CT Texture Analysis of Cervical Lymph Nodes on Contrast-Enhanced [18F] FDG-PET/CT Images to Differentiate Nodal Metastases from Reactive Lymphadenopathy in HIV-Positive Patients with Head and Neck Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: Differentiating nodal metastases from reactive adenopathy in HIV-infected patients with [18F] FDG-PET/CT can be challenging because lymph nodes in HIV-positive patients often show increased [18F] FDG uptake. The purpose of this study was to assess CT textural analysis characteristics of HIV-positive and HIV-negative lymph nodes on [18F] FDG-PET/CT to differentiate nodal metastases from disease-specific nodal reactivity. MATERIALS AND METHODS: Nine HIV-positive patients with head and neck squamous cell carcinoma (7 men, 2 women; 29-62 years of age; median age, 48 years) with 22 lymph nodes (≥1 cm) who underwent contrast-enhanced CT with [18F] FDG-PET followed by pathologic evaluation of cervical lymph nodes were retrospectively reviewed. Twenty-six HIV-negative patients with head and neck squamous cell carcinoma with 61 lymph nodes were evaluated as a control group. Each lymph node was manually segmented, and an in-house-developed Matlab-based texture analysis program extracted 41 texture features from each segmented volume. A mixed linear regression model was used to compare the pathologically proved malignant lymph nodes with benign nodes in the 2 enrolled groups. RESULTS: Thirteen (59%) lymph nodes in the HIV-positive group and 22 (36%) lymph nodes in the HIV-negative control group were confirmed as positive for metastases. There were 7 histogram features (P = .017-0.032), 3 gray-level co-occurrence features (P = .009-.025), and 9 gray-level run-length features (P < .001-.033) that demonstrated a significant difference in HIV-positive patients with either benign or malignant lymph nodes. CONCLUSIONS: CT texture analysis may be useful as a noninvasive method of obtaining additional quantitative information to differentiate nodal metastases from disease-specific nodal reactivity in HIV-positive patients with head and neck squamous cell carcinoma.

Bone Subtraction Iodine Imaging Using Area Detector CT for Evaluation of Skull Base Invasion by Nasopharyngeal Carcinoma.

BACKGROUND AND PURPOSE: Conventional CT has generally lower detectability of bone marrow invasion than MR imaging due to lower tissue contrast. The purpose of this study was to compare the diagnostic performance of conventional CT alone or in combination with bone subtraction iodine imaging using area detector CT for the evaluation of skull base invasion in patients with nasopharyngeal carcinoma. MATERIALS AND METHODS: Forty-four consecutive patients who underwent contrast-enhanced CT using 320-row area detector CT and contrast-enhanced MR imaging for nasopharyngeal carcinoma staging between April 2012 and November 2017 were enrolled in this retrospective study. Bone subtraction iodine images were generated by subtracting pre- and postcontrast volume scans using a high-resolution deformable registration algorithm. Two blinded observers evaluated skull base invasion at multiple sites (sphenoid body, clivus, bilateral base of the pterygoid process, and petrous bone) using conventional CT images alone or in combination with bone subtraction iodine images. Examination of MR and CT images by an experienced neuroradiologist was the reference standard for evaluating sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS: Twenty-six patients (59%) showed skull base invasion at 84 sites on the reference standard. Conventional CT plus bone subtraction iodine images showed higher sensitivity (92.9% versus 78.6%, P = .02) and specificity (95.6% versus 86.1%, P = .01) than conventional CT images alone for evaluating skull base invasion. The area under the receiver operating characteristic curve for conventional CT plus bone subtraction iodine (0.98) was significantly larger (P < .001) than the area under the receiver operating characteristic curve for conventional CT alone (0.90). CONCLUSIONS: Conventional CT plus bone subtraction iodine performs more closely to the accuracy of combining CT and MR imaging compared with conventional CT alone.

