Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials.

BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .

[How the DSM helps psychiatry move forward]. / Hoe de DSM de psychiatrie verder kan helpen.

The prospect of 'disease' in psychiatry has been debated for centuries. In the 21st century, this discussion often focusses on the usefulness of DSM classifications, the diagnostic manual of psychiatry. This criticism on the DSM is exemplary for our struggle to understand, classify and treat psychiatric problems. However, we tend to forget that the DSM system has provided a wealth of knowledge and structure to psychiatric care and science. Moreover, there is no elaborated alternative and an abolishment of the DSM will lead to confusion and polarisation. We should not throw the baby out with the bathwater. In this perspective, we argue how we can build on decades of experience with the DSM and how historical weighting and accurate use of the DSM can offer fertile grounds for refinement and precision of diagnostics in psychiatry.

Successful pulmonary endarterectomy in a patient with klinefelter syndrome.

Klinefelter syndrome (KS) is a frequent genetic disorder due to one or more supernumerary X chromosomes. KS is associated with an increased risk for venous thromboembolic events like deep venous thrombosis and pulmonary embolism. This paper describes a 37-year-old male patient with KS referred to our tertiary center with chronic thromboembolic pulmonary hypertension, and who was successfully treated by pulmonary endarterectomy.

In search for significant cognitive features in Klinefelter syndrome through cross-species comparison of a supernumerary X chromosome.

The behavioral characterization of animals that carry genetic disorder abnormalities in a controlled genetic and environmental background may be used to identify human deficits that are significant to understand underlying neurobiological mechanisms. Here, we studied whether previously reported object recognition impairments in mice with a supernumerary X chromosome relate to specific cognitive deficits in Klinefelter syndrome (47,XXY). We aimed to optimize face validity by studying temporal object recognition in human cognitive assays. Thirty-four boys with Klinefelter syndrome (mean age 12.01) were compared with 90 age-matched normal controls, on a broad range of visual object memory tasks, including tests for pattern and temporal order discrimination. The results indicate that subjects with Klinefelter syndrome have difficulty in the processing of visual object and pattern information. Visual object patterns seem difficult to discriminate especially when temporal information needs to be processed and reproduced. On the basis of cross-species comparison, we propose that impaired temporal processing of object pattern information is an important deficit in Klinefelter syndrome. The current study shows how cross-species behavioral characterization may be used as a starting point to understand the neurobiology of syndromal phenotypic expression. The features of this study may serve as markers for interventions in Klinefelter syndrome. Similar cross-species evaluations of standard mouse behavioral paradigms in different genetic contexts may be powerful tools to optimize genotype-phenotype relationships.

Rapid identification of Candida spp. in peritonitis patients by Raman spectroscopy.

This prospective study evaluated Raman spectroscopy for the identification of clinically relevant Candida spp. in peritonitis patients. A Raman database was developed by measuring spectra from 93 reference strains belonging to ten different Candida spp. Clinical samples were obtained from the surgical department and intensive care unit of a tertiary university hospital. In total, 88 peritoneal specimens from 45 patients with primary, secondary or tertiary peritonitis were included. Specimens were cultured initially on a selective Sabouraud medium that contained gentamicin to suppress bacterial growth. For conventional identification, a chromogenic medium was used for presumptive identification, followed by use of the Vitek 2 system for definitive identification (requiring a total time of 48-96 h). Raman measurements were taken on overnight cultures from Sabouraud-gentamicin medium. Thirty-one samples were positive for Candida by culture. Using multivariate statistical analyses, a prediction accuracy of 90% was obtained for Raman spectroscopy, which appears to offer an accurate and rapid (12-24 h) alternative for the identification of Candida spp. in peritonitis patients. The reduced turn-around time is of great clinical importance for the treatment of critically ill patients with invasive candidiasis in intensive care units.

Design and validation of an analyser to measure sulphur hexafluoride gas during respiration.

