Low-Dose High-Resolution TOF-PET Using Ionization-activated Multi-State Low-Z Detector Media.

We propose PET scanners using low atomic number media that undergo a persistent local change of state along the paths of the Compton recoil electrons. Measurement of the individual scattering locations and angles, deposited energies, and recoil electron directions allows using the kinematical constraints of the 2-body Compton scattering process to perform a statistical time-ordering of the scatterings, with a high probability of precisely identifying where the gamma first interacted in the detector. In these cases the Line-of-Response is measured with high resolution, determined by the underlying physics processes and not the detector segmentation. There are multiple such media that act through different mechanisms. As an example in which the change of state is quantum-mechanical through a change in molecular configuration, rather than thermodynamic, as in a bubble chamber, we present simulations of a two-state photoswitchable organic dye, a 'Switchillator', that is activated to a fluorescent-capable state by the ionization of the recoil electrons. The activated state is persistent, and can be optically excited multiple times to image individual activated molecules. Energy resolution is provided by counting the activated molecules. Location along the LOR is implemented by large-area time-of-flight MCP-PMT photodetectors with single photon time resolution in the tens of ps and sub-mm spatial resolution. Simulations indicate a large reduction of dose.

Air-transfer production method for large-area picosecond photodetectors.

We have designed and prototyped the process steps for the batch production of large-area micro-channel-plate photomultipliers (MCP-PMT) using the "air-transfer" assembly process developed with single LAPPDTM modules. Results are presented addressing the challenges of designing a robust package that can transmit large numbers of electrical signals for pad or strip readout from inside the vacuum tube and of hermetically sealing the large-perimeter window-body interface. We have also synthesized a photocathode in a large-area low-aspect-ratio volume and have shown that the micro-channel plates recover their functionality after cathode synthesis. These steps inform a design for a multi-module batch facility employing dual nested low-vacuum and ultra-high-vacuum systems in a small-footprint. The facility design provides full access to multiple MCP-PMT modules prior to hermetic pinch-off for leak-checking and real-time photocathode optimization.

The Military Extremity Trauma Amputation/Limb Salvage (METALS) study: outcomes of amputation versus limb salvage following major lower-extremity trauma.

BACKGROUND: The study was performed to examine the hypothesis that functional outcomes following major lower-extremity trauma sustained in the military would be similar between patients treated with amputation and those who underwent limb salvage. METHODS: This is a retrospective cohort study of 324 service members deployed to Afghanistan or Iraq who sustained a lower-limb injury requiring either amputation or limb salvage involving revascularization, bone graft/bone transport, local/free flap coverage, repair of a major nerve injury, or a complete compartment injury/compartment syndrome. The Short Musculoskeletal Function Assessment (SMFA) questionnaire was used to measure overall function. Standard instruments were used to measure depression (the Center for Epidemiologic Studies Depression Scale), posttraumatic stress disorder (PTSD Checklist-military version), chronic pain (Chronic Pain Grade Scale), and engagement in sports and leisure activities (Paffenbarger Physical Activity Questionnaire). The outcomes of amputation and salvage were compared by using regression analysis with adjustment for age, time until the interview, military rank, upper-limb and bilateral injuries, social support, and intensity of combat experiences. RESULTS: Overall response rates were modest (59.2%) and significantly different between those who underwent amputation (64.5%) and those treated with limb salvage (55.4%) (p = 0.02). In all SMFA domains except arm/hand function, the patients scored significantly worse than population norms. Also, 38.3% screened positive for depressive symptoms and 17.9%, for posttraumatic stress disorder (PTSD). One-third (34.0%) were not working, on active duty, or in school. After adjustment for covariates, participants with an amputation had better scores in all SMFA domains compared with those whose limbs had been salvaged (p < 0.01). They also had a lower likelihood of PTSD and a higher likelihood of being engaged in vigorous sports. There were no significant differences between the groups with regard to the percentage of patients with depressive symptoms, pain interfering with daily activities (pain interference), or work/school status. CONCLUSIONS: Major lower-limb trauma sustained in the military results in significant disability. Service members who undergo amputation appear to have better functional outcomes than those who undergo limb salvage. Caution is needed in interpreting these results as there was a potential for selection bias.

