Isolation of OXA-48-like carbapenemase-producing Escherichia coli susceptible to piperacillin/tazobactam in a Japanese patient without a history of travel abroad.

Oxacillinase (OXA)-48-like ß-lactamases are the most common carbapenemases in Enterobacterales in certain regions of the world and are being introduced on a regular basis into regions of non-endemicity. Japan has been characterized by low rates of carbapenemase-producing Enterobacterales, and among them, OXA-48-like carbapenemase-producing isolates are extremely rare. Here we describe a Japanese medical worker, without a history of travel abroad, who was diagnosed as having a community-acquired urinary tract infection, and whose urine sample was found to be positive for OXA-48-like carbapenemase-producing Escherichia coli. None of her close contacts had a history of foreign travel, and the same drug-resistant organism was not observed in other patients who had been hospitalized and undergone environmental culture tests in the same medical institution. This isolate was resistant to penicillins, narrow-spectrum cephalosporins, fluoroquinolones, and cefmetazole, but was susceptible to broad-spectrum cephalosporins, piperacillin/tazobactam, and meropenem and displayed reduced susceptibility to imipenem. The modified carbapenem inactivation test supported carbapenemase production, but inhibitor-based synergistic tests yielded negative results of carbapenemase production. Multiplex polymerase chain reaction revealed the presence of the carbapenemase gene (blaOXA-48) blaTEM and AmpC ß-lactamase gene (blaDHA). Singleplex polymerase chain reaction targeting the blaOXA-48 region amplified a product sequencing to nearly the full length (722 bp) and matching 100% with OXA-48. The present case highlights a new concern regarding OXA-48-like carbapenemase-producing Enterobacterales, which remain challenging to detect for clinical laboratories in regions of non-endemicity, and may already be latent in Japan.

Presumptive complicating Clostridium paraputrificum bacteremia as a presenting manifestation in a patient with undiagnosed ulcerative colitis followed by acute colonic pseudo-obstruction.

Clostridium paraputrificum is a member of the commensal flora of the gastrointestinal tract and skin. Despite being linked with cases of severe invasive infection, this organism is an uncommon pathogen in humans. Here, we report a case of undiagnosed ulcerative colitis in which the presentation was one of presumptive complicating C. paraputrificum bacteremia and, later, acute colonic pseudo-obstruction. The patient was an elderly male with prostate cancer who was admitted in a state of shock secondary to suspected septicemia from an abdominal source. Only one of two sets of anaerobic blood cultures were positive for C. paraputrificum. Endoscopic and pathological investigations revealed proctitis consistent with ulcerative colitis. The patient's abdominal manifestations worsened, and abdominal imaging demonstrated de novo massive colonic dilatation without any apparent mechanical obstruction. We speculated that C. paraputrificum bacteremia caused by undiagnosed ulcerative colitis had created ideal conditions for acute colonic pseudo-obstruction. This case demonstrates that C. paraputrificum bacteremia can be associated with latent severe gastrointestinal pathologies, indicating the need to investigate any abdominal source of infection, even if only a single blood culture is positive.

A case of fatal myxedema coma with electrocardiogram Osborne J-wave in a patient initially diagnosed with hypothyroidism.

