Preoperative photoacoustic versus indocyanine green lymphography in lymphaticovenular anastomosis outcomes for lower extremity lymphedema: A pilot study.

BACKGROUND: Identification of the proper lymphatics is important for successful lymphaticovenular anastomosis (LVA) for lymphedema; however, visualization of lymphatic vessels is challenging. Photoacoustic lymphangiography (PAL) can help visualize lymphatics more clearly than other modalities. Therefore, we investigated the usefulness of PAL and determined whether the clear and three-dimensional image of PAL affects LVA outcomes. METHODS: We recruited 22 female patients with lower extremity lymphedema. The operative time, number of incisions, number of anastomoses, lymphatic vessel detection rate (number of functional lymphatics identified during the operation/number of incisions), and limb volume changes preoperatively and 3 months postoperatively were compared retrospectively. The patients were divided according to whether PAL was performed or not, and results were compared between those undergoing PAL (PAL group; n = 10) and those who did not (near-infrared fluorescence [NIRF] group, n = 12). RESULTS: The mean age of the patients was 55.9 ± 15.1 years in the PAL group and 50.7 ± 14.9 years in the NIRF group. One patient in the PAL group and three in the NIRF group had primary lymphedema. Eighteen patients (PAL group, nine; and NIRF group, nine) had secondary lymphedema. Based on preoperative evaluation using the International Society of Lymphology (ISL) classification, eight patients were determined to be in stage 2 and two patients in late stage 2 in the PAL group. In contrast, in the NIRF group, one patient was determined to be in stage 0, three patients each in stage 1 and stage 2, and five patients in late stage 2. Lymphatic vessel detection rates were 93% (42 LVAs and 45 incisions) and 83% (50 LVAs and 60 incisions) in the groups with and without PAL, respectively (p = 0.42). Limb volume change was evaluated in five limbs of four patients and in seven limbs of five patients in the PAL and NIRF groups as 336.6 ± 203.6 mL (5.90% ± 3.27%) and 52.9 ± 260.7 mL (0.71% ± 4.27%), respectively. The PAL group showed a significant volume reduction. (p = .038). CONCLUSIONS: Detection of functional lymphatic vessels on PAL is useful for treating LVA.

The acute effect of roller massager on knee joint range of motion and muscle pain in older adults with total knee arthroplasty.

OBJECTIVES: Older adults with total knee arthroplasty (TKA) have a limited range of knee joint motion due to pain and stiffness. A roller massager (RM) has recently been suggested to decrease pain and increase joint range of motion (ROM). Therefore, this study aimed to investigate the acute effect of RM intervention on pain and knee joint ROM in older adults with TKA in the second postoperative week. METHODS: The participants were 23 patients (76.3±5.4 years) who had undergone TKA for knee OA. The degree of pain during the ROM measurements was measured using the visual analog scale before and immediately after the RM intervention. The RM intervention was performed on the thigh's lateral, central, and medial parts for three sets of 60 s using an RM. RESULTS: RM intervention could significantly increase knee flexion ROM (p<0.01, d=0.41, Δchange: 4.1±3.2°) and decrease pain during the knee ROM measurements (p<0.01, d=-0.53, Δchange: -11.9±21.0). CONCLUSIONS: The three sets of 60-s RM intervention significantly increased knee flexion ROM and reduced pain in older adults with TKA in the second postoperative week. These results show that RM intervention is an effective tool for treating stiffness and pain after TKA.

Measurement of lymphatic vessel depth using photoacoustic imaging.

