Complete validation of a continuous and blood-correlated sweat biosensing device with integrated sweat stimulation.

A wearable sweat biosensing device is demonstrated that stimulates sweat and continuously measures sweat ethanol concentrations at 25 s intervals, which is then correlated with blood ethanol during a >3 hour testing phase. The testing involves a baseline condition (no ethanol) followed by a rapid blood and sweat rise of ethanol (oral bolus), and finally, the physiological response of the body as ethanol concentrations return to baseline (metabolized). Data sets include multiple in vivo validation trials and careful in vitro characterization of the electrochemical enzymatic ethanol sensor against likely interferents. Furthermore, the data is analyzed through known pharmacokinetic models with a strong linear Pearson correlation of 0.9474-0.9996. The continuous nature of the data also allows analysis of blood-to-sweat lag times that range between 2.3 to 11.41 min for ethanol signal onset and 19.32 to 34.44 min for the overall pharmacokinetic curve lag time. This work represents a significant advance that builds upon a continuum of previous work. However, unresolved questions include operation for 24 hours or greater and with analytes beyond those commonly explored for sweat (electrolytes and metabolites). Regardless, this work validates that sweat biosensing can provide continuous and blood-correlated data in an integrated wearable device.

Measurement of the glucose transport time delay between the blood and aqueous humor of the eye for the eventual development of a noninvasive glucose sensor.

In the recent past, several noninvasive optically based methods have been proposed for physiologic glucose sensing. One proposed optical sensing site has been the eye, which, due to its unique optical properties, can be considered as a transparent optical window into the body. In particular, the aqueous humor within the anterior chamber of the eye has been shown to contain glucose levels correlated to those of blood. Concern, however, has been expressed that using the aqueous humor solution as a measure of blood glucose may be problematic due to the potential transport time delay between the blood and the aqueous humor glucose concentrations. This investigation was performed to measure the transport time delay in a rabbit model. The time delay between the blood and aqueous humor glucose concentrations was measured invasively in five New Zealand White rabbits over a series of weeks. An anesthesia protocol containing the drug Xylazine was used to elevate the blood glucose levels to a level commonly seen in diabetic patients. The difference between the glucose peak location times occurring in the blood and aqueous humor glucose response was measured and defined as the transport time delay. The average transport time lag was measured to be under 5 min. This measured time delay indicates that, indeed, the eye could potentially be used as a sensing site for indirect blood glucose measurements and may eventually aid the development of a noninvasive glucose sensor due to its unique optical properties compared to other biological tissues.

Prospective longitudinal analysis of postoperative shoulder function : a ten-year follow-up study of full-thickness rotator cuff tears.

BACKGROUND: Rotator cuff repair is associated with good short or mid-term results, but to date there have been no long-term functional outcome studies demonstrating durability of results over time. In most long-term studies, the results have been compared with those of historical controls or with those of other, short-term follow-up studies. The purpose of the present prospective study was to evaluate short and long-term shoulder function after surgical repair in a single population of patients in order to follow changes over time. METHODS: Thirty-three patients underwent surgery, performed by one surgeon, for the treatment of a chronic, symptomatic, full-thickness rotator cuff defect. Data were obtained from questionnaires and physical examinations preoperatively, at two years, and at ten years. Identical standardized pain and function questionnaires were used and clinical evaluation was performed in a consistent fashion at all time-periods. The activity level, Constant score, level of disability, shoulder function score, and patient's subjective rating of the outcome were determined at the time of the final follow-up and compared with the same parameters at the two-year follow-up examination in order to determine if early results change with time. RESULTS: At the ten-year follow-up examination, there was no change in the raw Constant score determined at the two-year examination. When the Constant score was normalized for expected age-related changes, the percentage of patients who had a satisfactory result at ten years was even greater than the percentage at two years. Activity level decreased significantly over the time-period (p = 0.005). At the final follow-up examination, twelve patients worked at the same occupation as they had when the two-year examination was performed, two worked at a less strenuous occupation, and the remaining patients were retired. Only two patients retired because of problems related to the shoulder. The level of disability decreased over the study period, and there was a small improvement in the patients' self-assessment shoulder function score. The patients' subjective assessment of the outcome remained unchanged. CONCLUSIONS: The results of open rotator cuff repair for chronic tears do not deteriorate with time (ten years). The level of disability decreases, presumably because of a concurrent decrease in the activity level and in the demand on the shoulder as the patient ages. It is important to consider age-related changes when assessing the final outcome.