Myxedema coma is a life-threatening endocrine emergency with a high mortality rate resulting from severe insufficiency of thyroid hormones. Intravenous levothyroxine replacement is considered the standard therapy for myxedema coma in many countries. In Japan, however, although there are diagnostic criteria highly suggestive or diagnostic for myxedema coma, no management strategy has been established, despite the availability of levothyroxine. Here we report a 75-year-old man with a history of Alzheimer's disease and schizophrenia who developed somnolence and generalized edema. Except for a pulse rate of 60 bpm, his vital signs and blood oxygen level were stable. Thyroid studies showed an elevated serum thyrotropin level of 219.2 µU/mL and a decreased serum free-thyroxine level of 0.15 ng/dL. On this basis he was diagnosed as having hypothyroidism rather than being highly suggestive for myxedema coma. Daily oral levothyroxine 25 µg was initiated and increased to 50 µg 3 days later. Seven days after being started on levothyroxine, the patient suddenly developed impaired consciousness, hypoxemia, hypotension, hypothermia, and hyponatremia. Electrocardiography revealed junctional bradycardia with Osborne J-wave. Myxedema coma was therefore diagnosed. He went into cardiac arrest in the emergency room but was resuscitated. Despite subsequent intravenous administration of hydrocortisone and levothyroxine, as well as intensive supportive care, he eventually died 12 hours after hospital admission. This case illustrates some of the challenges associated with the management of patients with signs highly suggestive/diagnostic of myxedema coma, including the optimal loading dosage and intervention timing of thyroid hormone replacement.

Vanishing Cardiac Tumor by Chemotherapy in a Patient With Diffuse Large B-Cell Lymphoma.

A 70-year-old Japanese man presented with a massive cardiac tumor associated with diffuse large B-cell lymphoma. Standard chemotherapy resulted in complete remission and the cardiac tumor disappeared. (Level of Difficulty: Intermediate.).

A multicenter non-randomized, uncontrolled single arm trial for evaluation of the efficacy and the safety of the treatment with favipiravir for patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a bunyavirus infection with high mortality. Favipiravir has shown effectiveness in preventing and treating SFTS virus (SFTSV) infection in animal models. A multicenter non-randomized, uncontrolled single arm trial was conducted to collect data on the safety and the effectiveness of favipiravir in treatment of SFTS patients. All participants received favipiravir orally (first-day loading dose of 1800 mg twice a day followed by 800 mg twice a day for 7-14 days in total). SFTSV RT-PCR and biochemistry tests were performed at designated time points. Outcomes were 28-day mortality, clinical improvement, viral load evolution, and adverse events (AEs). Twenty-six patients were enrolled, of whom 23 were analyzed. Four of these 23 patients died of multi-organ failure within one week (28-day mortality rate: 17.3%). Oral favipiravir was well tolerated in the surviving patients. AEs (abnormal hepatic function and insomnia) occurred in about 20% of the patients. Clinical symptoms improved in all patients who survived from a median of day 2 to day10. SFTSV RNA levels in the patients who died were significantly higher than those in the survivors (p = 0.0029). No viral genomes were detectable in the surviving patients a median of 8 days after favipiravir administration. The 28-day mortality rate in this study was lower than those of the previous studies in Japan. The high frequency of hepatic dysfunction as an AE was observed. However, it was unclear whether this was merely a side effect of favipiravir, because liver disorders are commonly seen in SFTS patients. The results of this trial support the effectiveness of favipiravir for patients with SFTS.

Monitoring of MYD88 L265P mutation by droplet digital polymerase chain reaction for prediction of early relapse in a patient with Bing-Neel syndrome.

Bing-Neel syndrome (BNS) is a rare neurologic complication of lymphoplasmacytic lymphoma (LPL) characterized by direct infiltration of lymphoplasmacytic cells (LPCs). Although no standard treatment has yet been established, patients with BNS harboring the MYD88 L265P mutation have been reported to respond favorably to ibrutinib, which can cross the blood-brain barrier and trigger apoptosis of MYD88 L265P-positive LPCs. However, it is still unclear whether monitoring of MYD88 L265P mutation status would be useful for predicting relapse/progression or for assisting diagnosis and evaluating response to chemotherapy. Here, we report the case of a patient with BNS receiving ibrutinib in whom we detected relapse early by monitoring for molecular residual disease (MRD) based on the presence of the MYD88 L265P mutation in cerebrospinal fluid (CSF) on droplet digital polymerase chain reaction assay. Persistent MRD increased 2 weeks before the onset of relapse symptoms without any abnormal imaging findings or evidence of clonal LPCs on CSF cytology, flow cytometry analysis, or immunofixation electrophoresis. Our findings suggest that an increase in MRD levels is correlated with relapse in patients with BNS.