An Application of Micro-channel Plate Photomultiplier Tube to Positron Emission Tomography.

We are developing a Time-of-Flight Positron Emission Tomography detector using flat panel micro-channel plate photomultiplier tubes (MCP PMT). The high-speed waveform sampling data acquisition is adopted to exploit the fast time response of MCP PMT efficiently by using transmission-line readout scheme. To demonstrate the feasibility of the proposed detector, prototype detector modules were built using Photonis XP85022 MCP PMT, transmission-line board (TL), and high-speed waveform sampling electronics equipped with DRS4 chips. The MCP/TL module was coupled to single LYSO crystal, and experimental tests have been conducted in a coincidence setup to measure the responses to 511 keV annihilation photon. The details of the prototype module, experimental setup, and the preliminary results are presented and discussed.

A Prototype TOF PET Detector Module Using a Micro-Channel Plate Photomultiplier Tube with Waveform Sampling.

We are exploring a large area flat panel micro-channel plate photomultiplier tube (MCP PMT) under development for an application to time-of-flight positron emission tomography (TOF PET). High speed waveform sampling with transmission-lines is adopted for reading out the signal with precise time and space information with a small number of low-power channels. As a demonstration of the concept, detector modules have been built using 2″×2″ Photonis Planacon MCP PMTs (XP85022) and prototype transmission-line (TL) boards. The signals from the MCP PMT through the transmission-lines are sampled by DRS4 evaluation boards running at 5 giga-samples per second (GS/s). The event information is extracted by processing the digitized waveforms. For experimental tests, a single 3×3×10 mm(3) LYSO crystal is optically coupled to each MCP PMT; the detector responses to 511 keV annihilation photon from a (22)Na source are measured using the data taken in coincidence mode. As a preliminary result, we obtain a position resolution of ∼2.8 mm (0.3 mm) (FWHM) along (perpendicular to) the transmission-line, ∼309 ps (FWHM) for coincidence time resolution, and ∼14% (FWHM) of energy resolution at 511 keV. This initial result gives a promise that the large area MCP PMT is applicable to TOF PET.

A Design of a PET Detector Using Micro-Channel Plate Photomultipliers with Transmission-Line Readout.

A computer simulation study has been conducted to investigate the feasibility of a positron emission tomography (PET) detector design by using micro-channel plate (MCP) photomultiplier tubes (PMT) with transmission-line (TL) read-out and waveform sampling. The detector unit consisted of a 24×24 array of pixelated LSO crystals, each of which was 4×4×25 mm(3) in size, and two 102×102 mm(2) MCP-PMTs coupled to both sides of the scintillator array. The crystal (and TL) pitch was 4.25 mm and reflective medium was inserted between the crystals. The transport of the optical photons inside the scintillator were simulated by using the Geant4 package. The output pulses of the MCP-PMT/TL unit were formed by applying the measured single photo-electron response of the MCP-PMT/TL unit to each individual photon that interacts with the photo-cathode of the MCP-PMT. The waveforms of the pulses at both ends of the TL strips were measured and analyzed to produce energy and timing information for the detected event. An experimental setup was developed by employing a Photonis Planacon MCP-PMT (XP85022) and a prototype TL board for measuring the single photo-electron response of the MCP-PMT/TL. The simulation was validated by comparing the predicted output pulses to measurements obtained with a single MCP-PMT/TL coupled to an LSO crystal exposed to 511 keV gamma rays. The validated simulation was then used to investigate the performance of the proposed new detector design. Our simulation result indicates an energy resolution of ~11% at 511 keV. When using a 400-600 keV energy window, we obtain a coincidence timing resolution of ~323 ps FWHM and a coincidence detection efficiency of ~40% for normally-incident 511keV photons. For the positioning accuracy, it is determined by the pitch of the TLs (and crystals) in the direction normal to the TLs and measured to be ~2.5 mm in the direction parallel to the TLs. The energy and timing obtained at the front- and back-end of the scintillator array also show differences that are correlated with the depth of interaction of the event.