OBJECTIVES: Information regarding the depth of lymphatic vessel is important for lymphatic surgeons because rapid identification of functional lymphatic vessels and veins is necessary to perform good lymphaticovenular anastomosis, which is a surgical procedure for lymphedema cases. Photoacoustic lymphangiography (PAL) may be useful for such identification because it allows the assessment of the depth of lymphatic vessels. Thus, we aimed to measure the lymphatic vessel depth using images obtained by PAL. METHODS: This study included healthy individuals and patients with lymphedema. In all participants, indocyanine green dissolved in dextrose was injected subcutaneously into the first and fourth webs of the foot and the lateral malleolus, and PAL was performed on the medial side of the lower leg. The lymphatic vessel depth was measured from the ankle joint, 10 cm above the medial malleolus, and 20 cm above the medial malleolus on PAL in the cross-sectional view and was compared between the participant groups. RESULTS: The healthy group (mean age, 43.3 ± 12.9 years) included 21 limbs of 4 male and 16 female healthy individuals (bilateral limbs of 1 patient were considered). The lymphedema group (mean age, 62.0 ± 11.7 years) included 17 limbs of 3 male and 14 female patients with lymphedema. The average lymphatic vessel depths from the ankle joint, 10 cm above the medial malleolus, and 20 cm above the medial malleolus were 2.6, 4.7, and 5.6 mm in the healthy group and 3.6, 7.3, and 7.4 mm in the lymphedema group, respectively. Lymphatic vessels were significantly deeper in the lymphedema group than in the healthy group at all measurement locations. CONCLUSIONS: Using PAL, we determined the lymphatic vessel depth in living bodies. By searching for the lymphatic vessels based on our findings, even surgeons who are relatively inexperienced with lymphatic surgery may be able to identify functional lymphatic vessels more efficiently.

Genital Feminizing Surgery without Vaginoplasty as a Safe, Aesthetic, and Cost-Effective Option for Gender-Affirming Surgery for Transwomen.

Gender affirming surgery (GAS) has important impacts for people with gender incongruence (GI), both physically and socially. As the societal acceptance of gender diversity spreads, the number of individuals with GI who wish to be identified as the gender of their choice is increasing. Indeed, many elderly people who have lived a long time with GI now wish to undergo GAS, but face greater surgical risks due to greater burdens of underlying medical conditions. Generally, vaginoplasty is performed for transwomen; however, this surgery is time-consuming and involves heavy bleeding, and thus, should be avoided in elderly people. A less invasive technique is needed. In this article, we describe a new, less invasive genital feminizing surgical technique for transwomen with reports from two clinical cases. We present this novel technique as a safe, aesthetic, and cost-effective option for gender-affirming surgery for transwomen.

Muscle Fiber Composition Changes after Selective Nerve Innervation.

Facial nerve paralysis interferes with mimetic muscle function. To reconstruct natural facial movement, free muscle flaps are transplanted as new muscles. However, it is difficult to maintain resting tonus. A dual innervation technique in which other nerves such as the hypoglossal nerve or contralateral facial nerve are added is often applied. Using 10-week-old rats (n = 10), the masseteric and hypoglossal nerves were cut, and the distal stump of the masseteric nerve and the proximal stump of the hypoglossal nerve were then sutured (suture group). In the other group, the masseteric nerve was cut and cauterized (cut group). Immunohistochemistry and microarray were performed on the extracted masseter muscle. The immunohistochemistry results suggested that the muscles in the suture group obtained oxidative characteristics. The microarray showed the genes involved in mitochondrial function, including Perm1. In summary, our data support the validity of the dualinnervation technique for facial paralysis treatment.

Application of Photoacoustic Imaging for Lymphedema Treatment.

BACKGROUND: Lymphatic vessels are difficult to identify using existing modalities as because of their small diameter and the transparency of the lymph fluid flowing through them. METHODS: Here, we introduce photoacoustic lymphangiography (PAL), a new modality widely used for lymphedema treatment, to observe limb lymphatic vessels. The photoacoustic imaging system used in this study can simultaneously visualize lymphatic vessels and veins with a high resolution (0.2 mm) and can also observe their three-dimensional relationship with each other. RESULTS: High-resolution images of the lymphatic vessels, detailed structure of the dermal back flow, and the three-dimensional positional relationship between the lymphatic vessels and veins were observed by PAL. CONCLUSION: The clear image provided by PAL could have a major application in pre- and postoperative use during lymphaticovenular anastomosis for lymphedema treatment.

Subcutaneous Lymphatic Vessels in the Lower Extremities: Comparison between Photoacoustic Lymphangiography and Near-Infrared Fluorescence Lymphangiography.