Occupational Lead Poisoning in a Patient with Acute Abdomen and Normocytic Anemia.

We herein report a 24-year-old male construction worker with occupational lead poisoning who presented with acute abdomen and normocytic anemia. The levels of urinary delta-aminolevulinic acid and free erythrocyte protoporphyrin were elevated without any increase in the level of urine porphobilinogen. Detection of an elevated blood lead level of 100 µg/dL confirmed a diagnosis of lead poisoning. Chelation therapy with calcium disodium ethylenediaminetetraacetate resulted in prompt improvement of the clinical symptoms and the blood lead level. Clinicians should be aware that lead poisoning caused by occupational exposure can still occur sporadically in construction workers in Japan.

Hemodialysis vascular access infection caused by Methylobacterium radiotolerans: The first confirmed case in Japan.

Methylobacterium species are heterotrophic and fastidious Gram-negative bacilli that can be opportunistic pathogens in immunocompromised patients. These species form pink-pigmented colonies on agar plates and have been frequently isolated from tap water in hospitals. Herein, we describe a case of vascular access-related bloodstream infection caused by Methylobacterium radiotolerans in an 82-year-old man who was undergoing hemodialysis and had an implanted permanent pacemaker. Gram-negative rods cultured from his peripheral blood after incubation for 7 days were identified as M. radiotolerans by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing. The patient was treated with meropenem and daptomycin for 8 days, and levofloxacin was subsequently given orally for 6 days. However, eleven days after completion of the treatment, the patient developed another febrile episode, and the vascular access line blood and his peripheral blood also grew M. radiotolerans. Meropenem and rifampicin were administered and the vascular access line was removed and replaced. Subsequently, oral levofloxacin and rifampicin treatment was maintained for 8 weeks and the patient recovered without removal of the permanent pacemaker. M. radiotolerans grew slowly in blood culture, and the isolate showed optimal growth on Reasoner's 2 Agar (R2A). To our knowledge, this is the first report of a hemodialysis vascular access-related bloodstream infection caused by M. radiotolerans in Japan. Our experience suggests that clinicians should be aware of the possibility of vascular access infection caused by M. radiotolerans.

Real-time Respiration Measurement during Sleep Using a Microwave Sensor.

Non-contact continuous respiratory monitoring during sleep is of high usability to early disease detection and daily health monitoring. This study introduces a novel microwave sensor prototype for real-time respiration measurement. The antennas of the sensor are placed below the bed sheet, and function by transmitting a series of microwave signals to detect the inhale-exhale body motions while breathing. Compared to other remote wireless monitors, our sensor is less interfered by environmental noises as well as without direct contact with the body. The received I/Q signals are merged into one output and process to detect the frequency of breathing. The performance is evaluated using overnight sleep data and compared with ground-truth data measured by standard PSG airflow sensor. Result achieves high detection rate of 98.88% with mean squared error (MSE) of 1.23 over 420 one-minute recordings. In addition, the sensor is able to detect respiration accurately regardless of a person's sleep position. We demonstrate that our microwave sensor is robust and usable for real-time respiratory monitoring.

Development of an FVIII Inhibitor in a Mild Hemophilia Patient with a Phe595Cys Mutation.

Mild hemophilia A is caused by a missense mutation in the FVIII gene that is responsible for a decrease in the FVIII:C to between 5% and 40%. The development of FVIII inhibitors has been reported in 3-13% of patients with mild hemophilia. Genetic risk factors for the development of inhibitors in mild hemophilia have been investigated. In the present study, we encountered a case of mild hemophilia with an FVIII inhibitor and identified the mutation responsible: a novel Phe595Cys mutation in the FVIII gene. In addition, this study showed that the inhibitor recognized exogenous wild-type FVIII and autologous mutant FVIII.