Comparison of MR Imaging and Dual-Energy CT for the Evaluation of Cartilage Invasion by Laryngeal and Hypopharyngeal Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: Dual-energy CT can distinguish iodine-enhanced tumors from nonossified cartilage and has been investigated for evaluating cartilage invasion in patients with laryngeal and hypopharyngeal squamous cell carcinomas. In this study, we compared the diagnostic accuracy of MR imaging and of a combination of weighted-average and iodine overlay dual-energy CT images in detecting cartilage invasion by laryngeal and hypopharyngeal squamous cell carcinomas, in particular thyroid cartilage invasion. MATERIALS AND METHODS: Fifty-five consecutive patients who underwent 3T MR imaging and 128-slice dual-energy CT for preoperative initial staging of laryngeal or hypopharyngeal squamous cell carcinomas were included. Two blinded observers evaluated laryngeal cartilage invasion on MR imaging and dual-energy CT using a combination of weighted-average and iodine-overlay images. Pathologic findings of surgically resected specimens were used as the reference standard for evaluating sensitivity, specificity, and the areas under the receiver operating characteristic curve of both modalities for cartilage invasion by each type of cartilage and for all cartilages together. Sensitivity and specificity were compared using the McNemar test and generalized linear mixed models. RESULTS: Dual-energy CT showed higher specificity than MR imaging for diagnosing all cartilage together (84% for MR imaging versus 98% for dual-energy CT, P < .004) and for thyroid cartilage (64% versus 100%, P < .001), with a similar average area under the curve (0.94 versus 0.95, P = .70). The sensitivity did not differ significantly for all cartilages together (97% versus 81%, P = .16) and for thyroid cartilage (100% versus 89%, P = .50), though there was a trend toward increased sensitivity with MR imaging. CONCLUSIONS: Dual-energy CT showed higher specificity and acceptable sensitivity in diagnosing laryngeal cartilage invasion compared with MR imaging.

CT Texture Analysis Potentially Predicts Local Failure in Head and Neck Squamous Cell Carcinoma Treated with Chemoradiotherapy.

BACKGROUND AND PURPOSE: The accurate prediction of prognosis and failure is crucial for optimizing treatment strategies for patients with cancer. The purpose of this study was to assess the performance of pretreatment CT texture analysis for the prediction of treatment failure in primary head and neck squamous cell carcinoma treated with chemoradiotherapy. MATERIALS AND METHODS: This retrospective study included 62 patients diagnosed with primary head and neck squamous cell carcinoma who underwent contrast-enhanced CT examinations for staging, followed by chemoradiotherapy. CT texture features of the whole primary tumor were measured using an in-house developed Matlab-based texture analysis program. Histogram, gray-level co-occurrence matrix, gray-level run-length, gray-level gradient matrix, and Laws features were used for texture feature extraction. Receiver operating characteristic analysis was used to identify the optimal threshold of any significant texture parameter. We used multivariate Cox proportional hazards models to examine the association between the CT texture parameter and local failure, adjusting for age, sex, smoking, primary tumor stage, primary tumor volume, and human papillomavirus status. RESULTS: Twenty-two patients (35.5%) developed local failure, and the remaining 40 (64.5%) showed local control. Multivariate analysis revealed that 3 histogram features (geometric mean [hazard ratio = 4.68, P = .026], harmonic mean [hazard ratio = 8.61, P = .004], and fourth moment [hazard ratio = 4.56, P = .048]) and 4 gray-level run-length features (short-run emphasis [hazard ratio = 3.75, P = .044], gray-level nonuniformity [hazard ratio = 5.72, P = .004], run-length nonuniformity [hazard ratio = 4.15, P = .043], and short-run low gray-level emphasis [hazard ratio = 5.94, P = .035]) were significant predictors of outcome after adjusting for clinical variables. CONCLUSIONS: Independent primary tumor CT texture analysis parameters are associated with local failure in patients with head and neck squamous cell carcinoma treated with chemoradiotherapy.

Quantitative Assessment of Variation in CT Parameters on Texture Features: Pilot Study Using a Nonanatomic Phantom.

Our aim was to evaluate changes in texture features based on variations in CT parameters on a phantom. Scans were performed with varying milliampere, kilovolt, section thickness, pitch, and acquisition mode. Forty-two texture features were extracted by using an in-house-developed Matlab program. Two-tailed t tests and false-detection analyses were performed with significant differences in texture features based on detector array configurations (Q values = 0.001-0.006), section thickness (Q values = 0.0002-0.001), and acquisition mode (Q values = 0.003-0.006). Variations in milliampere and kilovolt had no significant effect.