Laser in situ keratomileusis-induced optic neuropathy.

OBJECTIVE: To report a case of bilateral optic neuropathy after bilateral laser-assisted in situ keratomileusis (LASIK) surgery. DESIGN: Observational case report. METHODS: Complete eye examination with detailed evaluation of the optic nerve, detailed medical history, stereo disc photographs, GDx Nerve Fiber Analyzer testing, Humphrey 24-2 SITA visual field testing, diurnal intraocular pressure measurement, serologic evaluation, and magnetic resonance imaging of the brain and orbits. MAIN OUTCOME MEASURES: Optic nerve status, visual field status, and visual acuity. RESULTS: A subject with previously healthy optic nerves had bilateral optic neuropathy develop after LASIK surgery. This neuropathy manifested with a subjective decrease in visual field, normal visual acuity, normal color vision, relative afferent pupillary defect, increased cupping of the optic nerve with focal neuroretinal rim defects, decreased nerve fiber layer thickness, and nerve fiber bundle-type visual field defects. The subject had no other risk factors for optic neuropathy. No other cause of neuropathy was identified. CONCLUSIONS: Optic neuropathy is a potential vision-threatening complication of LASIK surgery. This complication may be due to barotrauma or ischemia related to extreme elevation of intraocular pressure by the suction ring. Careful examination of the optic nerve before and after LASIK surgery is warranted.

Human lens effect on in vivo scanning laser polarimetric measurements of retinal nerve fiber layer thickness.

OBJECTIVE: To determine the effect of the human lens on retinal nerve fiber layer measurements by scanning laser polarimetry. This technique uses the form birefringence of the retinal nerve fiber layer to estimate its thickness. The GDx Nerve Fiber Analyzer contains an optical retarder element to compensate for the birefringence of the human cornea. PATIENTS AND METHODS: Fourteen nonglaucomatous pseudophakic or aphakic eyes were matched by age and race to 14 nonglaucomatous phakic eyes. Intraocular pressure, optic nerve head evaluation by slit lamp biomicroscopy and visual fields were performed to establish the absence of glaucoma. The nerve fiber layer thickness measurements by the GDx Nerve Fiber Analyzer were compared between the two groups. RESULTS: The average nerve fiber layer thickness in the phakic group was 67.2+/-11.9 ,m and in the nonphakic group was 66.1 +/- 11.8 microm (P=0.80). CONCLUSION: The human lens has negligible influence on in vivo nerve fiber layer thickness measured by the GDx Nerve Fiber Analyzer.

The use of polarized laser light through the eye for noninvasive glucose monitoring.

BACKGROUND: In order to optimally manage diabetes mellitus, it is recommended blood glucose levels be monitored several times daily so an appropriate action can be taken to maintain tight control of these levels within a normal physiological range. All commercially available devices to measure blood glucose concentrations require the extraction of a drop of blood, normally obtained via the lancing of a finger. The main drawback to this method is the pain, often leading to low patient compliance. Therefore, a noninvasive glucose sensing method would greatly facilitate the management of diabetes. METHODS: In this article, we describe in vitro and in vivo results from a laser-based optical polarimetry system using the anterior chamber of the eye as a potential method to noninvasively monitor glucose levels in the body. RESULTS: It is shown, in vitro, that glucose can be predicted in the presence of albumin at physiological levels and, through the use of a novel light coupling mechanism, it is demonstrated that a polarimetric signal can be detected, in vivo, through a rabbit eye. CONCLUSIONS: Although the commercial production of a feasible noninvasive glucose monitoring method is still years away, laser-based polarimetry remains a viable alternative due to its potential to extract concentration information using the eye as a unique optical window into the body.

Light backscattering polarization patterns from turbid media: theory and experiment.

We present both experimental measurements and Monte-Carlo-based simulations of the diffusely backscattered intensity patterns that arise from illuminating a turbid medium with a polarized laser beam. It is rigorously shown that, because of axial symmetry of the system, only seven elements of the effective backscattering Mueller matrix are independent. A new numerical method that allows simultaneous calculation of all 16 elements of the two-dimensional Mueller matrix is used. To validate our method we compared calculations to measurements from a turbid medium that consisted of polystyrene spheres of different sizes and concentrations in deionized water. The experimental and numerical results are in excellent agreement.