The study presents the results of the development of an analyser to measure sulphur hexafluoride (SF6) gas in breathing circuits, for application is studies of lung function. The analyser consists of an in-line breathing circuit measurement transducer and a compact unit for signal treatment. The detector unit of the analyser consists of a near-infrared light source, a bandpass filter and a pyro-electrical detector. When incremental steps of SF6 gas between 0 and 2% were presented to the analyser, the maximum deviation from the theoretical calibration curve was calculated to be 0.01% SF6. The step response of the analyser (10-90%) was 250 ms. The sensitivity of the analyser to ambient temperature was 0.01% SF6 degrees C(-1) in the range between 0 and 2% SF6. It is concluded that the analyser presented is accurate, and has a sufficient response speed to be used in clinical measurement settings. Furthermore, the analyser is resistant to changes in temperature, gas flow, orientation and movement, which are likely to occur in clinical measurement settings.

Perioperative pharmacokinetics of cefotaxime in serum and bile during continuous and intermittent infusion in liver transplant patients.

BACKGROUND: Drug pharmacokinetics may be altered during liver transplantation. Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent killing and therefore continuous infusion might have pharmacodynamic advantages. OBJECTIVES: To determine the pharmacokinetics of CTX and desacetylcefotaxime (DCTX) in serum, bile and urine during continuous and intermittent infusion when performing liver transplantation. METHODS: Fifteen patients undergoing liver transplantation were studied after continuous infusion (CI) (4000 mg iv per 24 h following a loading dose of 1000 mg) and intermittent bolus infusion (BI) (1000 mg iv four times daily). Samples were collected during the first 48 h after liver transplantation. Concentrations of CTX and DCTX were determined by HPLC. RESULTS: During surgery, the mean concentration in serum after CI was 18 mg/L. The lowest serum concentration was 5 mg/L in the CI group and levels were undetectable in the BI group. Target serum concentrations of > or =4 mg/L were reached for 100% of the dosing interval during CI and approximately 60% during BI. Post-operatively, the mean concentration in serum after CI was 26 mg/L. The lowest serum concentration was 8 mg/L in the CI group and levels were undetectable after BI. The peroperative pharmacokinetics of CTX in this patient group were deranged and variable, mainly caused by an increased volume of distribution and decreased hepatic clearance. Metabolism was hampered, but DCTX area under the curve (AUC)/CTX AUC ratios varying between 0.7-0.9 were reached peroperatively. Post-operatively, DCTX AUC/CTX AUC ratios were higher (1.1-1.4). Unchanged CTX in bile was approximately 0.1% of the administered dose, leading to concentrations >4 mg/L throughout the dosing interval for both regimens. CONCLUSION: Although an intermittent bolus infusion of CTX 1000 mg produces t > target concentration for 60% of the dosing interval during liver transplantation, serum concentrations may be insufficient during the reperfusion phase. Continuous infusion overcomes this. Post-operatively, CTX clearance is impaired by decreased metabolic clearance and there is substantial accumulation of DCTX. In bile, sufficient concentrations of CTX and its active metabolite are reached with both regimens.

A fast, digitally controlled flow proportional gas injection system for studies in lung function.