Characteristic activities of lower limbs with body weight support ratio.

In this study, we investigated a lower limbs muscle activity during body weight support treadmill training (BWSTT). Informed consent was obtained from 16 healthy men. Experimental system consists of force plate, treadmill, three-dimensional motion analysis system, electromyograph, and body weight support device. Body weight support (BWS) was set every 15% increase from 0% to 45%. Walking speed was 4.17 km/h. The measurement data were reaction forces, joint angles, joint moments and lower limbs muscle activities. The vertical reaction force shows two peaks. Two peaks decreased with increase of BWS together. Joint angles did not show significant changes with BWS. However, only the extension of hip angle was decreased with BWS. The peaks of joint moment were decreased. Decrease of ankle joint moment was greatest compared with other moment. Decrease of peaks of muscle activity by BWS was observed during stance phase, and did not almost change during swing phase.

[Minimally invasive video-assisted thoracic surgery using radially expanding trocars].

We report a new and safer access device for thoracoscopic operation. This radially expanding trocar provides a smaller incision of skin and a lesser visceral, vascular or neural injury than a conventional cannula. Therefore, most of patients undergoing this operation do not feel much pain. Moreover, this device system is more cost effective than a conventional one. We prefer and recommend this minimally invasive technique for video-assisted thoracic surgery.

Elevated serum myosin light chain I in influenza patients.

OBJECTIVE: Myocarditis has been described as a complication of influenza. Patients with influenza may have symptoms and abnormal laboratory data (including chest X-ray, electrocardiogram, etc.) suggestive of myocarditis, although few observations have been made regarding the prevalence of asymptomatic myocardial injury. We investigated whether influenza can produce myocardial injury without cardiac symptoms. METHODS: During the epidemic of influenza A (H3N2) from 1998 to 1999 in Japan, we examined possible cardiac muscle damage associated with influenza in patients without apparent clinical myocardial injury by measuring serum myosin light chain concentrations. PATIENTS: Ninety-six influenza-positive patients (46 males and 50 females, average age 43.4 years) without impaired renal function were studied. RESULTS: Of these patients, 11 (11.4%) had elevated serum myosin light chain I concentrations. CONCLUSION: Asymptomatic myocardial injury may be present in patients with influenza even when they have no symptoms suggestive of myocardial injury.

[Costs of influenza therapy].

The costs of outpatients with influenza. Outbreak of influenza occurs every winter in Japan and it brings a huge impacts on society and the individual. We calculated the costs of medications and medical examinations for outpatients with influenza in hospital. After we confirmed the diagnosis of influenza by rapid diagnosis system (Directigen Flu A) or hemagglutinin inhibition test, neutralization test, comparison of costs was done between influenza patients (89 cases) and non influenza patients (212 cases). Mean cost of total medication and medical examinations were 14,800 +/- 980 yen for an influenza patient and 12,420 +/- 976 yen for a non influenza patient. This data showed that treatment of the influenza patient is more expensive than non influenza patient. It must be considered that prophylaxis with influenza vaccine and treatment with antiinfluenza drugs given in the early stage of influenza are useful for reducing medical costs.

Microvasculature of the rat eye: scanning electron microscopy of vascular corrosion casts.

Methylmethacrylate castings of the eye microvasculature were prepared from 10 Spargue-Dawley rats and studied by electron microscopy. The choroidal arterioles are larger in diameter than retinal arterioles, and have a shorter course to choroidal capillaries than retinal arterioles to retinal capillaries. Retinal capillaries are extremely thin in diameter and form a sparse retinal capillary network. The choriocapillaris is large and sinusoid-like, forming a compactly arranged network in the choroid. These differences in the microvasculature between the choroid and retina help explain the differences in ocular hemodynamics; that is, the blood flow in the choroid is faster than that in the retina. Capillaries of the iris show a zigzag configuration, which may be an accommodation for dilation and constriction of the pupil. Capillaries of the ciliary body are of large diameter forming leaf-like configurations, presumably to contribute to the secretion of the aqueous humor. Capillaries of the conjunctiva exhibit a somewhat coiled configuration, the arrangement of which reduce tension of the conjunctiva vessels caused by eyeball movement. Intra-arterial cushions, which control blood flow at the branching sites, are found in both choroidal or retinal arterioles.