A patient with severe fever with thrombocytopenia syndrome and hemophagocytic lymphohistiocytosis-associated involvement of the central nervous system.

Severe fever with thrombocytopenia syndrome (SFTS), a severe infectious disease caused by novel bunyavirus, SFTS virus (SFTSV), is endemic to China, Korea, and Japan. Most SFTS patients show abnormalities in consciousness. Pathological findings in the central nervous system (CNS) of SFTS patients are not reported. A 53-year-old Japanese man was admitted to Uwajima City Hospital with an 8-day history of fever and diarrhea. Laboratory tests revealed leukopenia, thrombocytopenia, and liver enzyme elevation. He was diagnosed as having severe fever with thrombocytopenia syndrome (SFTS) following detection of the SFTSV genome in his blood. Bone marrow aspiration revealed hemophagocytic lymphohistiocytosis. He suffered progressive CNS disturbance and died on day 13 from onset of first symptoms. The SFTSV genome load in blood and levels of certain cytokines increased over the disease course. Necrotizing lymphadenitis with systemic lymphoid tissues positive for nucleocapsid protein (NP) of SFTSV was revealed by immunohistochemical (IHC) analysis. SFTSV-NP-positive immunoblasts were detected in all organs examined, including the CNS, and in the vascular lumina of each organ. Parenchymal cells of all organs examined were negative for SFTSV-NP on IHC analysis. Microscopic examination of the pons showed focal neuronal cell degeneration with hemosiderin-laden macrophages around extended microvessels with perivascular inflammatory cell infiltration and intravascular fibrin deposition. Autopsy confirmed this patient with SFTS was positive for systemic hemophagocytic lymphohistiocytosis including in the CNS. This patient's neurological abnormalities may have been caused by both functional and organic abnormalities. These novel findings provide important insights into the pathophysiology of SFTS.

Unusual presentation of a severely ill patient having severe fever with thrombocytopenia syndrome: a case report.

BACKGROUND: Severe fever with thrombocytopenia syndrome is an emerging infectious disease caused by a novel phlebovirus belonging to the family Bunyaviridate. Emergence of encephalitis/encephalopathy during severe fever with thrombocytopenia syndrome progression has been identified as a major risk factor associated with a poor prognosis. Here we report the case of a severely ill patient with severe fever with thrombocytopenia syndrome virus-associated encephalitis/encephalopathy characterized by a lesion of the splenium, which resolved later. CASE PRESENTATION: A 56-year-old Japanese man presented with fever and diarrhea, followed by dysarthria. Diffusion-weighted magnetic resonance imaging demonstrated high signal intensity in the splenium of the corpus callosum. The severe fever with thrombocytopenia syndrome virus genome was detected in our patient's serum, and the clinical course was characterized by convulsion, stupor, and hemorrhagic manifestations, with disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis. Supportive therapy not including administration of corticosteroids led to gradual improvement of the clinical and laboratory findings, and magnetic resonance imaging demonstrated resolution of the splenial lesion. The serum severe fever with thrombocytopenia syndrome viral copy number, which was determined with the quantitative reverse-transcription polymerase chain reaction, rapidly decreased despite the severe clinical course. Our patient's overall condition improved, allowing him to be eventually discharged. CONCLUSIONS: Patients with encephalitis/encephalopathy due to severe fever with thrombocytopenia syndrome virus infection may have a favorable outcome, even if they exhibit splenial lesions and a severe clinical course; monitoring the serum viral load may be of value for prediction of outcome and potentially enables the avoidance of corticosteroids to intentionally cause opportunistic infection.

L-Arginine L-Glutamate Enhances Gastric Motor Function in Rats and Dogs and Improves Delayed Gastric Emptying in Dogs.