Background Detailed visualization of the lymphatic vessels would greatly assist in the diagnosis and monitoring of lymphatic diseases and aid in preoperative planning of lymphedema surgery and postoperative evaluation. Purpose To evaluate the usefulness of photoacoustic imaging (PAI) for obtaining three-dimensional images of both lymphatic vessels and surrounding venules. Materials and Methods In this prospective study, the authors recruited healthy participants from March 2018 to January 2019 and imaged lymphatic vessels in the lower limbs. Indocyanine green (5.0 mg/mL) was injected into the subcutaneous tissue of the first and fourth web spaces of the toes and below the lateral malleolus. After confirmation of the lymphatic flow with near-infrared fluorescence (NIRF) imaging as the reference standard, PAI was performed over a field of view of 270 × 180 mm. Subsequently, the number of enhancing lymphatic vessels was counted in both proximal and distal areas of the calf and compared between PAI and NIRF. Results Images of the lower limbs were obtained with PAI and NIRF in 15 participants (three men, 12 women; average age, 42 years ± 12 [standard deviation]). All participants exhibited a linear pattern on NIRF images, which is generally considered a reflection of good lymphatic function. A greater number of lymphatic vessels were observed with PAI than with NIRF in both the distal (mean: 3.6 vessels ± 1.2 vs 2.0 vessels ± 1.1, respectively; P < .05) and proximal (mean: 6.5 vessels ± 2.6 vs 2.6 vessels ± 1.6; P < .05) regions of the calf. Conclusion Compared with near-infrared fluorescence imaging, photoacoustic imaging provided a detailed, three-dimensional representation of the lymphatic vessels and facilitated an increased understanding of their relationship with the surrounding venules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Lillis and Krishnamurthy in this issue.

A Novel Surgical Approach for Refractory Secondary Lymphedema of the Lower Extremity Accompanying Micro-Arteriovenous Fistula.

Lymphaticovenous anastomosis (LVA) for lymphedema of the lower extremity has been established as a minimally invasive and effective surgical treatment to return static lymph fluid to the vein. However, we often experience cases in which the effect of LVA cannot be obtained sufficiently, or the anastomotic site becomes obstructed and the edema deteriorates over a long term. One of the causes is the combination of local venous hypertension (VT) by micro-arteriovenous fistula (mAVF). We report two cases of refractory lymphedema at the lower extremity caused by mAVF and incompetent perforating vein (IPV). In these cases, surgical ligation and separation of the mAVF and IPV is effective in reducing edema.

Role of a new bioassay for thyroid-stimulating antibodies (aequorin TSAb) in Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is characterized by an autoimmune reaction against thyrotropin (TSH) receptors and is diagnosed by TSH receptor antibody (TRAb). A novel assay for thyroid-stimulating antibody (TSAb) was recently introduced using a frozen Chinese hamster ovary cell line expressing TSH receptors, cyclic adenosine monophosphate (cAMP)-gated calcium channel, and aequorin (aequorin TSAb). The aim of this study was to evaluate the role of aequorin TSAb in GO. We studied 136 Japanese patients with GO (22 euthyroid and 8 hypothyroid GO patients) at our hospital. TRAbs were estimated by first generation TRAb (TRAb 1st), second generation TRAb (hTRAb 2nd), conventional porcine TSAb, and the new aequorin TSAb assays. Aequorin TSAb, porcine TSAb, TRAb 1st, and hTRAb 2nd were positive in 125/136 (92%), 110/136 (81%), 81/130 (62%), and 93/114 (82%) patients, respectively. In patients with hyperthyroid GO, they were positive in 98/106 (98%), 96/106 (91%), 78/101 (77%), and 84/93 (90%) patients, respectively. In patients with euthyroid GO, they were positive in 19/22 (86%), 9/22 (41%), 1/21 (5%), and 6/17 (35%) patients, respectively. Aequorin TSAb levels were significantly related to TRAb 1st (r = 0.4172, p < 0.0001), hTRAb 2nd (r = 0.2592, p < 0.0001), and porcine TSAb (r = 0.4665, p < 0.0001). Clinical activity score (CAS) was significantly greater in patients with high titers of aequorin TSAb than in those with low titers. Aequorin TSAb levels were significantly related to the signal intensity ratio of the enlarged eye muscle and proptosis evaluated by MRI before steroid pulse therapy. Aequorin TSAb assay was more sensitive than the conventional assays, especially in euthyroid GO.