Serum beta2-microglobulin reflects increased bone resorption in immobilized stroke patients.

OBJECTIVE: The so-called bone-derived growth factor, beta2-microglobulin, has a regulatory function in bone metabolism by stimulating osteoclast activity. We undertook this study because osteoclast activity is known to be enhanced in patients with immobilized stroke, suggesting that their beta2-microglobulin concentrations may be increased. DESIGN: We studied 79 patients with acute stroke hemiplegia, including 36 men and 43 postmenopausal women ranging in age between 51 and 70 yr. RESULTS: The mean Barthel Index was 43 and 42 for men and women, respectively. The serum beta2-microglobulin concentration was increased in male and female patients, compared with the findings of 44 age-matched control subjects, and the serum concentration of pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen was also increased in male and female patients, compared with the findings of the control subjects. Serum concentrations of pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen correlated negatively with Barthel Index scores in both genders, indicating increased bone resorption caused by immobilization in these patients. Linear regression analysis revealed a positive correlation between beta2-microglobulin and pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen in both genders. CONCLUSIONS: These findings suggest that beta2-microglobulin reflects osteoclastic activity in response to stroke-induced immobilization in both genders. Beta2-microglobulin is a useful indicator of bone resorption in patients with immobilized stroke.

Spontaneous polar anterior subcapsular lenticular opacity in Sprague-Dawley rats.

A spontaneous focal polar anterior subcapsular lenticular opacity characterized by focal epithelial proliferation was found in Charles River Sprague-Dawley rats from various breeding facilities around the world (France, Japan, and the United States). The incidence of this change slightly increased with age up to a maximal incidence of 9.8% in 28- to 35-week-old male rats (French source). Over that period, there was little change in the size of the opacity; however some rats that were examined over longer periods (more than 2 years of age) developed secondary anterior cortical changes, and rarely, histologic findings of pigmentation and/or mineralization. The lenticular change was present throughout the life of the animals and had no sex predilection; mode of inheritance was not investigated. Due to its small size, this lens opacity is more easily identified by use of slit lamp biomicroscopy than by use of indirect ophthalmoscopy, and serial sections of the eye aid in locating it for histologic evaluation.

Virus-associated haemophagocytic syndrome responsive to steroid pulse therapy and double filtration plasmapheresis.

We present an adult patient with haemophagocytic syndrome (HPS) successfully treated with a combination of steroid pulse therapy and double filtration plasmapheresis (DFPP). A 58-year-old male was admitted with high fever, severe renal dysfunction, liver dysfunction and an increased level of lactate dehydrogenase. A serological test for Epstein-Barr (EB) virus showed an elevation of EBNA-IgM antibody titre. There were increased haemophagocytic histiocytes in the bone marrow in addition to thrombocytopenia and disseminated intravascular coagulation (DIC) accompanied by organ dysfunction. EB virus associated haemophagocytic syndrome was diagnosed. On admission, interferon (IFN)-gamma, interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor (G-CSF) and macrophage (M)-CSF were elevated, and were promptly normalized after steroid pulse therapy was initiated. G-CSF and M-CSF gradually decreased after DFPPs was started. To control hypercytokinaemia until treatment for the underlying disease is initiated, steroid pulse therapy and double filtration plasmapheresis are useful.

Influence of immobilization upon calcium metabolism in the week following hemiplegic stroke.

Hip fractures on the paretic side are a serious post-stroke complication and may result from disuse hemiosteopenia, hypovitaminosis D, and an increasing risk of falls. To evaluate short-term immobilization effects, we assessed calcium metabolism in 89 patients 1 week after the hemiplegic stroke and in 36 controls. Patient activity was rated using the Barthel index (BI). Sera from stroke patients and control subjects were assayed for ionized calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OHD), 1, 25-dihydroxyvitamin D (1,25-(OH)(2)D), bone Gla protein (BGP; a bone formation marker) and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker). Patients' serum concentrations of ionized calcium and ICTP were higher than in controls and correlated negatively with BI; their BGP concentrations were low, correlating positively with BI. Concentrations of serum 25-OHD, 1,25-(OH)(2)D, and PTH also were low; serum 25-OHD was at a deficient level (<10 ng/ml) in nine patients (10%), an insufficient level (10-20 ng/ml) in 56 (63%), and a sufficient level (>20 ng/ml) in only 24 (27%). PTH correlated negatively with calcium and 1,25-(OH)(2)D. Hypovitaminosis D is common in acute stroke patients. Immobilization from acute hemiplegia can increase bone resorption and serum calcium, and inhibit PTH secretion and 1,25-(OH)(2)D production to add to the effects of hypovitaminosis D.