Amino acids are not only constituents of proteins, but also have multiple physiologic functions. Recent findings have revealed that ingested amino acids either activate luminal receptors or are metabolized, causing physiologic reactions in the gastrointestinal (GI) tract. We examined the effect of oral L-arginine L-glutamate (ArgGlu), a pharmaceutical amino acid salt used i.v. for the treatment of hyperammonemia, on gastric motor function in rats and dogs. Gastric emptying was determined using phenol red and 13C-breath test methods, whereas gastric relaxation was determined using the barostat method. ArgGlu (10-30 mg/kg, p.o.) dose-dependently promoted gastric emptying in rats. This effect was dependent on vagus nerve activation and comparable to that of the prokinetic mosapride. Intragastric ArgGlu (3-30 mg/kg intragastrically) also dose-dependently enhanced adaptive relaxation of rat stomachs, which was negated not by vagotomy of gastric branches, but by pretreatment with N omega-nitro-L-arginine methyl ester (20 mg/kg i.v.), a nitric oxide synthase inhibitor. Its relaxing effect on the stomach was also confirmed in dogs and was equally as efficacious as treatment with sumatriptan (1-3 mg/kg s.c.). ArgGlu (30 mg/kg p.o.) significantly reduced the half gastric emptying time in clonidine-induced delayed gastric emptying of solids in dogs, and its effect was comparable to that of cisapride (3 mg/kg p.o.). This study demonstrated that the pharmaceutical ingredient ArgGlu, currently used i.v., enhanced gastric motor function when administered orally, suggesting that it could be a new oral medicine indicated for treatment of upper GI hypofunction or dysfunction like functional dyspepsia.

Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol.

BACKGROUND: Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. METHODS: An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. RESULTS: Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. CONCLUSION: Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. TRIAL REGISTRY: http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.

Diffuse large B-cell lymphoma, not otherwise specified presenting with bone and bone marrow involvement in the absence of lymphadenopathy.

A 74-year-old woman visited our hospital because of right chest pain and fatigue. Laboratory examinations revealed pancytopenia and an elevated level of serum lactate dehydrogenase. Although bone lesions were detected by computed tomography, there was no lymphadenopathy. Blastoid cells were evident in the bone marrow. From the patient's medical history and results of immunohistological and chromosomal analysis, she was diagnosed as having diffuse large B-cell lymphoma, not otherwise specified. This form of presentation of diffuse large B-cell lymphoma is very rare, and emphasizes the need for careful evaluation of such cases, including bone marrow biopsy for accurate diagnosis.

[A Fatal Case of Severe Fever with Thrombocytopenia Syndrome Complicated by Hemophagocytic Lymphohistiocytosis].

Severe fever with thrombocytopenia syndrome (SFTS) is a recently identified emerging viral infectious disease in China that is caused by a novel phlebovirus in the family Bunyaviridae, SFTS virus, with an average case fatality rate of 12-30%. A cytokine storm with abnormally expressed cytokine profiles is associated with the disease severity. Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and lifethreatening syndrome associated with excessive immune activation. We report herein on a fatal case of SFTS complicated by HLH. Consecutive plasma exchange and immunomodulatory therapy was ineffective in our case. The pathognomonic histological feature was necrotizing lymphadenitis with massive hemophagocytosis of systemic lymphoid tissues with SFTS viruses and SFTS-RNA copies. No specific treatment of SFTS is available, and an effective treatment strategy for patients with rapidly progressing SFTS has not been established. Appropriate immunomodulatory therapy is necessary for SFTS patients complicated by HLH.

Acute abdomen due to group A streptococcus bacteremia caused by an isolate with a mutation in the csrS gene.