Effective combination of lymphatico-venous anastomosis and negative pressure wound therapy for lymphocyst: A Case Study.

Lymphorrhea and lymphocysts are complications that occur after lymph node dissection or biopsy and are difficult to treat. Conventional treatments for lymphocysts are not always effective. For instance, lymphatico-venous anastomosis has a limited treatment efficacy when the cyst wall is thickened, and negative pressure wound therapy is limited by the installation site and longer treatment times. To overcome these individual shortcomings, we aimed to assess whether a combination of both interventions would be effective. In this study, we report the application of a lymphatico-venous anastomosis combined with negative pressure wound therapy for treating bilateral inguinal lymph nodes and pelvic lymph node dissection following treatment of vaginal cancer. Short-term improvements were observed with no recurrence of lymphocysts at 1-year follow-up.

CD28 co-stimulation is dispensable for the steady state homeostasis of intestinal regulatory T cells.

It is well-established that CD28 co-stimulation is required for the development and the proliferation of thymus-derived regulatory T cells (tTregs). Meanwhile, the role of CD28 co-stimulation in the homeostasis of peripherally derived Tregs (pTregs) remains unclear. To clarify this issue, we analyzed Tregs in small and large intestines (SI and LI), the principle sites of pTreg development. Interestingly, and different from in the thymus, Tregs were abundant in the intestines of CD28-/- mice, and most of them were phenotypically pTregs. We showed that CD28-/- naive T cells differentiated into pTregs in the LI after oral exposure to antigens and that CD28-/- pTregs in the LI had the same highly proliferative activity as CD28+/- cells. CD28-/- pTregs acquired these Treg-specific features at transcriptional and epigenetics levels. On the other hand, some immune suppressive molecules were down-regulated in CD28-/- pTregs. Correspondingly, the suppressive activity of CD28-/- pTregs was weaker than CD28+/+ cells. These results indicate that the homeostasis of pTregs in the intestines is maintained even in the absence of CD28, whereas CD28 is required for the maximal suppressive activity of intestinal pTregs.

CD28 signaling in primary CD4(+) T cells: identification of both tyrosine phosphorylation-dependent and phosphorylation-independent pathways.

In addition to TCR signaling, the activation and proliferation of naive T cells require CD28-mediated co-stimulation. Once engaged, CD28 is phosphorylated and can then activate signaling pathways by recruiting molecules to its YMNM motif and two PxxP motifs. In this study, we analyzed the relationship between tyrosine phosphorylation and the co-stimulatory function of CD28 in murine primary CD4(+) T cells. Tyrosine phosphorylation is decreased in CD28 where the N-terminal PxxP motif is mutated (nPA). In cells expressing nPA, activation of Akt and functional co-stimulation were decreased. In contrast, where the C-terminal PxxP motif is mutated, tyrosine phosphorylation and activation of the ERK, Akt and NF-κB were intact, but proliferation and IL-2 production were decreased. Using the Y(189) to F mutant, we also demonstrated that in naive CD4(+) T cells, tyrosine at position 189 in the YMNM motif is critical for both tyrosine phosphorylation and the functional co-stimulatory effects of CD28. This mutation did not affect unfractionated T-cell populations. Overall, our data suggest that CD28 signaling uses tyrosine phosphorylation-dependent and phosphorylation-independent pathways.

A 1-Week Comprehensive Foam Rolling Intervention Program Can Improve Knee Pain but Not Muscle Function and Range of Motion in Patients with Total Knee Arthroplasty.

We investigate the effect of a 1-week comprehensive foam rolling (FR) intervention program on knee pain, range of motion (ROM), and muscle function in patients with TKA.Thirty patients with TKA were randomly allocated to FR (n = 15) or control (n = 15) groups. The control group received only regular physical therapy. Patients in the FR group performed the FR intervention in addition to their regular physical therapy twice daily from postoperative weeks two to three (60 s × 3 repetitions × 2 times/day × 6 days: total = 2160 s). Pain score, knee flexion and extension ROM, muscle strength, walking function, and balance function were measured before and after the FR intervention. From the second to third postoperative weeks, there were significant improvements in all variables, and the reduction in pain score at stretching was significantly greater in the FR group (-26.0 ± 1.4; p < 0.05) than in the control group (-12.5 ± 1.9). However, there was no significant difference in changes in the other variables except for the pain score at stretching between FR and control groups. A 1-week comprehensive FR intervention program in patients with TKA could reduce pain scores at stretching without a synergistic effect on physical function, i.e., walking speed, balance function, and muscle strength of the knee extensors muscles.