Treatment of growth failure with growth hormone in children with chronic kidney disease: an open-label long-term study.

AIMS: To assess long-term efficacy and safety of recombinant human growth hormone (GH) in children with chronic kidney disease (CKD). METHODS: An open-label, international, multicenter study. Children with CKD and growth failure received GH (0.35 mg/kg/week). The primary efficacy endpoint was a significant change in height velocity (HV) and height standard deviation score (SDS) versus baseline after 12 months of treatment, extended to 24 months, then to 5 years. RESULTS: In total, 81 patients enrolled (CKD Stage 4 - 5 = 37, on dialysis = 27, post-transplant = 17). After 12 and 24 months of treatment, increases were seen in mean (SD) HV (4.6 (3.1) to 9.0 (3.6) cm/year and 4.5 (3.3) to 7.5 (2.9) cm/year, respectively; both p < 0.001), mean (SD) height SDS (-3.7 (1.7) to -3.0 (1.7) and -3.6 (1.5) to -2.5 (1.5), respectively; both p < 0.001) and mean (SD) HV SDS (-2.4 (2.5) to 3.8 (4.5) and -2.4 (2.2) to 1.1 (3.8), respectively; both p < 0.001). A normal height SDS was seen in 1% of children at baseline, 17% after 12 months and 43% after 24 months of treatment. Improvements were similar across CKD subgroups with the greatest improvements in CKD Stage 4 - 5. Among 31 patients who completed about 5 years of treatment, four reached final height. There was no undue bone age acceleration and no deterioration of kidney function. Ten adverse events were related to GH treatment. CONCLUSIONS: In this long-term study, GH treatment was associated with significant improvements in growth and height in children with CKD and growth failure, and was well tolerated.

Spontaneous growth in growth hormone deficiency from birth until 7 years of age: development of disease-specific growth curves.

BACKGROUND: Little is known about spontaneous growth of growth hormone (GH)-deficient children during infancy and childhood. METHODS: Retrospectively, we calculated disease-specific pretreatment percentiles for height, weight, BMI and growth velocity of 113 GH-deficient boys and 41 GH-deficient girls from birth until 7 years of age, by mean and standard deviation. RESULTS: Infants with idiopathic GH deficiency (GHD) grow in disease-specific percentile channels. There is a significant difference in length and weight from birth onward compared to regional reference (p<0.001). Boys' birth length was 48.7+/-2.9 cm (p<0.001; -1.31+/-1.11 SDS), birth weight was 3.09+/-0.61 kg (p<0.01; -0.92+/-1.19 SDS), and BMI at birth was 12.9+/-1.7. Girls' birth length was 48.1+/-3.4 cm (p<0.05; -1.17+/-1.51 SDS), birth weight was 2.92+/-0.60 kg (p=0.05; -1.08+/-1.19 SDS), and BMI at birth was 12.6+/-2.2. There was a continuous loss of growth velocity, despite a wide variance in the first years, so height deficit became more evident with increasing age. CONCLUSION: GHD is a congenital disease no matter when height deficit becomes clinically evident, because GH-deficient children grow in disease-specific percentile channels with a highly significantly reduced length and weight, which demonstrates that GH is essential for adequate growth in infancy and early childhood.

Modified stoppa approach for acetabular fractures with anterior and posterior column displacement: quantification of radiographic reduction and analysis of interobserver variability.