Streptococcus pyogenes (group A streptococcus) is an aerobic gram-positive coccus that causes infections ranging from non-invasive pharyngitis to severely invasive necrotizing fasciitis. Mutations in csrS/csrR and rgg, negative regulator genes of group A streptococcus, are crucial factors in the pathogenesis of streptococcal toxic shock syndrome, which is a severe, invasive infection characterized by sudden onset of shock and multiorgan failure, resulting in a high mortality rate. Here we present a case of group A streptococcal bacteremia in a 28-year-old Japanese woman with no relevant previous medical history. The patient developed progressive abdominal symptoms that may have been due to spontaneous bacterial peritonitis, followed by a state of shock, which did not fulfill the proposed criteria for streptococcal toxic shock. The isolate was found to harbor a mutation in the negative regulator csrS gene, whereas the csrR and rgg genes were intact. It was noteworthy that this strain carrying a csrS mutation had caused group A streptococcal bacteremia characterized by acute abdomen as the presenting symptom in a young individual who had been previously healthy. This case indicates that group A streptococcus with csrS mutations has potential virulence factors that are associated with the onset of group A streptococcal bacteremia that does not meet the diagnostic criteria for streptococcal toxic shock syndrome.

[Diagnosis of disseminated bone marrow carcinomatosis from gastric carcinoma initially presenting as asymptomatic anemia].

A 75-year-old man who had undergone subtotal gastrectomy for advanced gastric cancer 18 years previously with no signs of recurrence visited our hospital because of anemia detected by medical examination. Although no clinical abnormalities were evident, treatment with iron and vitamin B12 was started. However, because serum ALP was elevated, metastatic bone cancer was suspected. Subsequently, upper gastrointestinal endoscopy revealed findings suggestive of residual gastric cancer, and examination of a biopsy specimen demonstrated signet ring cell carcinoma. Furthermore, cells in a bone marrow biopsy sample showed morphology similar to that of cells obtained by stomach biopsy. FDG-PET demonstrated FDG accumulation only in the bone and residual stomach. The final diagnosis was bone metastasis from residual gastric cancer, and disseminated carcinomatosis of the bone marrow. Thereafter, pancytopenia progressed rapidly, and the patient died due to disseminated intravascular coagulation. When serum ALP is elevated in patients with a history of gastric cancer, bone marrow carcinomatosis should be suspected irrespective of symptoms, and imaging studies and bone marrow examination should be performed.

Myeloid sarcoma in essential thrombocythemia that transformed into acute myeloid leukemia.

A 72-year-old man was diagnosed with essential thrombocythemia (ET) and was treated with hydroxyurea for approximately 5 years. He was well until April 2007. In May 2007, a slight fall in hemoglobin levels was found. In June 2007, an upper endoscopy performed to investigate the cause of anemia showed multiple polypoid lesions in the body of the stomach. A gastric biopsy showed a diffuse infiltration of very immature cells. Several additional immunohistochemical staining showed that the cells were positive for CD13, CD34, CD117, and HLA DR, but negative for myeloperoxidase, CD42b, glycophorin, B cell marker, T cell marker, cytokeratin and desmin. We finally diagnosed the condition as myeloid sarcoma. Subsequently, the patient's ET transformed into acute myeloid leukemia. To our knowledge, this is an exceedingly rare event involving a patient with essential thrombocythemia.

Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. Previous studies have demonstrated that chronic systemic exposure of Lewis rats to rotenone produced many features of PD, and cerebral tauopathy was also detected in the case of severe weight loss. The present study was designed to assess the neurotoxicity of rotenone after daily oral administration for 28 days at several doses in C57BL/6 mice. In addition, we examined the protective effects of 4-phenylbutyrate (4-PBA) on nigral dopamine (DA) neurons in rotenone-treated mice. 4-PBA was injected intraperitoneally daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone at high doses induced specific nigrostriatal DA neurodegeneration, motor deficits and the up-regulation of alpha-synuclein in the surviving DA neurons. In contrast to the Lewis rat model, cerebral tauopathy was not detected in this mouse model. 4-PBA inhibited rotenone-induced neuronal death and decreased the protein level of alpha-synuclein. These results suggest that this rotenone mouse model may be useful for understanding the mechanism of DA neurodegeneration in PD, and that 4-PBA has a neuroprotective effect in the treatment of PD.