The aim of this paper is to describe a device for flow proportional injection of tracer gas in the lungs of mechanically ventilated patients. This device may then be used for the study of the multiple breath indicator gas washout technique to determine the end-expiratory lung volume. Such a tracer gas injection device may also be used in the study of other techniques that rely on uptake and elimination of tracer gas by the lungs. In this paper, an injector is described which enables injection of indicator gas at a predetermined concentration in a breathing circuit independent of the type of breathing. The presented setup uses a control computer to produce steering signals to a multivalve array in proportion to the input breathing signals. The multivalve array consists of ten circular valves, each with a different diameter, which can be opened or closed individually according to the input signal of the array. By opening of a certain combination of valves an amount of sulphur hexafluoride gas proportional to the inspiratory breathing signal is released. The rate of transmission between the components of the injection system was 80 Hz. The injector has a full flow range between 0-10 L/min. The delay time between the breathing signal and the flow response was 70 ms. The aimed washin gas concentration of 1% SF6 was achieved after 0.5 s. The study describes the results of tests to determine valve-flow ratios, step response and dynamic response of the injector. The flow output response of the injector system was shown to increase in input frequencies above 3 Hz. The valve flow ratios showed the largest relative deviation in the two smallest valves of the 10 valve array, respectively 0.005 L/min (25%) and 0.002 L/min (20%). We conclude that the injector can achieve a stable concentration of indicator gas in a breathing system with an accuracy of 0.005 L/min to execute the multiple breath indicator washout test in human subjects. The results of the study indicate that the injector may be of use in other application fields in respiratory physiology in which breathing circuit injection of indicator gas is required.

Prospective study of the performance of vibrational spectroscopies for rapid identification of bacterial and fungal pathogens recovered from blood cultures.

Rapid identification of microbial pathogens reduces infection-related morbidity and mortality of hospitalized patients. Raman spectra and Fourier transform infrared (IR) spectra constitute highly specific spectroscopic fingerprints of microorganisms by which they can be identified. Little biomass is required, so that spectra of microcolonies can be obtained. A prospective clinical study was carried out in which the causative pathogens of bloodstream infections in hospitalized patients were identified. Reference libraries of Raman and IR spectra of bacterial and yeast pathogens highly prevalent in bloodstream infections were created. They were used to develop identification models based on linear discriminant analysis and artificial neural networks. These models were tested by carrying out vibrational spectroscopic identification in parallel with routine diagnostic phenotypic identification. Whereas routine identification has a typical turnaround time of 1 to 2 days, Raman and IR spectra of microcolonies were collected 6 to 8 h after microbial growth was detected by an automated blood culture system. One hundred fifteen samples were analyzed by Raman spectroscopy, of which 109 contained bacteria and 6 contained yeasts. One hundred twenty-one samples were analyzed by IR spectroscopy. Of these, 114 yielded bacteria and 7 were positive for yeasts. High identification accuracy was achieved in both the Raman (92.2%, 106 of 115) and IR (98.3%, 119 of 121) studies. Vibrational spectroscopic techniques enable simple, rapid, and accurate microbial identification. These advantages can be easily transferred to other applications in diagnostic microbiology, e.g., to accelerate identification of fastidious microorganisms.

Experience with a once-daily dosing program of aminoglycosides in critically ill patients.

BACKGROUND: As aminoglycosides show concentration-dependent killing, once-daily aminoglycoside (ODA) regimens have been instituted. Data on experience with ODA regimens in critically ill patients are limited. OBJECTIVES: 1) To evaluate the ODA-program in critically ill patients; 2) to describe the pharmacokinetics of aminoglycosides (gentamicin and tobramycin); and 3) to assess the incidence of nephrotoxicity associated with an ODA regimen in this specific of group patients. DESIGN: A prospective, descriptive study. SETTING: Eighteen-bed surgical and 12-bed medical intensive care unit in a referral centre. PATIENTS: Eighty-nine critically ill patients with a suspected or confirmed infection for which gentamicin or tobramycin was indicated and a creatinine clearance > 30 ml/min were monitored. One hundred and nine pharmacokinetic profiles were gathered. INTERVENTIONS: A first dose of 7 mg/kg/24 h of gentamicin or tobramycin was given to every patient independent of renal function. Subsequent doses were chosen on the basis of the pharmacokinetic results of the first dose. MEASUREMENTS: Serum samples were collected 1 h and 6 h after start of the aminoglycoside infusion. All samples were assayed by using immunofluorescence. Pharmacokinetic parameters were estimated using a one-compartment model. RESULTS: The volume of distribution of aminoglycosides was significantly higher in critical ill patients with septic shock than in those without. Consequently, the maximum concentration reached was significantly lower in patients with septic shock. In P. aeruginosa infections the mean (SD) estimated Cmax/MIC ratio was 10.3 (3.3). In n = 17 (49%) of the patients treated > 24 h ( n = 35), a dose adjustment or lengthening of interval was necessary. The recommended dosing interval based on the Hartford Hospital nomogram and one-serum concentration at 6 h was correct in only 62% of all cases. Signs of renal impairment occurred in n = 12 (14%) of the patients; in all survivors renal function recovered completely and no haemofiltration was needed. CONCLUSIONS: An ODA-regimen of 7 mg/kg produced Cmax/MIC ratios > 10 in the majority of critically ill patients in our population. Septic shock and renal dysfunction caused an aberrant pharmacokinetic profile of aminoglycosides in these patients. Therefore, individual therapeutic drug monitoring is warranted. Signs of renal impairment were common in the presence of shock, but appeared to be reversible.