Measurement and calculation of the two-dimensional backscattering Mueller matrix of a turbid medium.

We present both experimental and Monte Carlo-based simulation results for the diffusely backscattered intensity patterns that arise from illumination of a turbid medium with a polarized laser beam. A numerical method that allows the calculation of all 16 elements of the two-dimensional Muller matrix is used; moreover, it is shown that only seven matrix elements are independent. To validate our method, we compared our simulations with experimental measurements, using a turbid medium consisting of 2.02-microm -diameter polystyrene spheres suspended in deionized water. By varying the incident polarization and the analyzer optics for the experimental measurements, we obtained the diffuse backscattering Mueller matrix elements. The experimental and the numerical results are in good agreement.

Measurement and calculation of the two-dimensional backscattering Mueller matrix of a turbid medium: errata.

In our recent Letter,(1) several typographical errors were present. On p. 487, in Fig. 2, the equations for the following Mueller matrix elements should read as S(14) = (RO - LO), S(22) = (HH + VV) - (HV + VH), S(23) = (PH + MV) - (PV + MH), S(24) = (RH + LV) - (RV + LH), S(32) = (HP + VM) - (HM + VP), S(33) = (PP + MM) - (PM + MP), S(34) = (RP + LM) - (RM + LP), S(41) = (OR + OL), S(42) = (HR + VL) - (HL + VR), S(43) = (PR + ML) - (PL + MR), and S(44) = (RR + LL) - (RL + LR). Also on p. 487, in the left-hand column, line 10 from the top should read as follows: mfp? = 1/[mua + mus(1 - g)], was 0.957 cm.

Noninvasive glucose sensing utilizing a digital closed-loop polarimetric approach.

A polarimetric glucose sensor utilizing a digital closed-loop controller was designed and implemented during this study. Its potential as a noninvasive glucose sensor was evaluated in vitro for both glucose-doped water and bovine aqueous humor mediums. A physiological hyperglycemic concentration range was used in both calibration and validation of each set of experiments. Ideally, the end application of this system could estimate blood glucose concentrations indirectly by measuring the amount of rotation of a light beam's polarization state after it propagates through the aqueous humor contained within the anterior chamber of the eye. The polarimeter designed in this study differs from similar investigated systems in that it utilizes a digital closed-loop control system. This type of controller was implemented in order to further improve system repeatability and stability without sacrificing accuracy. Unique to this investigation, independent validation sets other than those used to create each respective calibration model were obtained. The results of the glucose-doped water experiments yielded mean standard errors of prediction for calibration and validation of 6.91 and 8.84 mg/dl, respectively. The mean standard errors of prediction during calibration and validation of the glucose-doped aqueous humor experiments were higher at 27.20 and 27.47 mg/dl, respectively, due to medium degradation over time while exposed to air.

Juvenile glaucoma linked to the GLC1A gene on chromosome 1q in a Panamanian family.

PURPOSE: To characterize clinically and genetically autosomal dominant juvenile-onset primary open-angle glaucoma in a Panamanian family. METHODS: Twenty members of a six-generation family underwent ophthalmologic examination and genetic screening with markers near the GLC1A gene on chromosome 1q. RESULTS: Linkage analysis disclosed evidence linking primary open-angle glaucoma in this family to the GLC1A gene on chromosome 1q, with a maximum lod score of 3.75 for marker D1S431 at an estimated recombination fraction of 0.00. CONCLUSIONS: This is the first report of a Panamanian family in which primary open-angle glaucoma is linked to the GLC1A gene on chromosome 1q.

Juvenile glaucoma linked to GLCIA in a Panamanian family.

