered to participate in the study. Intake for the study was completed in two and a half years from January 1991. There was no instance of serious toxicity or side effects subsequent to vaccination for which premature decoding was required. All the vaccine candidates were safe for human use. Decoding was done after the completion of the second resurvey in December 1998. Results for vaccine efficacy are based on examination of more than 70% of the original "vaccinated" cohort population, in both the first and the second resurveys. It was possible to assess the overall protective efficacy of the candidate vaccines against leprosy as such. Observed incidence rates were not sufficiently high to ascertain the protective efficacy of the candidate vaccines against progressive and serious forms of leprosy. BCG+ killed M. leprae provided 64% protection (CI 50.4-73.9), ICRC provided 65.5% protection (CI 48.0-77.0), M.w gave 25.7% protection (CI 1.9-43.8) and BCG gave 34.1% protection (CI 13.5-49.8). Protection observed with the ICRC vaccine and the combination vaccine (BCG+ killed M. leprae) meets the requirement of public health utility and these vaccines deserve further consideration for their ultimate applicability in leprosy prevention.

Sensitization and reactogenicity of two doses of candidate antileprosy vaccine Mycobacterium w.

M.w vaccine is one of the antileprosy vaccines under test in an ongoing comparative vaccine trial in South India. The objective of the present study was to examine the sensitizing ability, as measured by skin test reactions to Rees' MLSA and lepromin, and reactogenicity of M.w vaccine in the local population. Two doses of M.w, 1 x 10(9) bacilli and 5 x 10(9) bacilli, were used, in two separate studies of 395 and 400 "healthy" individuals aged 1-65 years. In each study, the study subjects received either M.w vaccine or normal saline (control), by random allocation. The results showed that healing of vaccination lesions was uneventful although the healing process was somewhat prolonged with the higher dose. The mean size of lesions was 7.0 mm and 9.5 mm with the low and high doses of the vaccine, respectively. The results also showed that M.w vaccine in a dose of 1 x 10(9) bacilli, failed to induce post-vaccination sensitization as measured by reactions to Rees' MLSA and by Fernandez and Mitsuda reactions to lepromin-A. However, when the dose of the vaccine was increased to 5 x 10(9) bacilli the mean sizes of post-vaccination reactions to Rees' MLSA and lepromin-A (both early and late) were significantly larger in the vaccine group compared to that in the control group. The sensitizing effect attributable to the vaccine was of the order of 1.5 mm to 1.8 mm.