Selective decontamination of the digestive tract to prevent postoperative infection: a randomized placebo-controlled trial in liver transplant patients.

OBJECTIVE: To determine the efficacy of selective decontamination of the digestive tract (SDD) in patients undergoing elective transplantation of the liver. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Two academic teaching hospitals. PATIENTS: Adult patients undergoing elective liver transplantation: 26 patients receiving SDD and 29 patients receiving a placebo. INTERVENTIONS: Patients undergoing SDD were administered 400 mg of norfloxacin once daily as soon as they were accepted for transplantation. Postoperative treatment for this group consisted of 2 mg of colistin, 1.8 mg of tobramycin, and 10 mg of amphotericin B, four times daily, combined with an oral paste containing a 2% solution of the same drugs until postoperative day 30. Prophylactic intravenous administration of antibiotics was not part of the SDD regimen in this study. Control patients were given a similar regimen with placebo drugs. MEASUREMENTS: The mean number of postoperative bacterial and fungal infections in the first 30 days after transplantation was the primary efficacy end point. Days on a ventilator, days spent in the intensive care unit, and medical costs were registered as secondary outcome variables. MAIN RESULTS: Of the 26 patients undergoing SDD, 22 (84.5%) developed an infection in the postoperative study period; in the placebo group (n = 29), these numbers were not significantly different (25 patients, 86%). The mean number of postoperative infectious episodes per patient was also not significantly different: 1.77 (SDD) vs. 1.93 (placebo). Infections involving Gram-negative aerobic bacteria and Candida species were significantly less frequent in patients receiving SDD (p <.001 and p <.05). Total costs were higher in the group receiving SDD. CONCLUSIONS: Selective decontamination of the digestive tract does not prevent infection in patients undergoing elective liver transplantation and increases the cost of their care. It does, however, affect the type of infection. Infections with Gram-negative bacilli and with Candida species are replaced by infections with Gram-positive cocci.

The value of plasma markers for the clinical behaviour of phaeochromocytomas.

OBJECTIVE: Phaeochromocytomas (PCCs) are widely known for their clinical unpredictability. This study intends to define predictive plasma markers for their variable postoperative behaviour. Furthermore, the diagnostic accuracy of these plasma tests was determined. DESIGN AND METHODS: A retrospective correlative study was performed in a series of 83 operated and four autopsied patients in order to correlate preoperative catecholamine (CAT) levels of 103 PCCs with their clinical behaviour. In a subset of cases, chromogranin-A (Chr-A) and enzymes/precursors of the CAT biosynthesis were studied for their predictive value. RESULTS: Basal CAT levels were elevated in 81/87 instances (sensitivity: 93%). Four of six cases with normal measurements showed only medullary hyperplasia. Larger PCCs, particularly those showing necrosis, capsular and vascular invasion, secreted higher CAT levels. Bilateral, hereditary tumours were less productive than their unilateral counterparts. Extra-adrenal PCCs secreted significantly lower levels of epinephrine (EPI) than intra-adrenal tumours. Fourteen patients developed metastases. According to Kaplan-Meier estimations, patients with higher levels of dopamine, norepinephrine (NE) and aromatic l-amino acid decarboxylase as well as lower ratios of EPI/EPI+NE, had significantly shorter metastases-free intervals. Existence of preoperative hypertension, left ventricular hypertrophy and measured blood pressures showed significant positive relationships with CAT levels, but not with Chr-A. CONCLUSIONS: These data showed that plasma CAT measurement is a sensitive method in the diagnostic work-up of PCCs. Those tumours producing normal levels are commonly small and asymptomatic. Furthermore, certain secretion patterns are indicative of the presence of metastases as well as the size and site of sporadic and syndrome-related PCCs.