Effect of ipriflavone on bone in elderly hemiplegic stroke patients with hypovitaminosis D.

A significant reduction in bone mineral density occurs in stroke patients on the hemiplegic side, correlating with the degree of paralysis and vitamin D deficiency due to malnutrition, sunlight deprivation, and immobilization-induced hypercalcemia, and increases the risk of hip fracture. We evaluated the effect of ipriflavone and 1alpha-hydroxyvitamin D3 [1alpha(OH)D3; vitamin D3] administration on bone mineral density preservation as compared with untreated controls. In a randomized and prospective study of 103 patients with hemiplegia after stroke (the mean duration of illness was 4.8 yr), 68 (34 patients in each group) were given 600 mg ipriflavone or 1 microg vitamin D3 daily for 12 mo, whereas the remaining 35 patients received no drug. Bone mineral density on the hemiplegic side decreased by 1.4% in the ipriflavone group, 3.8% in the vitamin D3 group, and 5.4% in the control group (P < .0001, ipriflavone v vitamin D3 and control). At baseline, all three groups of patients showed a 25-hydroxyvitamin D insufficiency, increased serum ionized calcium, and low levels of 1, 25-dihydroxyvitamin D, suggesting immobilization-induced hypercalcemia and inhibition of renal synthesis of 1, 25-dihydroxyvitamin D. After treatment, the serum 1, 25-dihydroxyvitamin D level increased by 139.9% in the ipriflavone group and by 26.9% in the vitamin D3 group. Significant decreases in the serum ionized calcium and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen, and increases in parathyroid hormone and bone Gla protein were observed in the ipriflavone group, whereas no changes occurred in the other two groups. One patient in the untreated group suffered a hip fracture, compared with none in the ipriflavone and vitamin D3 groups. These results suggest that ipriflavone is more efficacious than vitamin D3 in the prevention of decreased bone mineral density in hemiplegic stroke patients because it decreases serum calcium levels through inhibition of bone resorption and cause a subsequent increase in 1, 25-dihydroxyvitamin D concentration.

Effect of immobilization on vitamin D status and bone mass in chronically hospitalized disabled stroke patients.

OBJECTIVE: To assess the influence of immobilization upon vitamin D status and bone mass in chronically hospitalized, disabled, elderly patients following stroke. DESIGN: cross-sectional study. SETTING: Department of geriatric neurology in a Japanese hospital. SUBJECTS: 129 chronically hospitalized, disabled, elderly stroke patients and 28 age-matched controls. RESULTS: We observed a deficiency of both 1,25-dihydroxyvitamin D (1,25-[OH]2D; 24.3 pg/ml) and 25-hydroxyvitamin D concentrations (25-OHD; 11.7 ng/ml) in stroke patients compared with controls. A high serum ionized calcium (mean; 2.648 mEq/l) was an independent determinant of the Barthel index (66) and 1,25-[OH]2D. When the patients were categorized into three groups by 25-OHD level (deficient, insufficient and sufficient), there was no difference in the mean 1,25-[OH]2D levels. Parathyroid hormone levels were normal or low and did not correlate with 25-OHD. Serum bone turnover variables and bone mineral density (BMD) of the second metacarpal in patients were significantly decreased compared to control subjects. Independent determinants of BMD included Barthel index, 25-OHD and 1,25-[OH]2D. CONCLUSIONS: 1,25-[OH]2D deficiency in immobilized stroke patients is not caused by substrate (25-OHD) deficiency but by hypercalcaemia. Immobilization-induced hypercalcaemia may inhibit parathyroid hormone secretion and thus 1,25-[OH]2D production, resulting in decreased BMD. Immobilization itself also may be responsible for decreased BMD. Exogenous 1,25-[OH]2D (calcitriol) rather than dietary vitamin D supplementation may be required in disabled elderly stroke patients who have a deficiency of 1,25-[OH]2D in order to prevent hip fractures, which frequently occur in this population.