PURPOSE: To carry out clinical and genetic characterization of juvenile-onset primary open-angle glaucoma (POAG) inherited as an autosomal dominant trait in a Panamanian family. METHODS: Twenty-two members of a six-generation Panamanian family underwent an ophthalmologic evaluation. Blood samples were collected from 20 of these individuals for preparation of DNA for use in screening of microsatellite repeat genetic markers via polymerase chain reaction. RESULTS: Eleven living family members covering 4 generations were diagnosed as affected with open-angle glaucoma of primarily juvenile onset. Four of 6 other at-risk individuals examined and enrolled were characterized as unaffected and two as indeterminate. Two additional individuals were not included in this study because they were too young to characterize or to provide a blood sample. Three spouses of affected family members were also examined and found not to have glaucoma. Of clinical importance was the finding of markedly elevated intraocular pressure (IOP) in 2 affected brothers, both of whom were advised to have urgent filtration surgery; the finding of elevated IOP in the only seeing eye of the mother of these brothers, causing us to advise her to pursue more aggressive treatment; and the finding of early signs of glaucoma in a previously undiagnosed 9-year-old family member. Linkage analysis using selected microsatellite repeat markers in the 1q21-q31 region revealed strong evidence for linkage to the GLC1A gene with a maximum lod score of 3.75 for marker D1S431 at a recombination fraction of 0.00. CONCLUSIONS: The most likely interpretation of our data is that a mutation in the GLC1A gene is responsible for juvenile-onset POAG in this Panamanian family, thus expanding the countries of origin where this gene has been found to exist. The numbers of families with GLC1A glaucoma now reported from only a few centers worldwide raise questions about whether this disease may be more common than once thought. Evaluation of treatment histories and clinical outcomes in members of this and other previously reported families indicates that ophthalmologists need to understand the necessity for urgent filtration surgery in most cases of GLC1A glaucoma if vision is to be preserved.

Milk transfer of rhein in the rhesus monkey.

A HPLC method was developed to measure rhein, a laxatively active metabolite of sennosides A + B, in milk and plasma. Samples from 2 lactating rhesus monkeys were taken over 48 h after oral administration of sennosides (1 mg kg-1). Detectable rhein levels were found in plasma between 2 and 12 h and in milk between 4 and 12 h after administration, but rhein excretion in milk seems to be far below the dose necessary to elicit a laxative effect in the suckling offspring.

The trans-cis isomerization of trans-4'-(2-hydroxy-3,5-dibromo-benzylamino)cyclohexanol in vivo and in vitro in different species.

Isomerization of trans-4'-(2-hydroxy-3,5-dibromo-benzylamino)cyclohexanol (HDBC) in vivo has been investigated in horse, cow, dog, rat and man. Following oral administration of 4'-trans-HDBC to the horse, a very efficient first-pass trans-cis isomerization was observed. In the urine of the horse and cow, 40% and 29% respectively of the conjugated alcohols consisted of the 4'-cis isomer. Isomerization in rat and dog took place only to a small extent, and in man no 4'-cis isomer was detected. Oxidation of HDBC to the corresponding ketone, at pH 9.0, was highest with horse- and rat-liver 10 000 g supernatants and lowest with dog-liver supernatant. Reduction of the ketone with 10 000 g liver supernatants and with cryst. horse-liver alcohol dehydrogenase led to the formation of the alcohol containing 42-69% as the 4'-cis isomer, whereas after reduction with NaBH4 the alcohol contained only 20% of the 4'-cis isomer. This indicates that the conformer with the lower energy (1' and 4' position equatorially substituted) preferentially formed only during chemical reduction. A correlation between the formation of the ketone in vitro and the formation of 4'-cis-HDBC in vivo was observed in the horse, cow and dog. No similar correlation was found in the rat, where a high in vivo trans-cis isomerization might have been expected from the in vitro data.

[Rectal absorption of steroids]. / Zur rektalen Resorption von Steroiden.

The investigations were designed to evaluate the systemic absorption of two steroids from suppositories. The suppositories containing either 3H-hydrocortisone (1 mg) or 3H-prednisolone-21-hexanoate (1 mg) were administered to a group of 4 baboons restrained in chairs. The levels of radio-activity in the plasma and urine were measured up to 120 h following rectal administration, and these levels were compared with those of a subsequent intravenous administration (1 mg each). The results show that both hydrocortisone (H) and prednisolone-21-hexanoate (P) are rapidly (tmax = 2-3 h) and significantly (H: 60-78%, P: 47-58%) absorbed from suppositories and thus can also cause systemic effects.

The absorption, metabolism and excretion of (14C)-AR-L 115 BS in the baboon.