Establishment of a BRAF V595E-mutant canine prostate cancer cell line and the antitumor effects of MEK inhibitors against canine prostate cancer.

Canine prostate cancer (cPCa) is a malignant neoplasm with no effective therapy. The BRAF V595E mutation, corresponding to the human BRAF V600E mutation, is found frequently in cPCa. Activating BRAF mutations are recognized as oncogenic drivers, and blockade of MAPK/ERK phosphorylation may be an effective therapeutic target against BRAF-mutated tumours. The aim of this study was to establish a novel cPCa cell line and to clarify the antitumor effects of MEK inhibitors on cPCa in vitro and in vivo. We established the novel CHP-2 cPCa cell line that was derived from the prostatic tissue of a cPCa patient. Sequencing of the canine BRAF gene in two cPCa cell lines revealed the presence of the BRAF V595E mutation. MEK inhibitors (trametinib, cobimetinib and mirdametinib) strongly suppressed cell proliferation in vitro, and trametinib showed the highest efficacy against cPCa cells with minimal cytotoxicity to non-cancer COPK cells. Furthermore, we orally administered 0.3 or 1.0 mg/kg trametinib to CHP-2 xenografted mice and examined its antitumor effects in vivo. Trametinib reduced tumour volume, decreased phosphorylated ERK levels, and lowered Ki-67 expression in xenografts in a dose-dependent manner. Although no clear adverse events were observed with administration, trametinib-treated xenografts showed osteogenesis that was independent of dosage. Our results indicate that trametinib induces cell cycle arrest by inhibiting ERK activation, resulting in cPCa tumour regression in a dose-dependent manner. MEK inhibitors, in addition to BRAF inhibitors, may be a targeted agent option for cPCa with the BRAF V595E mutation.

Evaluation of the effect of age of the younger mice on the rejuvenation of the older mice by heterochronic parabiosis.

Heterochronic parabiosis is used to study the systemic effects of aging and involves surgically connecting two animals of different ages such that they have common blood circulation. Although this technique has been prevalent for a long time, there is no scientific consensus on the age of the animals that should be used. We hypothesized that the younger the animal, the greater would be its rejuvenating effect. Hence, to test this hypothesis, we created parabiosis of 67-week-old mice with younger mice of different ages (4-week-old and 8-week-old). We evaluated the changes in appearance and the expression IL-1A, IL-6, and Cdkn2a (p16) in the liver, kidney, brain, and skin. These cytokines belong to the senescence-associated secretory phenotype (SASP) factors, and are indicators of aging. Although we did not find any significant changes in the appearance of the mice, we found statistically significant differences in some SASP factors between the liver of the 4-week-old and 8-week-old pairs. However, overall, compared to the 8-week-old mice, the 4-week-old does not exert a significantly higher rejuvenation effect on the older mice. Hence, we concluded that the rejuvenation of older mice during heterochronic parabiosis might not be affected by the exact age of the younger mice.

Photoacoustic lymphangiography exhibits advantages over near-infrared fluorescence lymphangiography as a diagnostic tool in patients with lymphedema.