OBJECTIVES: To quantify the reduction of acetabular fractures with displacement of the anterior and posterior column by using only a single anterior approach that combines the modified Stoppa approach with the lateral window of the classic ilioinguinal approach. The second objective was to evaluate the interobserver variability of our technique for radiographic evaluation of the reduction. SETTING: Level I trauma referral center. PATIENTS: A consecutive cohort of 17 patients with displaced acetabular fractures treated operatively with use of only an anterior approach that combined the modified Stoppa approach with the lateral window of the ilioinguinal approach. To be included in the study, patients had to have at least 5 mm of posterior column displacement and had to have undergone no other approaches. OUTCOME MEASURES: Primary outcome was radiographic evidence of reduction as measured by a technique that evaluates five parameters of postoperative reduction. Interobserver variability was evaluated with interclass correlation. Secondary outcomes included operative time, blood loss, and complications. RESULTS: Anatomic reduction of the articular surface was obtained in 14 (82%) patients, imperfect radiographic reduction in three (18%), and poor radiographic reduction in none (0%). Average anterior column displacement improved from 17.5 mm preoperatively to 0.5 mm postoperatively. Average posterior column displacement improved from 13.0 mm to 1.2 mm. Average femoral head medialization improved from 12.5 mm to 1.0 mm. Average quadrilateral surface medialization improved from 15.2 mm to 0.6 mm. Four complications occurred in three patients, including one deep infection, one seroma, and two instances of symptoms in the lateral femoral cutaneous nerve. Our technique for grading the radiographic outcome yielded relatively high interobserver reliability preoperatively with interclass correlation values ranging from 0.72 to 0.96 for the five measured parameters. Postoperative reliability was worse. CONCLUSION: Anatomic or imperfect reduction of certain acetabular fractures involving displacement of both the anterior and posterior columns, even with significant (greater than 5 mm) displacement of the posterior column, can be obtained through the modified Stoppa window and the lateral window of the ilioinguinal approach. The method for evaluating preoperative displacement had excellent reliability.

A Multi-Threshold Sampling Method for TOF PET Signal Processing.

As an approach to realizing all-digital data acquisition for positron emission tomography (PET), we have previously proposed and studied a multi-threshold sampling method to generate samples of a PET event waveform with respect to a few user-defined amplitudes. In this sampling scheme, one can extract both the energy and timing information for an event. In this paper, we report our prototype implementation of this sampling method and the performance results obtained with this prototype. The prototype consists of two multi-threshold discriminator boards and a time-to-digital converter (TDC) board. Each of the multi-threshold discriminator boards takes one input and provides up to 8 threshold levels, which can be defined by users, for sampling the input signal. The TDC board employs the CERN HPTDC chip that determines the digitized times of the leading and falling edges of the discriminator output pulses. We connect our prototype electronics to the outputs of two Hamamatsu R9800 photomultiplier tubes (PMTs) that are individually coupled to a 6.25×6.25×25mm(3) LSO crystal. By analyzing waveform samples generated by using four thresholds, we obtain a coincidence timing resolution of about 340 ps and an ∼18% energy resolution at 511 keV. We are also able to estimate the decay-time constant from the resulting samples and obtain a mean value of 44ns with an ∼9 ns FWHM. In comparison, using digitized waveforms obtained at a 20 GSps sampling rate for the same LSO/PMT modules we obtain ∼300 ps coincidence timing resolution, ∼14% energy resolution at 511 keV, and ∼5 ns FWHM for the estimated decay-time constant. Details of the results on the timing and energy resolutions by using the multi-threshold method indicate that it is a promising approach for implementing digital PET data acquisition.

Antibiotic-impregnated calcium sulfate use in combat-related open fractures.

This article presents our experience with the use of antibiotic-impregnated calcium sulfate in the management of comminuted open fractures with a bony defect caused by combat-related blast injuries and high-energy wounds. Calcium sulfate was used 19 times in 15 patients (17 fractures) as a bone graft substitute and a carrier for antibiotics. The anatomic sites of the graft were as follows: 6 calcanei, 1 midfoot, 1 metatarsal, 5 tibiae, 3 femorae, and 1 humerus. The average number of procedures prior to grafting was 6.2 (range, 2-10; median, 6) with grafting performed at an average 28 days after injury (range, 9-194 days; median, 14 days). Average radiographic follow-up of 12 fractures not requiring repeat grafting or amputation was 8.5 months (range 1-19 months; median, 7 months), and all of these fractures demonstrated clinical and radiographic evidence of fracture healing and consolidation. Four patients subsequently underwent 5 transtibial amputations: 2 for persistent infection, 1 when the patient changed his mind against limb salvage acutely, and 2 for severe neurogenic pain. Including the 2 amputations for persistent infection, 4 patients (22.2%) required further surgical management of infection. Three patients (17.6%) subsequently developed heterotopic ossification at the graft site, which required surgical excision. Antibiotic-impregnated calcium sulfate is effective in treating severe, contaminated open fractures by reducing infection and assisting with fracture union.