Medical applications of Raman spectroscopy: from proof of principle to clinical implementation.

Raman spectroscopy has recently been applied ex vivo and in vivo to address various biomedical issues such as the early detection of cancers, monitoring of the effect of various agents on the skin, determination of atherosclerotic plaque composition, and rapid identification of pathogenic microorganisms. This leap in the number of applications and the number of groups active in this field has been facilitated by several technological advancements in lasers, CCD detectors, and fiber-optic probes. However, most of the studies are still at the proof of concept stage. We present a discussion on the status of the field today, as well as the problems and issues that still need to be resolved to bring this technology to hospital settings (i.e., the medical laboratory, surgical suites, or clinics). Taken from the viewpoint of clinicians and medical analysts, the potential of Raman spectroscopic techniques as new tools for biomedical applications is discussed and a path is proposed for the clinical implementation of these techniques.

Rapid identification of Candida species by confocal Raman microspectroscopy.

Candida species are important nosocomial pathogens associated with high mortality rates. Rapid detection and identification of Candida species can guide a clinician at an early stage to prescribe antifungal drugs or to adjust empirical therapy when resistant species are isolated. Confocal Raman microspectroscopy is highly suitable for the rapid identification of Candida species, since Raman spectra can be directly obtained from microcolonies on a solid culture medium after only 6 h of culturing. In this study, we have used a set of 42 Candida strains comprising five species that are frequently encountered in clinical microbiology to test the feasibility of the technique for the rapid identification of Candida species. The procedure was started either from a culture on Sabouraud medium or from a positive vial of an automated blood culture system. Prior to Raman measurements, strains were subcultured on Sabouraud medium for 6 h to form microcolonies. Using multivariate statistical analyses, a high prediction accuracy (97 to 100%) was obtained with the Raman method. Identification with Raman microspectroscopy may therefore be significantly faster than identification with commercial identification systems that allow various species to be identified and that often require 24 to 48 h before a reliable identification is obtained. We conclude that confocal Raman microspectroscopy offers a rapid, accurate, and easy-to-use alternative for the identification of clinically relevant Candida species.

Pharmacokinetics of ceftazidime in serum and peritoneal exudate during continuous versus intermittent administration to patients with severe intra-abdominal infections.