Rapid diagnosis of cryptococcal meningitis by microscopic examination of centrifuged cerebrospinal fluid sediment.

The classic India ink test is positive in only half of cryptococcal meningitis cases, and reliable, rapid cryptococcal antigen (CRAG) testing requires technical expertise and facilities not always available. We therefore examined cerebrospinal fluid (CSF) sediment using May-Giemsa, periodic acid-Schiff, and Gram stains in 16 patients with cryptococcal meningitis. The India ink test was positive in seven patients (44%), while microscopic examination of sediment revealed cryptococci in 13 (81%); in six of these 13 the India ink test was negative. Both methods failed to detect the pathogen in the remaining three patients. CRAG testing in CSF was negative in two patients (one with acquired immunodeficiency syndrome, one with diabetes mellitus) whose India ink test also was negative while cryptococci were identified in their CSF sediment. No false positives occurred with CSF May-Giemsa staining in 27 cases of aseptic meningitis with negative cultures for Cryptococcus. In all, microscopic examination of centrifuged and stained CSF sediment proved more sensitive for rapid diagnosis of cryptococcal meningitis than the India ink method, and in two of our patients cryptococci were seen in centrifuged CSF sediment despite negative CRAG and India ink tests.

Histiocytic necrotizing lymphadenitis (Kikuchi's disease) with aseptic meningitis.

Histiocytic necrotizing lymphadenitis, or Kikuchi's disease (KD), is a self-limited clinicopathologic entity recognized increasingly worldwide. A 27-year-old man with cervical lymphadenopathy and fever who was diagnosed with KD developed mild headache with no nuchal rigidity. The cerebrospinal fluid (CSF) was sterile and contained 78 white blood cells/mm3 with lymphocytes predominating, accompanied by smaller numbers of monocytes and granulocytes. This abnormality normalized spontaneously over 5 weeks. Eleven similar cases have been reported, all but one from Japan. The development of meningitis in KD was observed in four (9.8%) of 41 KD patients we have treated, suggesting that the meningitis was related to KD and not merely coincidental.

Effect of immobilization upon renal synthesis of 1,25-dihydroxyvitamin D in disabled elderly stroke patients.

A 1,25-dihydroxyvitamin D [1,25-(OH)2D] deficiency and immobilization-related increased serum calcium concentration have been observed in hemiplegic stroke patients. To elucidate the influence of increased serum calcium concentration on bone metabolism, we measured serum biochemical indices and bone mineral density (BMD) in the second metacarpals of 170 elderly subjects with hemiplegic stroke and 72 age-matched healthy controls. Serum concentrations of 25-hydroxyvitamin D [25-(OH)D], 1,25-(OH)2D, ionized calcium, intact parathyroid hormone (PTH), intact bone Gla protein (BGP), and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) were measured. An increased serum calcium concentration (mean 2.543 mEq/L) was observed in this population and correlated negatively with the Barthel index (mean 66), indicating immobilization-induced bone resorption with consequent increased serum calcium. Decreased serum concentrations of 1,25-(OH)2D (mean 25.0 pg/mL) and serum 25-OHD concentration (mean 11.6 ng/mL) were noted. Serum PTH was not increased (mean 34.8 pmol/L). Serum levels of BGP were decreased significantly, whereas serum ICTP concentrations were elevated (mean 15.2 ng/mL). A strong negative correlation was seen between the serum calcium concentration and 1,25-(OH)2D (p < 0.0001). BMD of the second metacarpal in patients was decreased significantly compared with control subjects and highly correlated with 25-(OH)D and 1,25-(OH)2D concentrations. Immobilization-related increased serum calcium levels may inhibit PTH secretion, and thus 1,25-(OH)2D production. In addition, 25-(OH)D insufficiency also may contribute to decreased concentration of 1,25-(OH)2D.