Recombinant human bone morphogenetic protein-2 for grade III open segmental tibial fractures from combat injuries in Iraq.

This is a retrospective consecutive case series of 138 Gustillo-Anderson type IIIB and IIIC segmental tibial fractures treated at Walter Reed Army Medical Center in soldiers injured in Iraq between March 2003 and March 2005. Five patients with a head injury and four who were lost to follow-up were excluded. The patients were treated definitively with either a ringed external fixator or a reamed intramedullary nail, evaluated in terms of supplementary bone grafting with either autogenous bone (group 1, 67 patients) or recombinant human bone morphogenetic protein-2 at 1.50 mg/ml applied to an absorbable collagen sponge (group 2, 62 patients). The mechanism of injury, defect size and classification, associated injuries, presence of infection, preliminary treatment/fixation, number of procedures before definitive management, time to and details of definitive management, subsequent infection, re-operation, smoking history and other complications were noted. Radiographs were assessed for union, delayed union or nonunion by an independent investigator. All the patients were male. Their mean age was 26.6 years (20 to 42) and the mean follow-up was for 15.6 months (12 to 32). Group 2 had a slightly higher profile of concomitant injuries and a slightly worse fracture classification, but these were not significant. The rate of union was 76% (51 of 67) for group 1 and 92% for group 2 (57 of 62; p = 0.015). There was also a higher rate of subsequent infection in group 1 (14.9%) compared with group 2 (3.2%; p = 0.001) and a higher rate of re-operation (28%) in group 1 (p = 0.003). There were no observed hypersensitivity reactions to the recombinant human bone morphogenetic protein-2 implant.

From Iraq back to Iraq: modern combat orthopaedic care.

War wounds are often large and complex, with high degrees of contamination and tissue loss differing significantly from typical civilian injuries. Infection has been a common complication driving the tenets of care, even in the antibiotic age. Fractures were historically treated with casting or traction because of the risk of infection with internal fixation. However, current civilian fracture care has evolved significantly with extensive use of internal and external fixation with early mobilization and other adjuncts to restore function earlier and more completely. Whether the application of modern techniques and implants can better restore function in patients with these severe injuries is currently being evaluated.

Treatment of open periarticular shoulder fractures sustained in combat-related injuries.

Open periarticular shoulder fractures present a tremendous challenge for orthopedic surgeons. These injuries, albeit rare, are typically caused by high-energy mechanisms and are associated with insult to multiple organ systems resulting in high morbidity and mortality. Although the civilian trauma literature includes several articles on outcomes of closed periarticular shoulder fractures, only 1 peer-reviewed article has focused on this specific open injury pattern. No standard management technique has been adopted for these injuries, and treatment patterns have anecdotally evolved from war to war. In this article, we review evacuation of patients, management of combat-related open periarticular shoulder injuries, and the pertinent literature; we supplement this review with a description of the recent experience of Drs. HMF and WCD. All cases of combat-related open fractures treated at our institution between March 2003 and January 2007 were reviewed. We identified 44 patients with open periarticular shoulder fractures (33 IIIA, 1 IIIB, 10 IIIC). Inpatient and outpatient medical records, x-rays, laboratory culture data, and photographic documentation records were reviewed. Mean follow-up was 34 months (range, 12-49 months). Rates of associated neurologic and vascular injury were 41% (18/44 patients), and 23% (10/44 patients), respectively. Other associated significant injuries occurred in 38/44 patients (86%). Internal fixation was used as definitive treatment in 26/44 patients (59%). Radiographic union occurred by a mean of 4.5 months (range, 3-9 months) after surgery. Postoperative deep infection/osteomyelitis occurred in 5/35 patients (14%) with more than 1-year follow-up data available. The overall amputation rate was 9%. Open combat-related periarticular shoulder fractures are complicated injuries, often associated with several traumatic comorbidities that together present difficult challenges to treatment. Meticulous surgical débridement is essential in managing these severely comminuted and contaminated open fractures. In cases in which internal fixation is used, careful timing and patient selection are required to minimize risk for osteomyelitis. Data collection is being continued in this patient cohort to allow for eventual reporting of functional outcomes.