OBJECTIVE: Photoacoustic imaging is a new technique that can evaluate the vascular system using photoacoustic effects. The present study compared the ability of the new photoacoustic lymphangiography (PAL) method and more standard near-infrared fluorescence (NIRF) to image the lymphatic system in patients with secondary lymphedema after gynecological cancer surgery. METHODS: Patients with secondary lymphedema in the lower extremities after gynecologic cancer surgery, who were assessed using PAL between May 2018 and January 2019, were recruited. NIRF was performed first using 5.0 mg/mL of indocyanine green injected using a 0.2-cc 30-gauge needle. Correlations between NIRF and PAL findings on patient images were subsequently examined. RESULTS: Seventeen patients with secondary lymphedema were enrolled. The mean age of the patients was 61 ± 11 years. The imaging sites were the medial lower leg in 15 patients, the posterior lower leg in 9 patients, the lateral lower leg in 7 patients, the medial knee in 4 patients, and other areas in 3 patients. A total of 38 pictures were obtained. Five distinct lymphatic patterns were observed over the entire sample using PAL: straight, winding, spiderweb, nebulous, and black-out pattern. Eighteen of the 24 limbs (75%) that exhibited a linear pattern in NIRF exhibited a straight pattern in PAL, and 19 of the 20 limbs (95%) that exhibited a splash pattern in NIRF exhibited a winding or spiderweb pattern in PAL. Eight limbs exhibiting diffuse patterns without linear or splash patterns with NIRF were all nebulous or black-out patterns in PAL. This suggests that more severe lymphatic degeneration was associated with poorer visualization in PAL. CONCLUSIONS: NIRF plays an important role in lymphedema treatment. In the present study, various PAL patterns were compared with those observed using NIRF. PAL provided clearer images including transectional views, which were not available using NIRF, and may promote further understanding of the changes in the lymphatic structure and function in patients with secondary lymphedema.

Photoacoustic lymphangiography is a possible alternative for lymphedema staging.

OBJECTIVE: Photoacoustic imaging is a new technique that uses the photoacoustic effect. In photoacoustic lymphangiography (PAL), images of the lymphatic vessels can be visualized using light-absorbing contrast agents. In the present study, we investigated the efficacy of PAL for lymphedema staging. METHODS: We performed PAL of the lower extremities and examined the clinical implications of using PAL for staging lymphedema by comparing the PAL images with those obtained using lymphoscintigraphy. Of 47 patients with lymphedema who had been outpatients or hospitalized at our institution between May 2018 and September 2020 and had undergone PAL, 15 with 18 limbs who had also undergone lymphoscintigraphy were included in the present study. The lymphoscintigraphy findings were classified using the Maegawa classification. We also investigated whether PAL could clearly visualize the lymphatic vessels and concisely reflect the disease state by counting the number of lymphatic vessels observed using PAL. RESULTS: The PAL findings were categorized into three groups: collecting lymphatic vessels, dermal backflow (DBF), and no lymphatic vessels. The collecting lymphatic vessels group corresponded to types 2 and 3 in the Maegawa classification; DBF corresponded to types 3 and 4, and the no lymphatic vessels group corresponded to type 4. The number of lymphatic vessels visualized using PAL was similar to that with lymphoscintigraphy. As the disease progressed, the number of lymphatic vessels observed decreased, increased DBF was detected, and, eventually, the lymphatic vessels were not visible, corresponding to the general changes observed via lymphoscintigraphy with stage progression. CONCLUSIONS: The findings from PAL and lymphoscintigraphy tended to correspond, suggesting that PAL could be useful for lymphedema staging.

Micro-arteriovenous fistula in patients with lower limb lymphedema.

BACKGROUND: A micro-arteriovenous fistula (AVF) is a minute, short shunt between an artery and a vein that does not pass through a capillary. We investigated the association between micro-AVFs and lymphedema using computed tomography angiography (CTA) and venous blood gas analysis. METHODS: In 95 patients with lower limb lymphedema, the presence or absence of early venous return (EVR) was compared between patients with primary and secondary lymphedema. Furthermore, we investigated the difference in the timing of edema onset in patients with secondary lymphedema with or without EVR using CTA. In 20 patients with lower limb lymphedema with confirmed early EVR in a unilateral lower limb, the partial pressure of oxygen (PO2) was compared between the lower limb with EVR and the contralateral lower limb. RESULTS: Secondary lymphedema with or without EVR occurred at an average of 36.0±59.3 months and 93.5±136.1 months, respectively; however, no significant difference was noted. PO2 was 57.6±11.7 mmHg and 44.1±16.4 mmHg in the EVR and non-EVR limbs, respectively, which was a significant difference (P=0.005). CONCLUSIONS: EVR and venous blood gas analysis suggested the presence of micro-AVFs in patients with lower extremity edema. Further research is warranted to examine the cause of micro-AVFs, to advance technology to facilitate the confirmation of micro-AVFs by angiography, and to improve lymphedema by ligation of micro-AVFs.