(14C)-Labelled 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) (base) was administered to male baboons by the p.o. (10 mg . kg-1 by capsule) and i.v. (2 mg.kg-1) routes. Comparison of routes and extent of excretion suggests the importance of biliary elimination and indicates that an oral dose of (14C)-AR-L 115 BS is almost quantitatively absorbed. Thus in 5 days, after the oral dose, a mean of 42% was excreted in the urine and 38% in faeces. Similarly in 0--5 days after the i.v. dose, a mean of 49% was excreted in urine and 31% in faeces. Substantial elimination of administered radioactivity was observed in the 0--24 h period: 52% following p.o. administration and 60% following i.v. administration. Plasma levels of total radioactivity peaked at 6 micrograms equiv.ml-1 4 h following an oral dose. The concentration of unchanged AR-L 115 BS at this time was ca. 4 micrograms . ml-1. 4 h following the lower i.v. dose, plasma concentrations of ca. 0.5 micrograms equiv.ml-1 were observed and were associated with ca. 0.2 micrograms . ml-1 unchanged drug. Two phases of elimination of total radioactivity from plasma after the i.v. dose could be distinguished with t1/2 ca. 2 h and ca. 48 h. An estimated late phase t1/2 of 48 h was also observed following the oral dose. Although less polar metabolites (chromatographically identical to the synthetic compounds AR-L 114 Cl (hydrochloride) and AR-L 113 Cl) were observed in the plasma at 4 h, the urine and faeces contained some polar metabolites which appeared to be neither glucuronide nor sulphate conjugates. The lower i.v. dose was apparently more extensively metabolised than the higher oral dose.

The metabolism of benzyl isothiocyanate and its cysteine conjugate.

1. The corresponding cysteine conjugate was formed when the GSH (reduced glutathione) or cysteinylglycine conjugates of benzyl isothiocyanate were incubated with rat liver or kidney homogenates. When the cysteine conjugate of benzyl isothiocyanate was similarly incubated in the presence of acetyl-CoA, the corresponding N-acetylcysteine conjugate (mercapturic acid) was formed. 2. The non-enzymic reaction of GSH with benzyl isothiocyanate was rapid and was catalysed by rat liver cytosol. 3. The mercapturic acid was excreted in the urine of rats dosed with benzyl isothiocyanate or its GSH, cysteinyl-glycine or cysteine conjugate, and was isolated as the dicyclohexylamine salt. 4. An oral dose of the cysteine conjugate of [14C]benzyl isothiocyanate was rapidly absorbed and excreted by rats and dogs. After 3 days, rats had excreted a mean of 92.4 and 5.6% of the dose in the urine and faeces respectively, and dogs had excreted a mean of 86.3 and 13.2% respectively. 5. After an oral dose of the cystein conjugate of [C]benzyl isothiocyanate, the major 14C-labelled metabolite in rat urine was the corresponding mercapturic acid (62% of the dose), whereas in dog urine it was hippuric acid (40% of the dose). 5. Mercapturic acid biosynthesis may be an important route of metabolism of certain isothiocyanates in some mammalian species.

The metabolic fate of the coronary vasodilator 4-(3,4,5-Trimethoxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine (cinepazide) in the rat, dog and man.

1. An oral dose of the coronary vasodilator 4-(3,4,5-trimethoxy[14C]cinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was well absorbed and more than 60% of the dose was excreted within 24 h. In 5 days, rats, dogs, and man excreted in the urine and faeces respectively 36.7% and 58.3%, 33.4% and 68.6%, and 61.3% and 38.1% dose. Faecal radioactivity was probably excreted via the bile. 2. Plasma concentrations of radioactivity reached a maximum within about 1 h in all three species and declined fairly rapidly (t0.5 less than 3 h). For several hours, more than 50% of the plasma radioactivity was due to unchanged drug. After correction for dose and body weight (normalization), peak plasma concentrations of unchanged drug in man, rat and dog were in the approximate ratio 100 :30:1. 3. Similar metabolites were excreted by the three species, but the relative proportions differed. Rats and man excreted 17.2% and 15.9% respectively as unchanged drug in the urine whereas dogs excreted only 3.6%. Rat bile and urine contained 4.3% and 9.8% dose respectively as glucuronides of the mono-O-demethylated compounds and dog and human urine contained 9.0% and 2.6% respectively of these metabolites. The corresponding pyrrolidone accounted for 2.5%, 5.5% and 5.1% respectively in rat, dog and human urine. Complete O-demethylation also occurred since 4-(3,4,5-trihydroxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was present in rat faeces (22.1% dose).