Definitive treatment of combat casualties at military medical centers.

More than 9,000 casualties have been evacuated during the current conflict, and more than 40,000 orthopaedic surgical procedures have been performed. The most severely injured patients are treated in the United States at military medical centers. Individualized reconstructive plans are developed, and patients are treated with state-of-the-art techniques. Rehabilitation includes the assistance of the physical medicine and rehabilitation, physical therapy, and occupational therapy services, as well as, when necessary, psychiatric or other services. The extreme challenges of treating war-related soft-tissue defects include neurovascular injuries, burns, heterotopic ossification, infection, prolonged recovery, and persistent pain. Such injuries do not allow full restoration of function. Because of such devastating injuries, and despite use of up-to-date methods, outcomes can be less than optimal.

Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia.

OBJECTIVE: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype- phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations. DESIGN AND METHODS: Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes. RESULTS: CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype-phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH. CONCLUSIONS: By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94-99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern.

OBJECTIVE: Ghrelin stimulates GH release and causes weight gain through increased food intake and reduced fat utilization. Ghrelin levels were shown to rise in the preprandial period and decrease shortly after meal consumption, suggesting a role as a possible meal initiator. However, ghrelin secretion in fasting subjects has not yet been studied in detail. DESIGN: 24-h ghrelin profiles were studied in six healthy volunteers (three females; 25.5 years; body mass index 22.8 kg/m(2)) and compared with GH, insulin and glucose levels. METHODS: Blood samples were taken every 20 min during a 24-h fasting period and total ghrelin levels were measured by RIA using a polyclonal rabbit antibody. The circadian pattern of ghrelin secretion and pulsatility (Cluster analysis) were evaluated. RESULTS: An increase and spontaneous decrease in ghrelin were seen at the timepoints of customary meals. Ghrelin was secreted in a pulsatile manner with approximately 8 peaks/24 h. An overall decrease in ghrelin levels was observed during the study period. There was no correlation of ghrelin with GH, insulin or blood glucose levels. CONCLUSIONS: This pilot study indicates that fasting ghrelin profiles display a circadian pattern similar to that described in people eating three times per day. In a fasting condition, GH, insulin and glucose do not appear to be involved in ghrelin regulation. In addition, we found that ghrelin is secreted in a pulsatile pattern. The variation in ghrelin independently of meals in fasting subjects supports previous observations that it is the brain that is primarily involved in the regulation of meal initiation.

Pronounced short stature in a girl with tricho-rhino-phalangeal syndrome II (TRPS II, Langer-Giedion syndrome) and growth hormone deficiency.

We report on a 10-year-old girl with tricho-rhino-phalangeal syndrome type II (TRPS II) and pronounced short stature (-4.8 SD). The patient has an interstitial chromosome 8q24.1 deletion of 12-15 Mb. The deletion spans all genes from CSMD3 to at least ANXA13 including the TRPS1 and EXT1 genes, which are responsible for the TRPS II phenotype. In addition to the features of TRPS II, the patient had growth hormone (GH) deficiency with diminished response in three stimulation tests. Therapy with 0.2 mg GH/kg/week led to an increase of growth velocity from 2.5 to 6.6 cm/year. To our knowledge, such a combination of TRPS II and GH deficiency has not yet been described.

Aharonov-Bohm effects in entangled molecules.

Molecules which are magnetic and conducting, if suitably entangled (e.g., catenanes and knots) could exhibit Aharonov-Bohm effects which can be viewed as particular examples of a Berry phase. The corrections to the quantum energy levels reflect the entangled geometry of the molecules and, while small (they are proportional to the square of the fine structure constant), may be observable. We illustrate these corrections for a number of catenated and knotted structures. For couplings between the components of a catenane (link), the Aharonov-Bohm corrections are determined by integer-valued linking numbers. For knots, the Aharonov-Bohm correction is proportional to the geometric writhe of the knot.