Associations of Dietary Salt and Its Sources with Hemoglobin A1c in Patients with Type 2 Diabetes Not Taking Anti-Diabetic Medications: Analysis Based on 6-Month Intervention with a Moderate Low-Carbohydrate Diet.

OBJECTIVE: Based on biological studies, the hyperglycemic effect mediated by sodium-glucose co-transporter 1 in the intestine is stronger for foods containing more sodium chloride. Observational studies have demonstrated that type 2 diabetes (T2DM) incidence increases as salt intake increases. We aimed to elucidate associations of total salt and its sources with hemoglobin A1c (HbA1c) in patients with T2DM. METHODS: We conducted an observational study using data from a 6-month moderate low-carbohydrate dietary intervention in 245 outpatients with T2DM (138 men) without antidiabetic medication. Intakes of total salt and its sources, carbohydrate and total energy were assessed at baseline and 6 months based on 3-day dietary records. Multiple regression analyses were performed to examine associations of Δtotal salt or its sources with ΔHbA1c. RESULTS: Salt intake significantly decreased in men (change: -0.92 ± 3.53 g/day) but not in women (0.11 ± 2.28). HbA1c (men: -1.5 ± 1.6%; women: -0.9 ± 1.3%), carbohydrate (men: -115 ± 104 g/day; women: -64 ± 71) and total energy (men: -439 ± 660 kcal/day; women: -192 ± 438) significantly decreased in both sexes. Multiple regression analysis revealed that reducing intakes of total salt and salt from salty snacks, meat processed foods, Chinese noodles with soup and table salt by 1.0 g was associated with decreases in HbA1c of 0.11% 1.18% 0.47% 0.38% and 0.26%, respectively, in men, while reducing salt from miso by 1.0 g was associated with a decrease in HbA1c of 0.30% in women. The associations were dependent on Δcarbohydrate or Δtotal energy in men, while the association of Δsalt from miso in women was independent of them. CONCLUSION: Reducing total salt and its sources had differential associations with HbA1c. Individual associations depended on Δcarbohydrate or Δtotal energy in men, while that of salt from miso in women was independent of them.

Reducing Carbohydrate from Individual Sources Has Differential Effects on Glycosylated Hemoglobin in Type 2 Diabetes Mellitus Patients on Moderate Low-Carbohydrate Diets.

Background: We evaluated decreases in glycosylated hemoglobin (HbA1c) achieved by reducing carbohydrate from various sources in type 2 diabetes mellitus patients. Methods: We followed up 138 male and 107 female outpatients on a moderate low-carbohydrate diet without diabetic medication for 6 months. Changes in carbohydrate sources (Δcarbohydrate) were assessed from 3-day dietary records at baseline and 6 months, and associations with changes in HbA1c (ΔHbA1c) were examined with Spearman's correlation coefficients (rs) and multiple regression analysis. Results: ΔHbA1c was -1.5%±1.6% in men and -0.9%±1.3% in women, while Δtotal carbohydrate was -115.3±103.7 g/day in men and -63.6±71.1 g/day in women. Positive associations with ΔHbA1c were found for Δtotal carbohydrate (rs=0.584), Δcarbohydrate from soft drinks (0.368), confectionery (0.361), rice (0.325), bread (0.221), Chinese soup noodles (0.199) in men, and Δtotal carbohydrate (0.547) and Δcarbohydrate from rice (0.376) and confectionery (0.195) in women. Reducing carbohydrate sources by 50 g achieved decreases in HbA1c of 0.43% for total carbohydrate, 1.33% for soft drinks, 0.88% for confectionery, 0.63% for bread, 0.82% for Chinese soup noodles and 0.34% for rice in men and 0.45% for total carbohydrate, 0.67% for confectionery and 0.34% for rice in women, although mean reductions in carbohydrate from these sources were much smaller than that from rice. Conclusion: Decreases in HbA1c achieved by reducing carbohydrate from soft drinks, confectionery, bread and Chinese soup noodles were 2- to 4-fold greater than that for rice. Our results will enable patients to decrease HbA1c efficiently (UMIN000009866).