Ceftazidime demonstrates time-dependent killing, which is maximal at 4 x or 5 x MIC for the organism, consequently continuous infusion (CI) has been proposed to ensure adequate ceftazidime concentrations for the entire course of therapy. Severe intra-abdominal infections (IAIs) require surgical or percutaneous drainage for management, and ceftazidime is frequently prescribed. Cardiovascular or metabolic changes and renal or liver dysfunction may alter drug pharmacokinetics during severe IAIs, and no data exist on concentrations of ceftazidime reached in the peritoneal fluid. The objectives here were to determine the pharmacokinetics of ceftazidime during continuous and intermittent administration in patients with severe IAIs, and to measure the concentrations of ceftazidime in the peritoneal exudate. Eighteen surgical patients with severe IAI and a creatinine clearance of >30 mL/min were studied. A non-randomized pilot study of six patients treated with CI alone was followed by a prospective, randomized comparative study of 12 patients. Pilot study patients received ceftazidime 1 g iv followed by a 4.5 g CI over 24 h. Randomized patients received either ceftazidime continuously as above or 1.5 g tds. Samples for pharmacokinetic analyses were collected on days 2 and 4. Ceftazidime concentrations were determined by high-performance liquid chromatography. CI resulted in a mean serum concentration >40 mg/L and a T> 4 x MIC for most pathogens encountered in severe IAIs for >90% of the course of therapy in both serum and peritoneal exudate. Eight-hourly administration resulted in T> 4 x MIC for most pathogens encountered in severe IAIs for >90% of the dosing interval, but in peritoneal exudate for only 44% of the dosing interval. During CI, AUCs in the peritoneal exudate were c. 60% of the concomitant serum AUCs. In critically ill surgical patients with severe IAIs, CI of ceftazidime resulted in more favourable concentrations in serum and peritoneal exudate than 8-hourly bolus infusion.

Determination of water concentration in brain tissue by Raman spectroscopy.

Brain edema is one of the most common morbidity factors in patients with intracranial neoplasms and cerebrovascular pathology. Monitoring of intracranial pressure gives only an indirect and global measure of brain swelling. We have made an assessment of the applicability of Raman spectroscopy as an alternative method for assessing brain edema, which measures the water concentration in the tissue directly. Partial least-squares models were developed on the basis of Raman spectra measured in the 2600-3800-cm(-1) region, which predict the water fraction of brain tissue in the 0.75-0.95 range, with an accuracy better than 0.01.

Investigating microbial (micro)colony heterogeneity by vibrational spectroscopy.

Fourier transform infrared and Raman microspectroscopy are currently being developed as new methods for the rapid identification of clinically relevant microorganisms. These methods involve measuring spectra from microcolonies which have been cultured for as little as 6 h, followed by the nonsubjective identification of microorganisms through the use of multivariate statistical analyses. To examine the biological heterogeneity of microorganism growth which is reflected in the spectra, measurements were acquired from various positions within (micro)colonies cultured for 6, 12, and 24 h. The studies reveal that there is little spectral variance in 6-h microcolonies. In contrast, the 12- and 24-h cultures exhibited a significant amount of heterogeneity. Hierarchical cluster analysis of the spectra from the various positions and depths reveals the presence of different layers in the colonies. Further analysis indicates that spectra acquired from the surface of the colonies exhibit higher levels of glycogen than do the deeper layers of the colony. Additionally, the spectra from the deeper layers present with higher RNA levels than the surface layers. Therefore, the 6-h colonies with their limited heterogeneity are more suitable for inclusion in a spectral database to be used for classification purposes. These results also demonstrate that vibrational spectroscopic techniques can be useful tools for studying the nature of colony development and biofilm formation.

In vivo confocal Raman microspectroscopy of the skin: noninvasive determination of molecular concentration profiles.

Confocal Raman spectroscopy is introduced as a noninvasive in vivo optical method to measure molecular concentration profiles in the skin. It is shown how it can be applied to determine the water concentration in the stratum corneum as a function of distance to the skin surface, with a depth resolution of 5 microm. The resulting in vivo concentration profiles are in qualitative and quantitative agreement with published data, obtained by in vitro X-ray microanalysis of skin samples. Semi-quantitative concentration profiles were determined for the major constituents of natural moisturizing factor (serine, glycine, pyrrolidone-5-carboxylic acid, arginine, ornithine, citrulline, alanine, histidine, urocanic acid) and for the sweat constituents lactate and urea. A detailed description is given of the signal analysis methodology that enables the extraction of this information from the skin Raman spectra. No other noninvasive in vivo method exists that enables an analysis of skin molecular composition as a function of distance to the skin surface with similar detail and spatial resolution. Therefore, it may be expected that in vivo confocal Raman spectroscopy will find many applications in basic and applied dermatologic research.